Efficient hybrid non-equilibrium molecular dynamics - Monte Carlo simulations with symmetric momentum reversal

NASA Astrophysics Data System (ADS)

Chen, Yunjie; Roux, Benoît

2014-09-01

Hybrid schemes combining the strength of molecular dynamics (MD) and Metropolis Monte Carlo (MC) offer a promising avenue to improve the sampling efficiency of computer simulations of complex systems. A number of recently proposed hybrid methods consider new configurations generated by driving the system via a non-equilibrium MD (neMD) trajectory, which are subsequently treated as putative candidates for Metropolis MC acceptance or rejection. To obey microscopic detailed balance, it is necessary to alter the momentum of the system at the beginning and/or the end of the neMD trajectory. This strict rule then guarantees that the random walk in configurational space generated by such hybrid neMD-MC algorithm will yield the proper equilibrium Boltzmann distribution. While a number of different constructs are possible, the most commonly used prescription has been to simply reverse the momenta of all the particles at the end of the neMD trajectory ("one-end momentum reversal"). Surprisingly, it is shown here that the choice of momentum reversal prescription can have a considerable effect on the rate of convergence of the hybrid neMD-MC algorithm, with the simple one-end momentum reversal encountering particularly acute problems. In these neMD-MC simulations, different regions of configurational space end up being essentially isolated from one another due to a very small transition rate between regions. In the worst-case scenario, it is almost as if the configurational space does not constitute a single communicating class that can be sampled efficiently by the algorithm, and extremely long neMD-MC simulations are needed to obtain proper equilibrium probability distributions. To address this issue, a novel momentum reversal prescription, symmetrized with respect to both the beginning and the end of the neMD trajectory ("symmetric two-ends momentum reversal"), is introduced. Illustrative simulations demonstrate that the hybrid neMD-MC algorithm robustly yields a correct equilibrium probability distribution with this prescription.

Molecular dynamics: deciphering the data.

PubMed

Dauber-Osguthorpe, P; Maunder, C M; Osguthorpe, D J

1996-06-01

The dynamic behaviour of molecules is important in determining their activity. Molecular dynamics (MD) simulations give a detailed description of motion, from small fluctuations to conformational transitions, and can include solvent effects. However, extracting useful information about conformational motion from a trajectory is not trivial. We have used digital signal-processing techniques to characterise the motion in MD simulations, including: calculating the frequency distribution, applying filtering functions, and extraction of vectors defining the characteristic motion for each frequency in an MD simulation. We describe here some typical results obtained for peptides and proteins. The nature of the low-frequency modes of motion, as obtained from MD and normal mode (NM) analysis, of Ace-(Ala)31-Nma and of a proline mutant is discussed. Low-frequency modes extracted from the MD trajectories of Rop protein and phospholipase A2 reveal characteristic motions of secondary structure elements, as well as concerned motions that are of significance to the protein's biological activity. MD simulations are also used frequently as a tool for conformational searches and for investigating protein folding/unfolding. We have developed a novel method that uses time-domain filtering to channel energy into conformational motion and thus enhance conformational transitions. The selectively enhanced molecular dynamics method is tested on the small molecule hexane.

Molecular dynamics: Deciphering the data

NASA Astrophysics Data System (ADS)

Dauber-Osguthorpe, Pnina; Maunder, Colette M.; Osguthorpe, David J.

1996-06-01

The dynamic behaviour of molecules is important in determining their activity. Molecular dynamics (MD) simulations give a detailed description of motion, from small fluctuations to conformational transitions, and can include solvent effects. However, extracting useful information about conformational motion from a trajectory is not trivial. We have used digital signal-processing techniques to characterise the motion in MD simulations, including: calculating the frequency distribution, applying filtering functions, and extraction of vectors defining the characteristic motion for each frequency in an MD simulation. We describe here some typical results obtained for peptides and proteins. The nature of the low-frequency modes of motion, as obtained from MD and normal mode (NM) analysis, of Ace-(Ala)31-Nma and of a proline mutant is discussed. Low-frequency modes extracted from the MD trajectories of Rop protein and phospholipase A2 reveal characteristic motions of secondary structure elements, as well as concerted motions that are of significance to the protein's biological activity. MD simulations are also used frequently as a tool for conformational searches and for investigating protein folding/unfolding. We have developed a novel method that uses time-domain filtering to channel energy into conformational motion and thus enhance conformational transitions. The selectively enhanced molecular dynamics method is tested on the small molecule hexane.

Enhanced configurational sampling with hybrid non-equilibrium molecular dynamics-Monte Carlo propagator

NASA Astrophysics Data System (ADS)

Suh, Donghyuk; Radak, Brian K.; Chipot, Christophe; Roux, Benoît

2018-01-01

Molecular dynamics (MD) trajectories based on classical equations of motion can be used to sample the configurational space of complex molecular systems. However, brute-force MD often converges slowly due to the ruggedness of the underlying potential energy surface. Several schemes have been proposed to address this problem by effectively smoothing the potential energy surface. However, in order to recover the proper Boltzmann equilibrium probability distribution, these approaches must then rely on statistical reweighting techniques or generate the simulations within a Hamiltonian tempering replica-exchange scheme. The present work puts forth a novel hybrid sampling propagator combining Metropolis-Hastings Monte Carlo (MC) with proposed moves generated by non-equilibrium MD (neMD). This hybrid neMD-MC propagator comprises three elementary elements: (i) an atomic system is dynamically propagated for some period of time using standard equilibrium MD on the correct potential energy surface; (ii) the system is then propagated for a brief period of time during what is referred to as a "boosting phase," via a time-dependent Hamiltonian that is evolved toward the perturbed potential energy surface and then back to the correct potential energy surface; (iii) the resulting configuration at the end of the neMD trajectory is then accepted or rejected according to a Metropolis criterion before returning to step 1. A symmetric two-end momentum reversal prescription is used at the end of the neMD trajectories to guarantee that the hybrid neMD-MC sampling propagator obeys microscopic detailed balance and rigorously yields the equilibrium Boltzmann distribution. The hybrid neMD-MC sampling propagator is designed and implemented to enhance the sampling by relying on the accelerated MD and solute tempering schemes. It is also combined with the adaptive biased force sampling algorithm to examine. Illustrative tests with specific biomolecular systems indicate that the method can yield a significant speedup.

Enhanced configurational sampling with hybrid non-equilibrium molecular dynamics-Monte Carlo propagator.

PubMed

Suh, Donghyuk; Radak, Brian K; Chipot, Christophe; Roux, Benoît

2018-01-07

Molecular dynamics (MD) trajectories based on classical equations of motion can be used to sample the configurational space of complex molecular systems. However, brute-force MD often converges slowly due to the ruggedness of the underlying potential energy surface. Several schemes have been proposed to address this problem by effectively smoothing the potential energy surface. However, in order to recover the proper Boltzmann equilibrium probability distribution, these approaches must then rely on statistical reweighting techniques or generate the simulations within a Hamiltonian tempering replica-exchange scheme. The present work puts forth a novel hybrid sampling propagator combining Metropolis-Hastings Monte Carlo (MC) with proposed moves generated by non-equilibrium MD (neMD). This hybrid neMD-MC propagator comprises three elementary elements: (i) an atomic system is dynamically propagated for some period of time using standard equilibrium MD on the correct potential energy surface; (ii) the system is then propagated for a brief period of time during what is referred to as a "boosting phase," via a time-dependent Hamiltonian that is evolved toward the perturbed potential energy surface and then back to the correct potential energy surface; (iii) the resulting configuration at the end of the neMD trajectory is then accepted or rejected according to a Metropolis criterion before returning to step 1. A symmetric two-end momentum reversal prescription is used at the end of the neMD trajectories to guarantee that the hybrid neMD-MC sampling propagator obeys microscopic detailed balance and rigorously yields the equilibrium Boltzmann distribution. The hybrid neMD-MC sampling propagator is designed and implemented to enhance the sampling by relying on the accelerated MD and solute tempering schemes. It is also combined with the adaptive biased force sampling algorithm to examine. Illustrative tests with specific biomolecular systems indicate that the method can yield a significant speedup.

ProtoMD: A prototyping toolkit for multiscale molecular dynamics

NASA Astrophysics Data System (ADS)

Somogyi, Endre; Mansour, Andrew Abi; Ortoleva, Peter J.

2016-05-01

ProtoMD is a toolkit that facilitates the development of algorithms for multiscale molecular dynamics (MD) simulations. It is designed for multiscale methods which capture the dynamic transfer of information across multiple spatial scales, such as the atomic to the mesoscopic scale, via coevolving microscopic and coarse-grained (CG) variables. ProtoMD can be also be used to calibrate parameters needed in traditional CG-MD methods. The toolkit integrates 'GROMACS wrapper' to initiate MD simulations, and 'MDAnalysis' to analyze and manipulate trajectory files. It facilitates experimentation with a spectrum of coarse-grained variables, prototyping rare events (such as chemical reactions), or simulating nanocharacterization experiments such as terahertz spectroscopy, AFM, nanopore, and time-of-flight mass spectroscopy. ProtoMD is written in python and is freely available under the GNU General Public License from github.com/CTCNano/proto_md.

The new program OPAL for molecular dynamics simulations and energy refinements of biological macromolecules.

PubMed

Luginbühl, P; Güntert, P; Billeter, M; Wüthrich, K

1996-09-01

A new program for molecular dynamics (MD) simulation and energy refinement of biological macromolecules, OPAL, is introduced. Combined with the supporting program TRAJEC for the analysis of MD trajectories, OPAL affords high efficiency and flexibility for work with different force fields, and offers a user-friendly interface and extensive trajectory analysis capabilities. Salient features are computational speeds of up to 1.5 GFlops on vector supercomputers such as the NEC SX-3, ellipsoidal boundaries to reduce the system size for studies in explicit solvents, and natural treatment of the hydrostatic pressure. Practical applications of OPAL are illustrated with MD simulations of pure water, energy minimization of the NMR structure of the mixed disulfide of a mutant E. coli glutaredoxin with glutathione in different solvent models, and MD simulations of a small protein, pheromone Er-2, using either instantaneous or time-averaged NMR restraints, or no restraints.

BIGNASim: a NoSQL database structure and analysis portal for nucleic acids simulation data.

PubMed

Hospital, Adam; Andrio, Pau; Cugnasco, Cesare; Codo, Laia; Becerra, Yolanda; Dans, Pablo D; Battistini, Federica; Torres, Jordi; Goñi, Ramón; Orozco, Modesto; Gelpí, Josep Ll

2016-01-04

Molecular dynamics simulation (MD) is, just behind genomics, the bioinformatics tool that generates the largest amounts of data, and that is using the largest amount of CPU time in supercomputing centres. MD trajectories are obtained after months of calculations, analysed in situ, and in practice forgotten. Several projects to generate stable trajectory databases have been developed for proteins, but no equivalence exists in the nucleic acids world. We present here a novel database system to store MD trajectories and analyses of nucleic acids. The initial data set available consists mainly of the benchmark of the new molecular dynamics force-field, parmBSC1. It contains 156 simulations, with over 120 μs of total simulation time. A deposition protocol is available to accept the submission of new trajectory data. The database is based on the combination of two NoSQL engines, Cassandra for storing trajectories and MongoDB to store analysis results and simulation metadata. The analyses available include backbone geometries, helical analysis, NMR observables and a variety of mechanical analyses. Individual trajectories and combined meta-trajectories can be downloaded from the portal. The system is accessible through http://mmb.irbbarcelona.org/BIGNASim/. Supplementary Material is also available on-line at http://mmb.irbbarcelona.org/BIGNASim/SuppMaterial/. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Enhanced Sampling of an Atomic Model with Hybrid Nonequilibrium Molecular Dynamics-Monte Carlo Simulations Guided by a Coarse-Grained Model.

PubMed

Chen, Yunjie; Roux, Benoît

2015-08-11

Molecular dynamics (MD) trajectories based on a classical equation of motion provide a straightforward, albeit somewhat inefficient approach, to explore and sample the configurational space of a complex molecular system. While a broad range of techniques can be used to accelerate and enhance the sampling efficiency of classical simulations, only algorithms that are consistent with the Boltzmann equilibrium distribution yield a proper statistical mechanical computational framework. Here, a multiscale hybrid algorithm relying simultaneously on all-atom fine-grained (FG) and coarse-grained (CG) representations of a system is designed to improve sampling efficiency by combining the strength of nonequilibrium molecular dynamics (neMD) and Metropolis Monte Carlo (MC). This CG-guided hybrid neMD-MC algorithm comprises six steps: (1) a FG configuration of an atomic system is dynamically propagated for some period of time using equilibrium MD; (2) the resulting FG configuration is mapped onto a simplified CG model; (3) the CG model is propagated for a brief time interval to yield a new CG configuration; (4) the resulting CG configuration is used as a target to guide the evolution of the FG system; (5) the FG configuration (from step 1) is driven via a nonequilibrium MD (neMD) simulation toward the CG target; (6) the resulting FG configuration at the end of the neMD trajectory is then accepted or rejected according to a Metropolis criterion before returning to step 1. A symmetric two-ends momentum reversal prescription is used for the neMD trajectories of the FG system to guarantee that the CG-guided hybrid neMD-MC algorithm obeys microscopic detailed balance and rigorously yields the equilibrium Boltzmann distribution. The enhanced sampling achieved with the method is illustrated with a model system with hindered diffusion and explicit-solvent peptide simulations. Illustrative tests indicate that the method can yield a speedup of about 80 times for the model system and up to 21 times for polyalanine and (AAQAA)3 in water.

Construction, MD simulation, and hydrodynamic validation of an all-atom model of a monoclonal IgG antibody.

PubMed

Brandt, J Paul; Patapoff, Thomas W; Aragon, Sergio R

2010-08-04

At 150 kDa, antibodies of the IgG class are too large for their structure to be determined with current NMR methodologies. Because of hinge-region flexibility, it is difficult to obtain atomic-level structural information from the crystal, and questions regarding antibody structure and dynamics in solution remain unaddressed. Here we describe the construction of a model of a human IgG1 monoclonal antibody (trastuzumab) from the crystal structures of fragments. We use a combination of molecular-dynamics (MD) simulation, continuum hydrodynamics modeling, and experimental diffusion measurements to explore antibody behavior in aqueous solution. Hydrodynamic modeling provides a link between the atomic-level details of MD simulation and the size- and shape-dependent data provided by hydrodynamic measurements. Eight independent 40 ns MD trajectories were obtained with the AMBER program suite. The ensemble average of the computed transport properties over all of the MD trajectories agrees remarkably well with the value of the translational diffusion coefficient obtained with dynamic light scattering at 20 degrees C and 27 degrees C, and the intrinsic viscosity measured at 20 degrees C. Therefore, our MD results likely represent a realistic sampling of the conformational space that an antibody explores in aqueous solution. 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Application of Multiplexed Replica Exchange Molecular Dynamics to the UNRES Force Field: Tests with alpha and alpha+beta Proteins.

PubMed

Czaplewski, Cezary; Kalinowski, Sebastian; Liwo, Adam; Scheraga, Harold A

2009-03-10

The replica exchange (RE) method is increasingly used to improve sampling in molecular dynamics (MD) simulations of biomolecular systems. Recently, we implemented the united-residue UNRES force field for mesoscopic MD. Initial results from UNRES MD simulations show that we are able to simulate folding events that take place in a microsecond or even a millisecond time scale. To speed up the search further, we applied the multiplexing replica exchange molecular dynamics (MREMD) method. The multiplexed variant (MREMD) of the RE method, developed by Rhee and Pande, differs from the original RE method in that several trajectories are run at a given temperature. Each set of trajectories run at a different temperature constitutes a layer. Exchanges are attempted not only within a single layer but also between layers. The code has been parallelized and scales up to 4000 processors. We present a comparison of canonical MD, REMD, and MREMD simulations of protein folding with the UNRES force-field. We demonstrate that the multiplexed procedure increases the power of replica exchange MD considerably and convergence of the thermodynamic quantities is achieved much faster.

Application of Multiplexed Replica Exchange Molecular Dynamics to the UNRES Force Field: Tests with α and α+β Proteins

PubMed Central

Czaplewski, Cezary; Kalinowski, Sebastian; Liwo, Adam; Scheraga, Harold A.

2009-01-01

The replica exchange (RE) method is increasingly used to improve sampling in molecular dynamics (MD) simulations of biomolecular systems. Recently, we implemented the united-residue UNRES force field for mesoscopic MD. Initial results from UNRES MD simulations show that we are able to simulate folding events that take place in a microsecond or even a millisecond time scale. To speed up the search further, we applied the multiplexing replica exchange molecular dynamics (MREMD) method. The multiplexed variant (MREMD) of the RE method, developed by Rhee and Pande, differs from the original RE method in that several trajectories are run at a given temperature. Each set of trajectories run at a different temperature constitutes a layer. Exchanges are attempted not only within a single layer but also between layers. The code has been parallelized and scales up to 4000 processors. We present a comparison of canonical MD, REMD, and MREMD simulations of protein folding with the UNRES force-field. We demonstrate that the multiplexed procedure increases the power of replica exchange MD considerably and convergence of the thermodynamic quantities is achieved much faster. PMID:20161452

Direct NOE simulation from long MD trajectories.

PubMed

Chalmers, G; Glushka, J N; Foley, B L; Woods, R J; Prestegard, J H

2016-04-01

A software package, MD2NOE, is presented which calculates Nuclear Overhauser Effect (NOE) build-up curves directly from molecular dynamics (MD) trajectories. It differs from traditional approaches in that it calculates correlation functions directly from the trajectory instead of extracting inverse sixth power distance terms as an intermediate step in calculating NOEs. This is particularly important for molecules that sample conformational states on a timescale similar to molecular reorientation. The package is tested on sucrose and results are shown to differ in small but significant ways from those calculated using an inverse sixth power assumption. Results are also compared to experiment and found to be in reasonable agreement despite an expected underestimation of water viscosity by the water model selected. Copyright © 2016 Elsevier Inc. All rights reserved.

An Effective Approach for Clustering InhA Molecular Dynamics Trajectory Using Substrate-Binding Cavity Features

PubMed Central

Ruiz, Duncan D. A.; Norberto de Souza, Osmar

2015-01-01

Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size. Most studies investigate different algorithms using pairwise Root-Mean Square Deviation (RMSD) values for all, or part of the MD conformations. Nevertheless, the RMSD only may not be the most appropriate gauge to cluster conformations when the target receptor has a plastic active site, since they are influenced by changes that occur on other parts of the structure. Hence, we have applied two partitioning methods (k-means and k-medoids) and four agglomerative hierarchical methods (Complete linkage, Ward’s, Unweighted Pair Group Method and Weighted Pair Group Method) to analyze and compare the quality of partitions between a data set composed of properties from an enzyme receptor substrate-binding cavity and two data sets created using different RMSD approaches. Ensembles of representative MD conformations were generated by selecting a medoid of each group from all partitions analyzed. We investigated the performance of our new method for evaluating binding conformation of drug candidates to the InhA enzyme, which were performed by cross-docking experiments between a 20 ns MD trajectory and 20 different ligands. Statistical analyses showed that the novel ensemble, which is represented by only 0.48% of the MD conformations, was able to reproduce 75% of all dynamic behaviors within the binding cavity for the docking experiments performed. Moreover, this new approach not only outperforms the other two RMSD-clustering solutions, but it also shows to be a promising strategy to distill biologically relevant information from MD trajectories, especially for docking purposes. PMID:26218832

An Effective Approach for Clustering InhA Molecular Dynamics Trajectory Using Substrate-Binding Cavity Features.

PubMed

De Paris, Renata; Quevedo, Christian V; Ruiz, Duncan D A; Norberto de Souza, Osmar

2015-01-01

Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size. Most studies investigate different algorithms using pairwise Root-Mean Square Deviation (RMSD) values for all, or part of the MD conformations. Nevertheless, the RMSD only may not be the most appropriate gauge to cluster conformations when the target receptor has a plastic active site, since they are influenced by changes that occur on other parts of the structure. Hence, we have applied two partitioning methods (k-means and k-medoids) and four agglomerative hierarchical methods (Complete linkage, Ward's, Unweighted Pair Group Method and Weighted Pair Group Method) to analyze and compare the quality of partitions between a data set composed of properties from an enzyme receptor substrate-binding cavity and two data sets created using different RMSD approaches. Ensembles of representative MD conformations were generated by selecting a medoid of each group from all partitions analyzed. We investigated the performance of our new method for evaluating binding conformation of drug candidates to the InhA enzyme, which were performed by cross-docking experiments between a 20 ns MD trajectory and 20 different ligands. Statistical analyses showed that the novel ensemble, which is represented by only 0.48% of the MD conformations, was able to reproduce 75% of all dynamic behaviors within the binding cavity for the docking experiments performed. Moreover, this new approach not only outperforms the other two RMSD-clustering solutions, but it also shows to be a promising strategy to distill biologically relevant information from MD trajectories, especially for docking purposes.

Enhanced Sampling of an Atomic Model with Hybrid Nonequilibrium Molecular Dynamics—Monte Carlo Simulations Guided by a Coarse-Grained Model

PubMed Central

2015-01-01

Molecular dynamics (MD) trajectories based on a classical equation of motion provide a straightforward, albeit somewhat inefficient approach, to explore and sample the configurational space of a complex molecular system. While a broad range of techniques can be used to accelerate and enhance the sampling efficiency of classical simulations, only algorithms that are consistent with the Boltzmann equilibrium distribution yield a proper statistical mechanical computational framework. Here, a multiscale hybrid algorithm relying simultaneously on all-atom fine-grained (FG) and coarse-grained (CG) representations of a system is designed to improve sampling efficiency by combining the strength of nonequilibrium molecular dynamics (neMD) and Metropolis Monte Carlo (MC). This CG-guided hybrid neMD-MC algorithm comprises six steps: (1) a FG configuration of an atomic system is dynamically propagated for some period of time using equilibrium MD; (2) the resulting FG configuration is mapped onto a simplified CG model; (3) the CG model is propagated for a brief time interval to yield a new CG configuration; (4) the resulting CG configuration is used as a target to guide the evolution of the FG system; (5) the FG configuration (from step 1) is driven via a nonequilibrium MD (neMD) simulation toward the CG target; (6) the resulting FG configuration at the end of the neMD trajectory is then accepted or rejected according to a Metropolis criterion before returning to step 1. A symmetric two-ends momentum reversal prescription is used for the neMD trajectories of the FG system to guarantee that the CG-guided hybrid neMD-MC algorithm obeys microscopic detailed balance and rigorously yields the equilibrium Boltzmann distribution. The enhanced sampling achieved with the method is illustrated with a model system with hindered diffusion and explicit-solvent peptide simulations. Illustrative tests indicate that the method can yield a speedup of about 80 times for the model system and up to 21 times for polyalanine and (AAQAA)3 in water. PMID:26574442

Conformational flexibility of two RNA trimers explored by computational tools and database search.

PubMed

Fadrná, Eva; Koca, Jaroslav

2003-04-01

Two RNA sequences, AAA and AUG, were studied by the conformational search program CICADA and by molecular dynamics (MD) in the framework of the AMBER force field, and also via thorough PDB database search. CICADA was used to provide detailed information about conformers and conformational interconversions on the energy surfaces of the above molecules. Several conformational families were found for both sequences. Analysis of the results shows differences, especially between the energy of the single families, and also in flexibility and concerted conformational movement. Therefore, several MD trajectories (altogether 16 ns) were run to obtain more details about both the stability of conformers belonging to different conformational families and about the dynamics of the two systems. Results show that the trajectories strongly depend on the starting structure. When the MD start from the global minimum found by CICADA, they provide a stable run, while MD starting from another conformational family generates a trajectory where several different conformational families are visited. The results obtained by theoretical methods are compared with the thorough database search data. It is concluded that all except for the highest energy conformational families found in theoretical result also appear in experimental data. Registry numbers: adenylyl-(3' --> 5')-adenylyl-(3' --> 5')-adenosine [917-44-2] adenylyl-(3' --> 5')-uridylyl-(3' --> 5')-guanosine [3494-35-7].

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples.

PubMed

Oblinsky, Daniel G; Vanschouwen, Bryan M B; Gordon, Heather L; Rothstein, Stuart M

2009-12-14

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the beta1 domain of protein G.

Procrustean rotation in concert with principal component analysis of molecular dynamics trajectories: Quantifying global and local differences between conformational samples

NASA Astrophysics Data System (ADS)

Oblinsky, Daniel G.; VanSchouwen, Bryan M. B.; Gordon, Heather L.; Rothstein, Stuart M.

2009-12-01

Given the principal component analysis (PCA) of a molecular dynamics (MD) conformational trajectory for a model protein, we perform orthogonal Procrustean rotation to "best fit" the PCA squared-loading matrix to that of a target matrix computed for a related but different molecular system. The sum of squared deviations of the elements of the rotated matrix from those of the target, known as the error of fit (EOF), provides a quantitative measure of the dissimilarity between the two conformational samples. To estimate precision of the EOF, we perform bootstrap resampling of the molecular conformations within the trajectories, generating a distribution of EOF values for the system and target. The average EOF per variable is determined and visualized to ascertain where, locally, system and target sample properties differ. We illustrate this approach by analyzing MD trajectories for the wild-type and four selected mutants of the β1 domain of protein G.

Solvation Structure and Thermodynamic Mapping (SSTMap): An Open-Source, Flexible Package for the Analysis of Water in Molecular Dynamics Trajectories.

PubMed

Haider, Kamran; Cruz, Anthony; Ramsey, Steven; Gilson, Michael K; Kurtzman, Tom

2018-01-09

We have developed SSTMap, a software package for mapping structural and thermodynamic water properties in molecular dynamics trajectories. The package introduces automated analysis and mapping of local measures of frustration and enhancement of water structure. The thermodynamic calculations are based on Inhomogeneous Fluid Solvation Theory (IST), which is implemented using both site-based and grid-based approaches. The package also extends the applicability of solvation analysis calculations to multiple molecular dynamics (MD) simulation programs by using existing cross-platform tools for parsing MD parameter and trajectory files. SSTMap is implemented in Python and contains both command-line tools and a Python module to facilitate flexibility in setting up calculations and for automated generation of large data sets involving analysis of multiple solutes. Output is generated in formats compatible with popular Python data science packages. This tool will be used by the molecular modeling community for computational analysis of water in problems of biophysical interest such as ligand binding and protein function.

Ensemble MD simulations restrained via crystallographic data: Accurate structure leads to accurate dynamics

PubMed Central

Xue, Yi; Skrynnikov, Nikolai R

2014-01-01

Currently, the best existing molecular dynamics (MD) force fields cannot accurately reproduce the global free-energy minimum which realizes the experimental protein structure. As a result, long MD trajectories tend to drift away from the starting coordinates (e.g., crystallographic structures). To address this problem, we have devised a new simulation strategy aimed at protein crystals. An MD simulation of protein crystal is essentially an ensemble simulation involving multiple protein molecules in a crystal unit cell (or a block of unit cells). To ensure that average protein coordinates remain correct during the simulation, we introduced crystallography-based restraints into the MD protocol. Because these restraints are aimed at the ensemble-average structure, they have only minimal impact on conformational dynamics of the individual protein molecules. So long as the average structure remains reasonable, the proteins move in a native-like fashion as dictated by the original force field. To validate this approach, we have used the data from solid-state NMR spectroscopy, which is the orthogonal experimental technique uniquely sensitive to protein local dynamics. The new method has been tested on the well-established model protein, ubiquitin. The ensemble-restrained MD simulations produced lower crystallographic R factors than conventional simulations; they also led to more accurate predictions for crystallographic temperature factors, solid-state chemical shifts, and backbone order parameters. The predictions for 15N R1 relaxation rates are at least as accurate as those obtained from conventional simulations. Taken together, these results suggest that the presented trajectories may be among the most realistic protein MD simulations ever reported. In this context, the ensemble restraints based on high-resolution crystallographic data can be viewed as protein-specific empirical corrections to the standard force fields. PMID:24452989

IBiSA_Tools: A Computational Toolkit for Ion-Binding State Analysis in Molecular Dynamics Trajectories of Ion Channels.

PubMed

Kasahara, Kota; Kinoshita, Kengo

2016-01-01

Ion conduction mechanisms of ion channels are a long-standing conundrum. Although the molecular dynamics (MD) method has been extensively used to simulate ion conduction dynamics at the atomic level, analysis and interpretation of MD results are not straightforward due to complexity of the dynamics. In our previous reports, we proposed an analytical method called ion-binding state analysis to scrutinize and summarize ion conduction mechanisms by taking advantage of a variety of analytical protocols, e.g., the complex network analysis, sequence alignment, and hierarchical clustering. This approach effectively revealed the ion conduction mechanisms and their dependence on the conditions, i.e., ion concentration and membrane voltage. Here, we present an easy-to-use computational toolkit for ion-binding state analysis, called IBiSA_tools. This toolkit consists of a C++ program and a series of Python and R scripts. From the trajectory file of MD simulations and a structure file, users can generate several images and statistics of ion conduction processes. A complex network named ion-binding state graph is generated in a standard graph format (graph modeling language; GML), which can be visualized by standard network analyzers such as Cytoscape. As a tutorial, a trajectory of a 50 ns MD simulation of the Kv1.2 channel is also distributed with the toolkit. Users can trace the entire process of ion-binding state analysis step by step. The novel method for analysis of ion conduction mechanisms of ion channels can be easily used by means of IBiSA_tools. This software is distributed under an open source license at the following URL: http://www.ritsumei.ac.jp/~ktkshr/ibisa_tools/.

Transition paths of Met-enkephalin from Markov state modeling of a molecular dynamics trajectory.

PubMed

Banerjee, Rahul; Cukier, Robert I

2014-03-20

Conformational states and their interconversion pathways of the zwitterionic form of the pentapeptide Met-enkephalin (MetEnk) are identified. An explicit solvent molecular dynamics (MD) trajectory is used to construct a Markov state model (MSM) based on dihedral space clustering of the trajectory, and transition path theory (TPT) is applied to identify pathways between open and closed conformers. In the MD trajectory, only four of the eight backbone dihedrals exhibit bistable behavior. Defining a conformer as the string XXXX with X = "+" or "-" denoting, respectively, positive or negative values of a given dihedral angle and obtaining the populations of these conformers shows that only four conformers are highly populated, implying a strong correlation among these dihedrals. Clustering in dihedral space to construct the MSM finds the same four bistable dihedral angles. These state populations are very similar to those found directly from the MD trajectory. TPT is used to obtain pathways, parametrized by committor values, in dihedral state space that are followed in transitioning from closed to open states. Pathway costs are estimated by introducing a kinetics-based procedure that orders pathways from least (shortest) to greater cost paths. The least costly pathways in dihedral space are found to only involve the same XXXX set of dihedral angles, and the conformers accessed in the closed to open transition pathways are identified. For these major pathways, a correlation between reaction path progress (committors) and the end-to-end distance is identified. A dihedral space principal component analysis of the MD trajectory shows that the first three modes capture most of the overall fluctuation, and pick out the same four dihedrals having essentially all the weight in those modes. A MSM based on root-mean-square backbone clustering was also carried out, with good agreement found with dihedral clustering for the static information, but with results that differ significantly for the pathway analysis.

Parallel cascade selection molecular dynamics for efficient conformational sampling and free energy calculation of proteins

NASA Astrophysics Data System (ADS)

Kitao, Akio; Harada, Ryuhei; Nishihara, Yasutaka; Tran, Duy Phuoc

2016-12-01

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) was proposed as an efficient conformational sampling method to investigate conformational transition pathway of proteins. In PaCS-MD, cycles of (i) selection of initial structures for multiple independent MD simulations and (ii) conformational sampling by independent MD simulations are repeated until the convergence of the sampling. The selection is conducted so that protein conformation gradually approaches a target. The selection of snapshots is a key to enhance conformational changes by increasing the probability of rare event occurrence. Since the procedure of PaCS-MD is simple, no modification of MD programs is required; the selections of initial structures and the restart of the next cycle in the MD simulations can be handled with relatively simple scripts with straightforward implementation. Trajectories generated by PaCS-MD were further analyzed by the Markov state model (MSM), which enables calculation of free energy landscape. The combination of PaCS-MD and MSM is reported in this work.

gRINN: a tool for calculation of residue interaction energies and protein energy network analysis of molecular dynamics simulations.

PubMed

Serçinoglu, Onur; Ozbek, Pemra

2018-05-25

Atomistic molecular dynamics (MD) simulations generate a wealth of information related to the dynamics of proteins. If properly analyzed, this information can lead to new insights regarding protein function and assist wet-lab experiments. Aiming to identify interactions between individual amino acid residues and the role played by each in the context of MD simulations, we present a stand-alone software called gRINN (get Residue Interaction eNergies and Networks). gRINN features graphical user interfaces (GUIs) and a command-line interface for generating and analyzing pairwise residue interaction energies and energy correlations from protein MD simulation trajectories. gRINN utilizes the features of NAMD or GROMACS MD simulation packages and automatizes the steps necessary to extract residue-residue interaction energies from user-supplied simulation trajectories, greatly simplifying the analysis for the end-user. A GUI, including an embedded molecular viewer, is provided for visualization of interaction energy time-series, distributions, an interaction energy matrix, interaction energy correlations and a residue correlation matrix. gRINN additionally offers construction and analysis of Protein Energy Networks, providing residue-based metrics such as degrees, betweenness-centralities, closeness centralities as well as shortest path analysis. gRINN is free and open to all users without login requirement at http://grinn.readthedocs.io.

ST-analyzer: a web-based user interface for simulation trajectory analysis.

PubMed

Jeong, Jong Cheol; Jo, Sunhwan; Wu, Emilia L; Qi, Yifei; Monje-Galvan, Viviana; Yeom, Min Sun; Gorenstein, Lev; Chen, Feng; Klauda, Jeffery B; Im, Wonpil

2014-05-05

Molecular dynamics (MD) simulation has become one of the key tools to obtain deeper insights into biological systems using various levels of descriptions such as all-atom, united-atom, and coarse-grained models. Recent advances in computing resources and MD programs have significantly accelerated the simulation time and thus increased the amount of trajectory data. Although many laboratories routinely perform MD simulations, analyzing MD trajectories is still time consuming and often a difficult task. ST-analyzer, http://im.bioinformatics.ku.edu/st-analyzer, is a standalone graphical user interface (GUI) toolset to perform various trajectory analyses. ST-analyzer has several outstanding features compared to other existing analysis tools: (i) handling various formats of trajectory files from MD programs, such as CHARMM, NAMD, GROMACS, and Amber, (ii) intuitive web-based GUI environment--minimizing administrative load and reducing burdens on the user from adapting new software environments, (iii) platform independent design--working with any existing operating system, (iv) easy integration into job queuing systems--providing options of batch processing either on the cluster or in an interactive mode, and (v) providing independence between foreground GUI and background modules--making it easier to add personal modules or to recycle/integrate pre-existing scripts utilizing other analysis tools. The current ST-analyzer contains nine main analysis modules that together contain 18 options, including density profile, lipid deuterium order parameters, surface area per lipid, and membrane hydrophobic thickness. This article introduces ST-analyzer with its design, implementation, and features, and also illustrates practical analysis of lipid bilayer simulations. Copyright © 2014 Wiley Periodicals, Inc.

Correlated motion of protein subdomains and large-scale conformational flexibility of RecA protein filament

NASA Astrophysics Data System (ADS)

Yu, Garmay; A, Shvetsov; D, Karelov; D, Lebedev; A, Radulescu; M, Petukhov; V, Isaev-Ivanov

2012-02-01

Based on X-ray crystallographic data available at Protein Data Bank, we have built molecular dynamics (MD) models of homologous recombinases RecA from E. coli and D. radiodurans. Functional form of RecA enzyme, which is known to be a long helical filament, was approximated by a trimer, simulated in periodic water box. The MD trajectories were analyzed in terms of large-scale conformational motions that could be detectable by neutron and X-ray scattering techniques. The analysis revealed that large-scale RecA monomer dynamics can be described in terms of relative motions of 7 subdomains. Motion of C-terminal domain was the major contributor to the overall dynamics of protein. Principal component analysis (PCA) of the MD trajectories in the atom coordinate space showed that rotation of C-domain is correlated with the conformational changes in the central domain and N-terminal domain, that forms the monomer-monomer interface. Thus, even though C-terminal domain is relatively far from the interface, its orientation is correlated with large-scale filament conformation. PCA of the trajectories in the main chain dihedral angle coordinate space implicates a co-existence of a several different large-scale conformations of the modeled trimer. In order to clarify the relationship of independent domain orientation with large-scale filament conformation, we have performed analysis of independent domain motion and its implications on the filament geometry.

Fluctuating hydrodynamics for multiscale modeling and simulation: energy and heat transfer in molecular fluids.

PubMed

Shang, Barry Z; Voulgarakis, Nikolaos K; Chu, Jhih-Wei

2012-07-28

This work illustrates that fluctuating hydrodynamics (FHD) simulations can be used to capture the thermodynamic and hydrodynamic responses of molecular fluids at the nanoscale, including those associated with energy and heat transfer. Using all-atom molecular dynamics (MD) trajectories as the reference data, the atomistic coordinates of each snapshot are mapped onto mass, momentum, and energy density fields on Eulerian grids to generate a corresponding field trajectory. The molecular length-scale associated with finite molecule size is explicitly imposed during this coarse-graining by requiring that the variances of density fields scale inversely with the grid volume. From the fluctuations of field variables, the response functions and transport coefficients encoded in the all-atom MD trajectory are computed. By using the extracted fluid properties in FHD simulations, we show that the fluctuations and relaxation of hydrodynamic fields quantitatively match with those observed in the reference all-atom MD trajectory, hence establishing compatibility between the atomistic and field representations. We also show that inclusion of energy transfer in the FHD equations can more accurately capture the thermodynamic and hydrodynamic responses of molecular fluids. The results indicate that the proposed MD-to-FHD mapping with explicit consideration of finite molecule size provides a robust framework for coarse-graining the solution phase of complex molecular systems.

All-atom molecular dynamics simulations of spin labelled double and single-strand DNA for EPR studies.

PubMed

Prior, C; Danilāne, L; Oganesyan, V S

2018-05-16

We report the first application of fully atomistic molecular dynamics (MD) simulations to the prediction of electron paramagnetic resonance (EPR) spectra of spin labelled DNA. Models for two structurally different DNA spin probes with either the rigid or flexible position of the nitroxide group in the base pair, employed in experimental studies previously, have been developed. By the application of the combined MD-EPR simulation methodology we aimed at the following. Firstly, to provide a test bed against a sensitive spectroscopic technique for the recently developed improved version of the parmbsc1 force field for MD modelling of DNA. The predicted EPR spectra show good agreement with the experimental ones available from the literature, thus confirming the accuracy of the currently employed DNA force fields. Secondly, to provide a quantitative interpretation of the motional contributions into the dynamics of spin probes in both duplex and single-strand DNA fragments and to analyse their perturbing effects on the local DNA structure. Finally, a combination of MD and EPR allowed us to test the validity of the application of the Model-Free (M-F) approach coupled with the partial averaging of magnetic tensors to the simulation of EPR spectra of DNA systems by comparing the resultant EPR spectra with those simulated directly from MD trajectories. The advantage of the M-F based EPR simulation approach over the direct propagation techniques is that it requires motional and order parameters that can be calculated from shorter MD trajectories. The reported MD-EPR methodology is transferable to the prediction and interpretation of EPR spectra of higher order DNA structures with novel types of spin labels.

Principal component and normal mode analysis of proteins; a quantitative comparison using the GroEL subunit.

PubMed

Skjaerven, Lars; Martinez, Aurora; Reuter, Nathalie

2011-01-01

Principal component analysis (PCA) and normal mode analysis (NMA) have emerged as two invaluable tools for studying conformational changes in proteins. To compare these approaches for studying protein dynamics, we have used a subunit of the GroEL chaperone, whose dynamics is well characterized. We first show that both PCA on trajectories from molecular dynamics (MD) simulations and NMA reveal a general dynamical behavior in agreement with what has previously been described for GroEL. We thus compare the reproducibility of PCA on independent MD runs and subsequently investigate the influence of the length of the MD simulations. We show that there is a relatively poor one-to-one correspondence between eigenvectors obtained from two independent runs and conclude that caution should be taken when analyzing principal components individually. We also observe that increasing the simulation length does not improve the agreement with the experimental structural difference. In fact, relatively short MD simulations are sufficient for this purpose. We observe a rapid convergence of the eigenvectors (after ca. 6 ns). Although there is not always a clear one-to-one correspondence, there is a qualitatively good agreement between the movements described by the first five modes obtained with the three different approaches; PCA, all-atoms NMA, and coarse-grained NMA. It is particularly interesting to relate this to the computational cost of the three methods. The results we obtain on the GroEL subunit contribute to the generalization of robust and reproducible strategies for the study of protein dynamics, using either NMA or PCA of trajectories from MD simulations. © 2010 Wiley-Liss, Inc.

Essential dynamics/factor analysis for the interpretation of molecular dynamics trajectories

NASA Astrophysics Data System (ADS)

Kaźmierkiewicz, R.; Czaplewski, C.; Lammek, B.; Ciarkowski, J.

1999-01-01

Subject of this work is the analysis of molecular dynamics (MD) trajectories of neurophysins I (NPI) and II (NPII) and their complexes with the neurophyseal nonapeptide hormones oxytocin (OT) and vasopresssin (VP), respectively, simulated in water. NPs serve in the neurosecretory granules as carrier proteins for the hormones before their release to the blood. The starting data consisted of two pairs of different trajectories for each of the (NPII/VP)2 and (NPI/OT)2 heterotetramers and two more trajectories for the NPII2 and NPI2 homodimers (six trajectories in total). Using essential dynamics which, to our judgement, is equivalent to factor analysis, we found that only about 10 degrees of freedom per trajectory are necessary and sufficient to describe in full the motions relevant for the function of the protein. This is consistent with these motions to explain about 90% of the total variance of the system. These principal degrees of freedom represent slow anharmonic motional modes, clearly pointing at distinguished mobility of the atoms involved in the protein's functionality.

Folding of a helix is critically stabilized by polarization of backbone hydrogen bonds: study in explicit water.

PubMed

Duan, Li L; Gao, Ya; Mei, Ye; Zhang, Qing G; Tang, Bo; Zhang, John Z H

2012-03-15

Multiple single-trajectory molecular dynamics (MD) simulation at room temperature (300 K) in explicit water was carried out to study the folding dynamics of an α-helix (PDB 2I9M ) using a polarized charge scheme that includes electronic polarization of backbone hydrogen bonds. Starting from an extended conformation, the 17-residue peptide was successfully folded into the native structure (α-helix) between 80 and 130 ns with a root-mean-square deviation of ~1.0 Å. Analysis of the time-dependent trajectories revealed that helix formation of the peptide started at the terminals and progressed toward the center of the peptide. For comparison, MD trajectories generated under various versions of standard AMBER force fields failed to show any significant or stable helix formation in our simulation. Our result shows clear evidence that the electronic polarization of backbone hydrogen bonds energetically stabilizes the helix formation and is critical to the stable folding of the short helix structure. © 2012 American Chemical Society

Non-monotonic dynamics of water in its binary mixture with 1,2-dimethoxy ethane: A combined THz spectroscopic and MD simulation study.

PubMed

Das Mahanta, Debasish; Patra, Animesh; Samanta, Nirnay; Luong, Trung Quan; Mukherjee, Biswaroop; Mitra, Rajib Kumar

2016-10-28

A combined experimental (mid- and far-infrared FTIR spectroscopy and THz time domain spectroscopy (TTDS) (0.3-1.6 THz)) and molecular dynamics (MD) simulation technique are used to understand the evolution of the structure and dynamics of water in its binary mixture with 1,2-dimethoxy ethane (DME) over the entire concentration range. The cooperative hydrogen bond dynamics of water obtained from Debye relaxation of TTDS data reveals a non-monotonous behaviour in which the collective dynamics is much faster in the low X w region (where X w is the mole fraction of water in the mixture), whereas in X w ∼ 0.8 region, the dynamics gets slower than that of pure water. The concentration dependence of the reorientation times of water, calculated from the MD simulations, also captures this non-monotonous character. The MD simulation trajectories reveal presence of large amplitude angular jumps, which dominate the orientational relaxation. We rationalize the non-monotonous, concentration dependent orientational dynamics by identifying two different physical mechanisms which operate at high and low water concentration regimes.

Ab Initio Molecular Dynamics Studies on Substitution vs. Electron Transfer Reactions of Substituted Ketyl Radical Anions with Chloroalkanes: How Do the Two Products Form in a Borderline Mechanism?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamataka, H.; Aida, Misako; Dupuis, Michel

We present a qualitative analysis, based on ab initio molecular dynamics (MD) calculations, of the SN2/ET mechanistic spectrum for three reactions: (1) HC(CN)=O.- + CH3Cl, (2) HC(CN)=O.- + (CH3)2CHCl, and (3) H2C=O.- + CH3Cl, passing through their SN2-like transition states. The finite temperature (298 K) direct-MD simulations indicate that the trajectories for reaction 1 appear to have a propensity towards SN2 products, the propensity for trajectories for reaction 2 seems to be towards ET products, whereas trajectories for reaction 3 appear to show no particular propensity towards either ET or SN2 products. The mechanistic diversity is consistent with the electronmore » donating ability of the ketyl species and steric bulkiness of chloroalkanes. We find that the trajectories have characteristics that reflect strongly the types of process (SN2 trajectories in reactions 1 and 3 vs. ET trajectories in reactions 2 and 3). Trajectories that lead to SN2 products are simple with C-C bond formation and C-Cl bond breaking essentially completed within 50 fs. By contrast, trajectories leading to ET products are more complex with a sudden electron reorganization taking place within 15 - 30 fs and the major bonding changes and electron and spin reorganizations completed after 250 fs.« less

A reduced basis method for molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Vincent-Finley, Rachel Elisabeth

In this dissertation, we develop a method for molecular simulation based on principal component analysis (PCA) of a molecular dynamics trajectory and least squares approximation of a potential energy function. Molecular dynamics (MD) simulation is a computational tool used to study molecular systems as they evolve through time. With respect to protein dynamics, local motions, such as bond stretching, occur within femtoseconds, while rigid body and large-scale motions, occur within a range of nanoseconds to seconds. To capture motion at all levels, time steps on the order of a femtosecond are employed when solving the equations of motion and simulations must continue long enough to capture the desired large-scale motion. To date, simulations of solvated proteins on the order of nanoseconds have been reported. It is typically the case that simulations of a few nanoseconds do not provide adequate information for the study of large-scale motions. Thus, the development of techniques that allow longer simulation times can advance the study of protein function and dynamics. In this dissertation we use principal component analysis (PCA) to identify the dominant characteristics of an MD trajectory and to represent the coordinates with respect to these characteristics. We augment PCA with an updating scheme based on a reduced representation of a molecule and consider equations of motion with respect to the reduced representation. We apply our method to butane and BPTI and compare the results to standard MD simulations of these molecules. Our results indicate that the molecular activity with respect to our simulation method is analogous to that observed in the standard MD simulation with simulations on the order of picoseconds.

Application of principal component analysis in protein unfolding: an all-atom molecular dynamics simulation study.

PubMed

Das, Atanu; Mukhopadhyay, Chaitali

2007-10-28

We have performed molecular dynamics (MD) simulation of the thermal denaturation of one protein and one peptide-ubiquitin and melittin. To identify the correlation in dynamics among various secondary structural fragments and also the individual contribution of different residues towards thermal unfolding, principal component analysis method was applied in order to give a new insight to protein dynamics by analyzing the contribution of coefficients of principal components. The cross-correlation matrix obtained from MD simulation trajectory provided important information regarding the anisotropy of backbone dynamics that leads to unfolding. Unfolding of ubiquitin was found to be a three-state process, while that of melittin, though smaller and mostly helical, is more complicated.

Application of principal component analysis in protein unfolding: An all-atom molecular dynamics simulation study

NASA Astrophysics Data System (ADS)

Das, Atanu; Mukhopadhyay, Chaitali

2007-10-01

We have performed molecular dynamics (MD) simulation of the thermal denaturation of one protein and one peptide—ubiquitin and melittin. To identify the correlation in dynamics among various secondary structural fragments and also the individual contribution of different residues towards thermal unfolding, principal component analysis method was applied in order to give a new insight to protein dynamics by analyzing the contribution of coefficients of principal components. The cross-correlation matrix obtained from MD simulation trajectory provided important information regarding the anisotropy of backbone dynamics that leads to unfolding. Unfolding of ubiquitin was found to be a three-state process, while that of melittin, though smaller and mostly helical, is more complicated.

Network visualization of conformational sampling during molecular dynamics simulation.

PubMed

Ahlstrom, Logan S; Baker, Joseph Lee; Ehrlich, Kent; Campbell, Zachary T; Patel, Sunita; Vorontsov, Ivan I; Tama, Florence; Miyashita, Osamu

2013-11-01

Effective data reduction methods are necessary for uncovering the inherent conformational relationships present in large molecular dynamics (MD) trajectories. Clustering algorithms provide a means to interpret the conformational sampling of molecules during simulation by grouping trajectory snapshots into a few subgroups, or clusters, but the relationships between the individual clusters may not be readily understood. Here we show that network analysis can be used to visualize the dominant conformational states explored during simulation as well as the connectivity between them, providing a more coherent description of conformational space than traditional clustering techniques alone. We compare the results of network visualization against 11 clustering algorithms and principal component conformer plots. Several MD simulations of proteins undergoing different conformational changes demonstrate the effectiveness of networks in reaching functional conclusions. Copyright © 2013 Elsevier Inc. All rights reserved.

Microscopic modeling of gas-surface scattering. I. A combined molecular dynamics-rate equation approach

NASA Astrophysics Data System (ADS)

Filinov, A.; Bonitz, M.; Loffhagen, D.

2018-06-01

A combination of first principle molecular dynamics (MD) simulations with a rate equation model (MD-RE approach) is presented to study the trapping and the scattering of rare gas atoms from metal surfaces. The temporal evolution of the atom fractions that are either adsorbed or scattered into the continuum is investigated in detail. We demonstrate that for this description one has to consider trapped, quasi-trapped and scattering states, and present an energetic definition of these states. The rate equations contain the transition probabilities between the states. We demonstrate how these rate equations can be derived from kinetic theory. Moreover, we present a rigorous way to determine the transition probabilities from a microscopic analysis of the particle trajectories generated by MD simulations. Once the system reaches quasi-equilibrium, the rates converge to stationary values, and the subsequent thermal adsorption/desorption dynamics is completely described by the rate equations without the need to perform further time-consuming MD simulations. As a proof of concept of our approach, MD simulations for argon atoms interacting with a platinum (111) surface are presented. A detailed deterministic trajectory analysis is performed, and the transition rates are constructed. The dependence of the rates on the incidence conditions and the lattice temperature is analyzed. Based on this example, we analyze the time scale of the gas-surface system to approach the quasi-stationary state. The MD-RE model has great relevance for the plasma-surface modeling as it makes an extension of accurate simulations to long, experimentally relevant time scales possible. Its application to the computation of atomic sticking probabilities is given in the second part (paper II).

Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase.

PubMed

Karamzadeh, Razieh; Karimi-Jafari, Mohammad Hossein; Sharifi-Zarchi, Ali; Chitsaz, Hamidreza; Salekdeh, Ghasem Hosseini; Moosavi-Movahedi, Ali Akbar

2017-06-16

The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes. Then, important structural features that exhibit considerable differences in dynamics of redox states are extracted by statistical machine learning methods. Mapping the structural variations to time series of residue interaction networks also provides a holistic representation of the dynamical redox differences. With emphasizing on persistent long-lasting interactions, an approach is proposed that compiled these time series networks to a single dynamic residue interaction network (DRIN). Differential comparison of DRIN in oxidized and reduced states reveals chains of residue interactions that represent potential allosteric paths between catalytic and ligand binding sites of hPDI.

How to Run FAST Simulations.

PubMed

Zimmerman, M I; Bowman, G R

2016-01-01

Molecular dynamics (MD) simulations are a powerful tool for understanding enzymes' structures and functions with full atomistic detail. These physics-based simulations model the dynamics of a protein in solution and store snapshots of its atomic coordinates at discrete time intervals. Analysis of the snapshots from these trajectories provides thermodynamic and kinetic properties such as conformational free energies, binding free energies, and transition times. Unfortunately, simulating biologically relevant timescales with brute force MD simulations requires enormous computing resources. In this chapter we detail a goal-oriented sampling algorithm, called fluctuation amplification of specific traits, that quickly generates pertinent thermodynamic and kinetic information by using an iterative series of short MD simulations to explore the vast depths of conformational space. © 2016 Elsevier Inc. All rights reserved.

Prediction of EPR Spectra of Lyotropic Liquid Crystals using a Combination of Molecular Dynamics Simulations and the Model-Free Approach.

PubMed

Prior, Christopher; Oganesyan, Vasily S

2017-09-21

We report the first application of fully atomistic molecular dynamics (MD) simulations to the prediction of the motional electron paramagnetic resonance (EPR) spectra of lyotropic liquid crystals in different aggregation states doped with a paramagnetic spin probe. The purpose of this study is twofold. First, given that EPR spectra are highly sensitive to the motions and order of the spin probes doped within lyotropic aggregates, simulation of EPR line shapes from the results of MD modelling provides an ultimate test bed for the force fields currently employed to model such systems. Second, the EPR line shapes are simulated using the motional parameters extracted from MD trajectories using the Model-Free (MF) approach. Thus a combined MD-EPR methodology allowed us to test directly the validity of the application of the MF approach to systems with multi-component molecular motions. All-atom MD simulations using the General AMBER Force Field (GAFF) have been performed on sodium dodecyl sulfate (SDS) and dodecyltrimethylammonium chloride (DTAC) liquid crystals. The resulting MD trajectories were used to predict and interpret the EPR spectra of pre-micellar, micellar, rod and lamellar aggregates. The predicted EPR spectra demonstrate good agreement with most of experimental line shapes thus confirming the validity of both the force fields employed and the MF approach for the studied systems. At the same time simulation results confirm that GAFF tends to overestimate the packing and the order of the carbonyl chains of the surfactant molecules. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Flexible and Comprehensive Implementation of MD-PMM Approach in a General and Robust Code.

PubMed

Carrillo-Parramon, Oliver; Del Galdo, Sara; Aschi, Massimiliano; Mancini, Giordano; Amadei, Andrea; Barone, Vincenzo

2017-11-14

The Perturbed Matrix Method (PMM) approach to be used in combination with Molecular Dynamics (MD) trajectories (MD-PMM) has been recoded from scratch, improved in several aspects, and implemented in the Gaussian suite of programs for allowing a user-friendly and yet flexible tool to estimate quantum chemistry observables in complex systems in condensed phases. Particular attention has been devoted to a description of rigid and flexible quantum centers together with powerful essential dynamics and clustering approaches. The default implementation is fully black-box and does not require any external action concerning both MD and PMM sections. At the same time, fine-tuning of different parameters and use of external data are allowed in all the steps of the procedure. Two specific systems (Tyrosine and Uridine) have been reinvestigated with the new version of the code in order to validate the implementation, check the performances, and illustrate some new features.

Pyrite: A blender plugin for visualizing molecular dynamics simulations using industry-standard rendering techniques.

PubMed

Rajendiran, Nivedita; Durrant, Jacob D

2018-05-05

Molecular dynamics (MD) simulations provide critical insights into many biological mechanisms. Programs such as VMD, Chimera, and PyMOL can produce impressive simulation visualizations, but they lack many advanced rendering algorithms common in the film and video-game industries. In contrast, the modeling program Blender includes such algorithms but cannot import MD-simulation data. MD trajectories often require many gigabytes of memory/disk space, complicating Blender import. We present Pyrite, a Blender plugin that overcomes these limitations. Pyrite allows researchers to visualize MD simulations within Blender, with full access to Blender's cutting-edge rendering techniques. We expect Pyrite-generated images to appeal to students and non-specialists alike. A copy of the plugin is available at http://durrantlab.com/pyrite/, released under the terms of the GNU General Public License Version 3. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

QAARM: quasi-anharmonic autoregressive model reveals molecular recognition pathways in ubiquitin

PubMed Central

Savol, Andrej J.; Burger, Virginia M.; Agarwal, Pratul K.; Ramanathan, Arvind; Chennubhotla, Chakra S.

2011-01-01

Motivation: Molecular dynamics (MD) simulations have dramatically improved the atomistic understanding of protein motions, energetics and function. These growing datasets have necessitated a corresponding emphasis on trajectory analysis methods for characterizing simulation data, particularly since functional protein motions and transitions are often rare and/or intricate events. Observing that such events give rise to long-tailed spatial distributions, we recently developed a higher-order statistics based dimensionality reduction method, called quasi-anharmonic analysis (QAA), for identifying biophysically-relevant reaction coordinates and substates within MD simulations. Further characterization of conformation space should consider the temporal dynamics specific to each identified substate. Results: Our model uses hierarchical clustering to learn energetically coherent substates and dynamic modes of motion from a 0.5 μs ubiqutin simulation. Autoregressive (AR) modeling within and between states enables a compact and generative description of the conformational landscape as it relates to functional transitions between binding poses. Lacking a predictive component, QAA is extended here within a general AR model appreciative of the trajectory's temporal dependencies and the specific, local dynamics accessible to a protein within identified energy wells. These metastable states and their transition rates are extracted within a QAA-derived subspace using hierarchical Markov clustering to provide parameter sets for the second-order AR model. We show the learned model can be extrapolated to synthesize trajectories of arbitrary length. Contact: ramanathana@ornl.gov; chakracs@pitt.edu PMID:21685101

Long Dynamics Simulations of Proteins Using Atomistic Force Fields and a Continuum Representation of Solvent Effects: Calculation of Structural and Dynamic Properties

PubMed Central

Li, Xianfeng; Hassan, Sergio A.; Mehler, Ernest L.

2006-01-01

Long dynamics simulations were carried out on the B1 immunoglobulin-binding domain of streptococcal protein G (ProtG) and bovine pancreatic trypsin inhibitor (BPTI) using atomistic descriptions of the proteins and a continuum representation of solvent effects. To mimic frictional and random collision effects, Langevin dynamics (LD) were used. The main goal of the calculations was to explore the stability of tens-of-nanosecond trajectories as generated by this molecular mechanics approximation and to analyze in detail structural and dynamical properties. Conformational fluctuations, order parameters, cross correlation matrices, residue solvent accessibilities, pKa values of titratable groups, and hydrogen-bonding (HB) patterns were calculated from all of the trajectories and compared with available experimental data. The simulations comprised over 40 ns per trajectory for ProtG and over 30 ns per trajectory for BPTI. For comparison, explicit water molecular dynamics simulations (EW/MD) of 3 ns and 4 ns, respectively, were also carried out. Two continuum simulations were performed on each protein using the CHARMM program, one with the all-atom PAR22 representation of the protein force field (here referred to as PAR22/LD simulations) and the other with the modifications introduced by the recently developed CMAP potential (CMAP/LD simulations). The explicit solvent simulations were performed with PAR22 only. Solvent effects are described by a continuum model based on screened Coulomb potentials (SCP) reported earlier, i.e., the SCP-based implicit solvent model (SCP–ISM). For ProtG, both the PAR22/LD and the CMAP/LD 40-ns trajectories were stable, yielding Cα root mean square deviations (RMSD) of about 1.0 and 0.8 Å respectively along the entire simulation time, compared to 0.8 Å for the EW/MD simulation. For BPTI, only the CMAP/LD trajectory was stable for the entire 30-ns simulation, with a Cα RMSD of ≈ 1.4 Å, while the PAR22/LD trajectory became unstable early in the simulation, reaching a Cα RMSD of about 2.7 Å and remaining at this value until the end of the simulation; the Cα RMSD of the EW/MD simulation was about 1.5 Å. The source of the instabilities of the BPTI trajectories in the PAR22/LD simulations was explored by an analysis of the backbone torsion angles. To further validate the findings from this analysis of BPTI, a 35-ns SCP–ISM simulation of Ubiquitin (Ubq) was carried out. For this protein, the CMAP/LD simulation was stable for the entire simulation time (Cα RMSD of ≈1.0 Å), while the PAR22/LD trajectory showed a trend similar to that in BPTI, reaching a Cα RMSD of ≈1.5 Å at 7 ns. All the calculated properties were found to be in agreement with the corresponding experimental values, although local deviations were also observed. HB patterns were also well reproduced by all the continuum solvent simulations with the exception of solvent-exposed side chain–side chain (sc–sc) HB in ProtG, where several of the HB interactions observed in the crystal structure and in the EW/MD simulation were lost. The overall analysis reported in this work suggests that the combination of an atomistic representation of a protein with a CMAP/CHARMM force field and a continuum representation of solvent effects such as the SCP–ISM provides a good description of structural and dynamic properties obtained from long computer simulations. Although the SCP–ISM simulations (CMAP/LD) reported here were shown to be stable and the properties well reproduced, further refinement is needed to attain a level of accuracy suitable for more challenging biological applications, particularly the study of protein–protein interactions. PMID:15959866

Reproducing Quantum Probability Distributions at the Speed of Classical Dynamics: A New Approach for Developing Force-Field Functors.

PubMed

Sundar, Vikram; Gelbwaser-Klimovsky, David; Aspuru-Guzik, Alán

2018-04-05

Modeling nuclear quantum effects is required for accurate molecular dynamics (MD) simulations of molecules. The community has paid special attention to water and other biomolecules that show hydrogen bonding. Standard methods of modeling nuclear quantum effects like Ring Polymer Molecular Dynamics (RPMD) are computationally costlier than running classical trajectories. A force-field functor (FFF) is an alternative method that computes an effective force field that replicates quantum properties of the original force field. In this work, we propose an efficient method of computing FFF using the Wigner-Kirkwood expansion. As a test case, we calculate a range of thermodynamic properties of Neon, obtaining the same level of accuracy as RPMD, but with the shorter runtime of classical simulations. By modifying existing MD programs, the proposed method could be used in the future to increase the efficiency and accuracy of MD simulations involving water and proteins.

Enhanced sampling simulations to construct free-energy landscape of protein-partner substrate interaction.

PubMed

Ikebe, Jinzen; Umezawa, Koji; Higo, Junichi

2016-03-01

Molecular dynamics (MD) simulations using all-atom and explicit solvent models provide valuable information on the detailed behavior of protein-partner substrate binding at the atomic level. As the power of computational resources increase, MD simulations are being used more widely and easily. However, it is still difficult to investigate the thermodynamic properties of protein-partner substrate binding and protein folding with conventional MD simulations. Enhanced sampling methods have been developed to sample conformations that reflect equilibrium conditions in a more efficient manner than conventional MD simulations, thereby allowing the construction of accurate free-energy landscapes. In this review, we discuss these enhanced sampling methods using a series of case-by-case examples. In particular, we review enhanced sampling methods conforming to trivial trajectory parallelization, virtual-system coupled multicanonical MD, and adaptive lambda square dynamics. These methods have been recently developed based on the existing method of multicanonical MD simulation. Their applications are reviewed with an emphasis on describing their practical implementation. In our concluding remarks we explore extensions of the enhanced sampling methods that may allow for even more efficient sampling.

Conformational and functional analysis of molecular dynamics trajectories by Self-Organising Maps

PubMed Central

2011-01-01

Background Molecular dynamics (MD) simulations are powerful tools to investigate the conformational dynamics of proteins that is often a critical element of their function. Identification of functionally relevant conformations is generally done clustering the large ensemble of structures that are generated. Recently, Self-Organising Maps (SOMs) were reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data mining problems. We present a novel strategy to analyse and compare conformational ensembles of protein domains using a two-level approach that combines SOMs and hierarchical clustering. Results The conformational dynamics of the α-spectrin SH3 protein domain and six single mutants were analysed by MD simulations. The Cα's Cartesian coordinates of conformations sampled in the essential space were used as input data vectors for SOM training, then complete linkage clustering was performed on the SOM prototype vectors. A specific protocol to optimize a SOM for structural ensembles was proposed: the optimal SOM was selected by means of a Taguchi experimental design plan applied to different data sets, and the optimal sampling rate of the MD trajectory was selected. The proposed two-level approach was applied to single trajectories of the SH3 domain independently as well as to groups of them at the same time. The results demonstrated the potential of this approach in the analysis of large ensembles of molecular structures: the possibility of producing a topological mapping of the conformational space in a simple 2D visualisation, as well as of effectively highlighting differences in the conformational dynamics directly related to biological functions. Conclusions The use of a two-level approach combining SOMs and hierarchical clustering for conformational analysis of structural ensembles of proteins was proposed. It can easily be extended to other study cases and to conformational ensembles from other sources. PMID:21569575

Development of interatomic potential of Ge(1- x - y )Si x Sn y ternary alloy semiconductors for classical lattice dynamics simulation

NASA Astrophysics Data System (ADS)

Tomita, Motohiro; Ogasawara, Masataka; Terada, Takuya; Watanabe, Takanobu

2018-04-01

We provide the parameters of Stillinger-Weber potentials for GeSiSn ternary mixed systems. These parameters can be used in molecular dynamics (MD) simulations to reproduce phonon properties and thermal conductivities. The phonon dispersion relation is derived from the dynamical structure factor, which is calculated by the space-time Fourier transform of atomic trajectories in an MD simulation. The phonon properties and thermal conductivities of GeSiSn ternary crystals calculated using these parameters mostly reproduced both the findings of previous experiments and earlier calculations made using MD simulations. The atomic composition dependence of these properties in GeSiSn ternary crystals obtained by previous studies (both experimental and theoretical) and the calculated data were almost exactly reproduced by our proposed parameters. Moreover, the results of the MD simulation agree with the previous calculations made using a time-independent phonon Boltzmann transport equation with complicated scattering mechanisms. These scattering mechanisms are very important in complicated nanostructures, as they allow the heat-transfer properties to be more accurately calculated by MD simulations. This work enables us to predict the phonon- and heat-related properties of bulk group IV alloys, especially ternary alloys.

Tetramethylpyrazine-Loaded Hydrogels: Preparation, Penetration Through a Subcutaneous-Mucous-Membrane Model, and a Molecular Dynamics Simulation.

PubMed

Xia, Hongmei; Xu, Yinxiang; Cheng, Zhiqing; Cheng, Yongfeng

2017-07-01

Tetramethylpyrazine (TMP) was extracted from Ligusticum chuanxiong hort. The compound is known to have a variety of medicinal functions; in particular, it is used for the treatment of cerebral ischemic diseases. TMP-loaded hydrogels offer an excellent preparation with the capacity to bypass the blood-brain barrier, allowing treatment of the brain through intranasal administration. We prepared TMP-loaded hydrogels using carbomer 940 and evaluated the release of TMP from the hydrogel. We determined the release rate using Franz-type diffusion cell experiments with a subcutaneous-mucous-membrane model and also by a molecular dynamics (MD) simulation. In general, the former method was more complicated than the latter was. The dynamic behavior of TMP release from the hydrogel was revealed by analysis of the mean square displacement of the trajectory in the MD simulation. The coefficient of TMP diffusion from the hydrogel was calculated at different temperatures (277, 298, and 310 K) by using MD software. The results showed that the coefficient of diffusion increased with an increase in temperature. This trend was observed both experimentally and in the MD simulation. Therefore, the MD simulation was a complementary method to verify the experimental data.

General order parameter based correlation analysis of protein backbone motions between experimental NMR relaxation measurements and molecular dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Qing; Shi, Chaowei; Yu, Lu

Internal backbone dynamic motions are essential for different protein functions and occur on a wide range of time scales, from femtoseconds to seconds. Molecular dynamic (MD) simulations and nuclear magnetic resonance (NMR) spin relaxation measurements are valuable tools to gain access to fast (nanosecond) internal motions. However, there exist few reports on correlation analysis between MD and NMR relaxation data. Here, backbone relaxation measurements of {sup 15}N-labeled SH3 (Src homology 3) domain proteins in aqueous buffer were used to generate general order parameters (S{sup 2}) using a model-free approach. Simultaneously, 80 ns MD simulations of SH3 domain proteins in amore » defined hydrated box at neutral pH were conducted and the general order parameters (S{sup 2}) were derived from the MD trajectory. Correlation analysis using the Gromos force field indicated that S{sup 2} values from NMR relaxation measurements and MD simulations were significantly different. MD simulations were performed on models with different charge states for three histidine residues, and with different water models, which were SPC (simple point charge) water model and SPC/E (extended simple point charge) water model. S{sup 2} parameters from MD simulations with charges for all three histidines and with the SPC/E water model correlated well with S{sup 2} calculated from the experimental NMR relaxation measurements, in a site-specific manner. - Highlights: • Correlation analysis between NMR relaxation measurements and MD simulations. • General order parameter (S{sup 2}) as common reference between the two methods. • Different protein dynamics with different Histidine charge states in neutral pH. • Different protein dynamics with different water models.« less

Visualizing global properties of a molecular dynamics trajectory.

PubMed

Zhou, Hao; Li, Shangyang; Makowski, Lee

2016-01-01

Molecular dynamics (MD) trajectories are very large data sets that contain substantial information about the dynamic behavior of a protein. Condensing these data into a form that can provide intuitively useful understanding of the molecular behavior during the trajectory is a substantial challenge that has received relatively little attention. Here, we introduce the sigma-r plot, a plot of the standard deviation of intermolecular distances as a function of that distance. This representation of global dynamics contains within a single, one-dimensional plot, the average range of motion between pairs of atoms within a macromolecule. Comparison of sigma-r plots calculated from 10 ns trajectories of proteins representing the four major SCOP fold classes indicates diversity of dynamic behaviors which are recognizably different among the four classes. Differences in domain structure and molecular weight also produce recognizable features in sigma-r plots, reflective of differences in global dynamics. Plots generated from trajectories with progressively increasing simulation time reflect the increased sampling of the structural ensemble as a function of time. Single amino acid replacements can give rise to changes in global dynamics detectable through comparison of sigma-r plots. Dynamic behavior of substructures can be monitored by careful choice of interatomic vectors included in the calculation. These examples provide demonstrations of the utility of the sigma-r plot to provide a simple measure of the global dynamics of a macromolecule. © 2015 Wiley Periodicals, Inc.

Hydration effects on the electrostatic potential around tuftsin.

PubMed

Valdeavella, C V; Blatt, H D; Yang, L; Pettitt, B M

1999-08-01

The electrostatic potential and component dielectric constants from molecular dynamics (MD) trajectories of tuftsin, a tetrapeptide with the amino acid sequence Thr-Lys-Pro-Arg in water and in saline solution are presented. The results obtained from the analysis of the MD trajectories for the total electrostatic potential at points on a grid using the Ewald technique are compared with the solution to the Poisson-Boltzmann (PB) equation. The latter was solved using several sets of dielectric constant parameters. The effects of structural averaging on the PB results were also considered. Solute conformational mobility in simulations gives rise to an electrostatic potential map around the solute dominated by the solute monopole (or lowest order multipole). The detailed spatial variation of the electrostatic potential on the molecular surface brought about by the compounded effects of the distribution of water and ions close to the peptide, solvent mobility, and solute conformational mobility are not qualitatively reproducible from a reparametrization of the input solute and solvent dielectric constants to the PB equation for a single structure or for structurally averaged PB calculations. Nevertheless, by fitting the PB to the MD electrostatic potential surfaces with the dielectric constants as fitting parameters, we found that the values that give the best fit are the values calculated from the MD trajectories. Implications of using such field calculations on the design of tuftsin peptide analogues are discussed.

Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery

PubMed Central

Thangapandian, Sundarapandian; John, Shalini; Lee, Yuno; Kim, Songmi; Lee, Keun Woo

2011-01-01

Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.0.5 package. Various analyses of trajectories obtained from MD simulations have displayed the changes upon inhibitor binding. Thus utilization of the dynamically-responded protein structures in pharmacophore development has the added advantage of considering the conformational flexibility of protein. The MD trajectories were clustered based on single-linkage method and representative structures were taken to be used in the pharmacophore model development. Active site complimenting structure-based pharmacophore models were developed using Discovery Studio 2.5 program and validated using a dataset of known HDAC8 inhibitors. Virtual screening of chemical database coupled with drug-like filter has identified drug-like hit compounds that match the pharmacophore models. Molecular docking of these hits reduced the false positives and identified two potential compounds to be used in future HDAC8 inhibitor design. PMID:22272142

Milestoning with coarse memory

NASA Astrophysics Data System (ADS)

Hawk, Alexander T.

2013-04-01

Milestoning is a method used to calculate the kinetics of molecular processes occurring on timescales inaccessible to traditional molecular dynamics (MD) simulations. In the method, the phase space of the system is partitioned by milestones (hypersurfaces), trajectories are initialized on each milestone, and short MD simulations are performed to calculate transitions between neighboring milestones. Long trajectories of the system are then reconstructed with a semi-Markov process from the observed statistics of transition. The procedure is typically justified by the assumption that trajectories lose memory between crossing successive milestones. Here we present Milestoning with Coarse Memory (MCM), a generalization of Milestoning that relaxes the memory loss assumption of conventional Milestoning. In the method, milestones are defined and sample transitions are calculated in the standard Milestoning way. Then, after it is clear where trajectories sample milestones, the milestones are broken up into distinct neighborhoods (clusters), and each sample transition is associated with two clusters: the cluster containing the coordinates the trajectory was initialized in, and the cluster (on the terminal milestone) containing trajectory's final coordinates. Long trajectories of the system are then reconstructed with a semi-Markov process in an extended state space built from milestone and cluster indices. To test the method, we apply it to a process that is particularly ill suited for Milestoning: the dynamics of a polymer confined to a narrow cylinder. We show that Milestoning calculations of both the mean first passage time and the mean transit time of reversal—which occurs when the end-to-end vector reverses direction—are significantly improved when MCM is applied. Finally, we note the overhead of performing MCM on top of conventional Milestoning is negligible.

Fluctuation Flooding Method (FFM) for accelerating conformational transitions of proteins.

PubMed

Harada, Ryuhei; Takano, Yu; Shigeta, Yasuteru

2014-03-28

A powerful conformational sampling method for accelerating structural transitions of proteins, "Fluctuation Flooding Method (FFM)," is proposed. In FFM, cycles of the following steps enhance the transitions: (i) extractions of largely fluctuating snapshots along anisotropic modes obtained from trajectories of multiple independent molecular dynamics (MD) simulations and (ii) conformational re-sampling of the snapshots via re-generations of initial velocities when re-starting MD simulations. In an application to bacteriophage T4 lysozyme, FFM successfully accelerated the open-closed transition with the 6 ns simulation starting solely from the open state, although the 1-μs canonical MD simulation failed to sample such a rare event.

Fluctuation Flooding Method (FFM) for accelerating conformational transitions of proteins

NASA Astrophysics Data System (ADS)

Harada, Ryuhei; Takano, Yu; Shigeta, Yasuteru

2014-03-01

A powerful conformational sampling method for accelerating structural transitions of proteins, "Fluctuation Flooding Method (FFM)," is proposed. In FFM, cycles of the following steps enhance the transitions: (i) extractions of largely fluctuating snapshots along anisotropic modes obtained from trajectories of multiple independent molecular dynamics (MD) simulations and (ii) conformational re-sampling of the snapshots via re-generations of initial velocities when re-starting MD simulations. In an application to bacteriophage T4 lysozyme, FFM successfully accelerated the open-closed transition with the 6 ns simulation starting solely from the open state, although the 1-μs canonical MD simulation failed to sample such a rare event.

On the importance of collective excitations for thermal transport in graphene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gill-Comeau, Maxime; Lewis, Laurent J., E-mail: Laurent.Lewis@UMontreal.CA

2015-05-11

We use equilibrium molecular dynamics (MD) simulations to study heat transport in bulk single-layer graphene. Through a modal analysis of the MD trajectories employing a time-domain formulation, we find that collective excitations involving flexural acoustic (ZA) phonons, which have been neglected in the previous MD studies, actually dominate the heat flow, generating as much as 78% of the flux. These collective excitations are, however, much less significant if the atomic displacements are constrained in the lattice plane. Although relaxation is slow, we find graphene to be a regular (non-anomalous) heat conductor for sample sizes of order 40 μm and more.

Achieving Rigorous Accelerated Conformational Sampling in Explicit Solvent.

PubMed

Doshi, Urmi; Hamelberg, Donald

2014-04-03

Molecular dynamics simulations can provide valuable atomistic insights into biomolecular function. However, the accuracy of molecular simulations on general-purpose computers depends on the time scale of the events of interest. Advanced simulation methods, such as accelerated molecular dynamics, have shown tremendous promise in sampling the conformational dynamics of biomolecules, where standard molecular dynamics simulations are nonergodic. Here we present a sampling method based on accelerated molecular dynamics in which rotatable dihedral angles and nonbonded interactions are boosted separately. This method (RaMD-db) is a different implementation of the dual-boost accelerated molecular dynamics, introduced earlier. The advantage is that this method speeds up sampling of the conformational space of biomolecules in explicit solvent, as the degrees of freedom most relevant for conformational transitions are accelerated. We tested RaMD-db on one of the most difficult sampling problems - protein folding. Starting from fully extended polypeptide chains, two fast folding α-helical proteins (Trpcage and the double mutant of C-terminal fragment of Villin headpiece) and a designed β-hairpin (Chignolin) were completely folded to their native structures in very short simulation time. Multiple folding/unfolding transitions could be observed in a single trajectory. Our results show that RaMD-db is a promisingly fast and efficient sampling method for conformational transitions in explicit solvent. RaMD-db thus opens new avenues for understanding biomolecular self-assembly and functional dynamics occurring on long time and length scales.

Exploring protein kinase conformation using swarm-enhanced sampling molecular dynamics.

PubMed

Atzori, Alessio; Bruce, Neil J; Burusco, Kepa K; Wroblowski, Berthold; Bonnet, Pascal; Bryce, Richard A

2014-10-27

Protein plasticity, while often linked to biological function, also provides opportunities for rational design of selective and potent inhibitors of their function. The application of computational methods to the prediction of concealed protein concavities is challenging, as the motions involved can be significant and occur over long time scales. Here we introduce the swarm-enhanced sampling molecular dynamics (sesMD) method as a tool to improve sampling of conformational landscapes. In this approach, a swarm of replica simulations interact cooperatively via a set of pairwise potentials incorporating attractive and repulsive components. We apply the sesMD approach to explore the conformations of the DFG motif in the protein p38α mitogen-activated protein kinase. In contrast to multiple MD simulations, sesMD trajectories sample a range of DFG conformations, some of which map onto existing crystal structures. Simulated structures intermediate between the DFG-in and DFG-out conformations are predicted to have druggable pockets of interest for structure-based ligand design.

Structural dynamics of supercooled water from quasielastic neutron scattering and molecular simulations.

PubMed

Qvist, Johan; Schober, Helmut; Halle, Bertil

2011-04-14

One of the outstanding challenges presented by liquid water is to understand how molecules can move on a picosecond time scale despite being incorporated in a three-dimensional network of relatively strong H-bonds. This challenge is exacerbated in the supercooled state, where the dramatic slowing down of structural dynamics is reminiscent of the, equally poorly understood, generic behavior of liquids near the glass transition temperature. By probing single-molecule dynamics on a wide range of time and length scales, quasielastic neutron scattering (QENS) can potentially reveal the mechanistic details of water's structural dynamics, but because of interpretational ambiguities this potential has not been fully realized. To resolve these issues, we present here an extensive set of high-quality QENS data from water in the range 253-293 K and a corresponding set of molecular dynamics (MD) simulations to facilitate and validate the interpretation. Using a model-free approach, we analyze the QENS data in terms of two motional components. Based on the dynamical clustering observed in MD trajectories, we identify these components with two distinct types of structural dynamics: picosecond local (L) structural fluctuations within dynamical basins and slower interbasin jumps (J). The Q-dependence of the dominant QENS component, associated with J dynamics, can be quantitatively rationalized with a continuous-time random walk (CTRW) model with an apparent jump length that depends on low-order moments of the jump length and waiting time distributions. Using a simple coarse-graining algorithm to quantitatively identify dynamical basins, we map the newtonian MD trajectory on a CTRW trajectory, from which the jump length and waiting time distributions are computed. The jump length distribution is gaussian and the rms jump length increases from 1.5 to 1.9 Å as the temperature increases from 253 to 293 K. The rms basin radius increases from 0.71 to 0.75 Å over the same range. The waiting time distribution is exponential at all investigated temperatures, ruling out significant dynamical heterogeneity. However, a simulation at 238 K reveals a small but significant dynamical heterogeneity. The macroscopic diffusion coefficient deduced from the QENS data agrees quantitatively with NMR and tracer results. We compare our QENS analysis with existing approaches, arguing that the apparent dynamical heterogeneity implied by stretched exponential fitting functions results from the failure to distinguish intrabasin (L) from interbasin (J) structural dynamics. We propose that the apparent dynamical singularity at ∼220 K corresponds to freezing out of J dynamics, while the calorimetric glass transition corresponds to freezing out of L dynamics.

Structural dynamics of supercooled water from quasielastic neutron scattering and molecular simulations

NASA Astrophysics Data System (ADS)

Qvist, Johan; Schober, Helmut; Halle, Bertil

2011-04-01

One of the outstanding challenges presented by liquid water is to understand how molecules can move on a picosecond time scale despite being incorporated in a three-dimensional network of relatively strong H-bonds. This challenge is exacerbated in the supercooled state, where the dramatic slowing down of structural dynamics is reminiscent of the, equally poorly understood, generic behavior of liquids near the glass transition temperature. By probing single-molecule dynamics on a wide range of time and length scales, quasielastic neutron scattering (QENS) can potentially reveal the mechanistic details of water's structural dynamics, but because of interpretational ambiguities this potential has not been fully realized. To resolve these issues, we present here an extensive set of high-quality QENS data from water in the range 253-293 K and a corresponding set of molecular dynamics (MD) simulations to facilitate and validate the interpretation. Using a model-free approach, we analyze the QENS data in terms of two motional components. Based on the dynamical clustering observed in MD trajectories, we identify these components with two distinct types of structural dynamics: picosecond local (L) structural fluctuations within dynamical basins and slower interbasin jumps (J). The Q-dependence of the dominant QENS component, associated with J dynamics, can be quantitatively rationalized with a continuous-time random walk (CTRW) model with an apparent jump length that depends on low-order moments of the jump length and waiting time distributions. Using a simple coarse-graining algorithm to quantitatively identify dynamical basins, we map the Newtonian MD trajectory on a CTRW trajectory, from which the jump length and waiting time distributions are computed. The jump length distribution is Gaussian and the rms jump length increases from 1.5 to 1.9 Å as the temperature increases from 253 to 293 K. The rms basin radius increases from 0.71 to 0.75 Å over the same range. The waiting time distribution is exponential at all investigated temperatures, ruling out significant dynamical heterogeneity. However, a simulation at 238 K reveals a small but significant dynamical heterogeneity. The macroscopic diffusion coefficient deduced from the QENS data agrees quantitatively with NMR and tracer results. We compare our QENS analysis with existing approaches, arguing that the apparent dynamical heterogeneity implied by stretched exponential fitting functions results from the failure to distinguish intrabasin (L) from interbasin (J) structural dynamics. We propose that the apparent dynamical singularity at ˜220 K corresponds to freezing out of J dynamics, while the calorimetric glass transition corresponds to freezing out of L dynamics.

Identification of Rare Lewis Oligosaccharide Conformers in Aqueous Solution Using Enhanced Sampling Molecular Dynamics.

PubMed

Alibay, Irfan; Burusco, Kepa K; Bruce, Neil J; Bryce, Richard A

2018-03-08

Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free-energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling, and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 μs trajectories; these simulations find a predominance of closed conformer and a range of low-occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the 4 C 1 form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 μs unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.

Multivariate frequency domain analysis of protein dynamics

NASA Astrophysics Data System (ADS)

Matsunaga, Yasuhiro; Fuchigami, Sotaro; Kidera, Akinori

2009-03-01

Multivariate frequency domain analysis (MFDA) is proposed to characterize collective vibrational dynamics of protein obtained by a molecular dynamics (MD) simulation. MFDA performs principal component analysis (PCA) for a bandpass filtered multivariate time series using the multitaper method of spectral estimation. By applying MFDA to MD trajectories of bovine pancreatic trypsin inhibitor, we determined the collective vibrational modes in the frequency domain, which were identified by their vibrational frequencies and eigenvectors. At near zero temperature, the vibrational modes determined by MFDA agreed well with those calculated by normal mode analysis. At 300 K, the vibrational modes exhibited characteristic features that were considerably different from the principal modes of the static distribution given by the standard PCA. The influences of aqueous environments were discussed based on two different sets of vibrational modes, one derived from a MD simulation in water and the other from a simulation in vacuum. Using the varimax rotation, an algorithm of the multivariate statistical analysis, the representative orthogonal set of eigenmodes was determined at each vibrational frequency.

Watching proteins function with picosecond X-ray crystallography and molecular dynamics simulations.

NASA Astrophysics Data System (ADS)

Anfinrud, Philip

2006-03-01

Time-resolved electron density maps of myoglobin, a ligand-binding heme protein, have been stitched together into movies that unveil with < 2-å spatial resolution and 150-ps time-resolution the correlated protein motions that accompany and/or mediate ligand migration within the hydrophobic interior of a protein. A joint analysis of all-atom molecular dynamics (MD) calculations and picosecond time-resolved X-ray structures provides single-molecule insights into mechanisms of protein function. Ensemble-averaged MD simulations of the L29F mutant of myoglobin following ligand dissociation reproduce the direction, amplitude, and timescales of crystallographically-determined structural changes. This close agreement with experiments at comparable resolution in space and time validates the individual MD trajectories, which identify and structurally characterize a conformational switch that directs dissociated ligands to one of two nearby protein cavities. This unique combination of simulation and experiment unveils functional protein motions and illustrates at an atomic level relationships among protein structure, dynamics, and function. In collaboration with Friedrich Schotte and Gerhard Hummer, NIH.

A Pipeline To Enhance Ligand Virtual Screening: Integrating Molecular Dynamics and Fingerprints for Ligand and Proteins.

PubMed

Spyrakis, Francesca; Benedetti, Paolo; Decherchi, Sergio; Rocchia, Walter; Cavalli, Andrea; Alcaro, Stefano; Ortuso, Francesco; Baroni, Massimo; Cruciani, Gabriele

2015-10-26

The importance of taking into account protein flexibility in drug design and virtual ligand screening (VS) has been widely debated in the literature, and molecular dynamics (MD) has been recognized as one of the most powerful tools for investigating intrinsic protein dynamics. Nevertheless, deciphering the amount of information hidden in MD simulations and recognizing a significant minimal set of states to be used in virtual screening experiments can be quite complicated. Here we present an integrated MD-FLAP (molecular dynamics-fingerprints for ligand and proteins) approach, comprising a pipeline of molecular dynamics, clustering and linear discriminant analysis, for enhancing accuracy and efficacy in VS campaigns. We first extracted a limited number of representative structures from tens of nanoseconds of MD trajectories by means of the k-medoids clustering algorithm as implemented in the BiKi Life Science Suite ( http://www.bikitech.com [accessed July 21, 2015]). Then, instead of applying arbitrary selection criteria, that is, RMSD, pharmacophore properties, or enrichment performances, we allowed the linear discriminant analysis algorithm implemented in FLAP ( http://www.moldiscovery.com [accessed July 21, 2015]) to automatically choose the best performing conformational states among medoids and X-ray structures. Retrospective virtual screenings confirmed that ensemble receptor protocols outperform single rigid receptor approaches, proved that computationally generated conformations comprise the same quantity/quality of information included in X-ray structures, and pointed to the MD-FLAP approach as a valuable tool for improving VS performances.

Dynamics of Water Associated with Lithium Ions Distributed in Polyethylene Oxide

DOE PAGES

Zhang, Zhe; Ohl, Michael; Diallo, Souleymane O.; ...

2015-11-03

We studied the dynamics of water in polyethylene oxide (PEO)/LiCl solution with quasielastic neutron scattering experiments and molecular dynamics (MD) simulations. Two different time scales of water diffusion representing interfacial water and bulk water dynamics have been identified. Furthermore, the measured diffusion coefficient of interfacial water remained 5–10 times smaller than that of bulk water, but both were slowed by approximately 50% in the presence of Li +. Detailed analysis of MD trajectories suggests that Li + is favorably found at the surface of the hydration layer, and the probability to find the caged Li + configuration formed by themore » PEO is lower than for the noncaged Li +-PEO configuration. In both configurations, however, the slowing down of water molecules is driven by reorienting water molecules and creating water-Li + hydration complexes. Moreover, performing the MD simulation with different ions (Na + and K +) revealed that smaller ionic radius of the ions is a key factor in disrupting the formation of PEO cages by allowing spaces for water molecules to come in between the ion and PEO.« less

Dynamics of Water Associated with Lithium Ions Distributed in Polyethylene Oxide

NASA Astrophysics Data System (ADS)

Zhang, Zhe; Ohl, Michael; Diallo, Souleymane O.; Jalarvo, Niina H.; Hong, Kunlun; Han, Youngkyu; Smith, Gregory S.; Do, Changwoo

2015-11-01

The dynamics of water in polyethylene oxide (PEO)/LiCl solution has been studied with quasielastic neutron scattering experiments and molecular dynamics (MD) simulations. Two different time scales of water diffusion representing interfacial water and bulk water dynamics have been identified. The measured diffusion coefficient of interfacial water remained 5-10 times smaller than that of bulk water, but both were slowed by approximately 50% in the presence of Li+ . Detailed analysis of MD trajectories suggests that Li+ is favorably found at the surface of the hydration layer, and the probability to find the caged Li+ configuration formed by the PEO is lower than for the noncaged Li+-PEO configuration. In both configurations, however, the slowing down of water molecules is driven by reorienting water molecules and creating water-Li+ hydration complexes. Performing the MD simulation with different ions (Na+ and K+ ) revealed that smaller ionic radius of the ions is a key factor in disrupting the formation of PEO cages by allowing spaces for water molecules to come in between the ion and PEO.

Dynamics of Water Associated with Lithium Ions Distributed in Polyethylene Oxide.

PubMed

Zhang, Zhe; Ohl, Michael; Diallo, Souleymane O; Jalarvo, Niina H; Hong, Kunlun; Han, Youngkyu; Smith, Gregory S; Do, Changwoo

2015-11-06

The dynamics of water in polyethylene oxide (PEO)/LiCl solution has been studied with quasielastic neutron scattering experiments and molecular dynamics (MD) simulations. Two different time scales of water diffusion representing interfacial water and bulk water dynamics have been identified. The measured diffusion coefficient of interfacial water remained 5-10 times smaller than that of bulk water, but both were slowed by approximately 50% in the presence of Li(+). Detailed analysis of MD trajectories suggests that Li(+) is favorably found at the surface of the hydration layer, and the probability to find the caged Li(+) configuration formed by the PEO is lower than for the noncaged Li(+)-PEO configuration. In both configurations, however, the slowing down of water molecules is driven by reorienting water molecules and creating water-Li(+) hydration complexes. Performing the MD simulation with different ions (Na(+) and K(+)) revealed that smaller ionic radius of the ions is a key factor in disrupting the formation of PEO cages by allowing spaces for water molecules to come in between the ion and PEO.

Free-energy landscape, principal component analysis, and structural clustering to identify representative conformations from molecular dynamics simulations: the myoglobin case.

PubMed

Papaleo, Elena; Mereghetti, Paolo; Fantucci, Piercarlo; Grandori, Rita; De Gioia, Luca

2009-01-01

Several molecular dynamics (MD) simulations were used to sample conformations in the neighborhood of the native structure of holo-myoglobin (holo-Mb), collecting trajectories spanning 0.22 micros at 300 K. Principal component (PCA) and free-energy landscape (FEL) analyses, integrated by cluster analysis, which was performed considering the position and structures of the individual helices of the globin fold, were carried out. The coherence between the different structural clusters and the basins of the FEL, together with the convergence of parameters derived by PCA indicates that an accurate description of the Mb conformational space around the native state was achieved by multiple MD trajectories spanning at least 0.14 micros. The integration of FEL, PCA, and structural clustering was shown to be a very useful approach to gain an overall view of the conformational landscape accessible to a protein and to identify representative protein substates. This method could be also used to investigate the conformational and dynamical properties of Mb apo-, mutant, or delete versions, in which greater conformational variability is expected and, therefore identification of representative substates from the simulations is relevant to disclose structure-function relationship.

Towards predictive molecular dynamics simulations of DNA: electrostatics and solution/crystal environments

NASA Astrophysics Data System (ADS)

Babin, Volodymr; Baucom, Jason; Darden, Thomas; Sagui, Celeste

2006-03-01

We have investigated to what extend molecular dynamics (MD) simulatons can reproduce DNA sequence-specific features, given different electrostatic descriptions and different cell environments. For this purpose, we have carried out multiple unrestrained MD simulations of the duplex d(CCAACGTTGG)2. With respect to the electrostatic descriptions, two different force fields were studied: a traditional description based on atomic point charges and a polarizable force field. With respect to the cell environment, the difference between crystal and solution environments is emphasized, as well as the structural importance of divalent ions. By imposing the correct experimental unit cell environment, an initial configuration with two ideal B-DNA duplexes in the unit cell is shown to converge to the crystallographic structure. To the best of our knowledge, this provides the first example of a multiple nanosecond MD trajectory that shows and ideal structure converging to an experimental one, with a significant decay of the RMSD.

Fast recovery of free energy landscapes via diffusion-map-directed molecular dynamics.

PubMed

Preto, Jordane; Clementi, Cecilia

2014-09-28

The reaction pathways characterizing macromolecular systems of biological interest are associated with high free energy barriers. Resorting to the standard all-atom molecular dynamics (MD) to explore such critical regions may be inappropriate as the time needed to observe the relevant transitions can be remarkably long. In this paper, we present a new method called Extended Diffusion-Map-directed Molecular Dynamics (extended DM-d-MD) used to enhance the sampling of MD trajectories in such a way as to rapidly cover all important regions of the free energy landscape including deep metastable states and critical transition paths. Moreover, extended DM-d-MD was combined with a reweighting scheme enabling to save on-the-fly information about the Boltzmann distribution. Our algorithm was successfully applied to two systems, alanine dipeptide and alanine-12. Due to the enhanced sampling, the Boltzmann distribution is recovered much faster than in plain MD simulations. For alanine dipeptide, we report a speedup of one order of magnitude with respect to plain MD simulations. For alanine-12, our algorithm allows us to highlight all important unfolded basins in several days of computation when one single misfolded event is barely observable within the same amount of computational time by plain MD simulations. Our method is reaction coordinate free, shows little dependence on the a priori knowledge of the system, and can be implemented in such a way that the biased steps are not computationally expensive with respect to MD simulations thus making our approach well adapted for larger complex systems from which little information is known.

Spaceflight dynamics 1993; AAS/NASA International Symposium, 8th, Greenbelt, MD, Apr. 26-30, 1993, Parts 1 & 2

NASA Technical Reports Server (NTRS)

Teles, Jerome (Editor); Samii, Mina V. (Editor)

1993-01-01

A conference on spaceflight dynamics produced papers in the areas of orbit determination, spacecraft tracking, autonomous navigation, the Deep Space Program Science Experiment Mission (DSPSE), the Global Positioning System, attitude control, geostationary satellites, interplanetary missions and trajectories, applications of estimation theory, flight dynamics systems, low-Earth orbit missions, orbital mechanics, mission experience in attitude dynamics, mission experience in sensor studies, attitude dynamics theory and simulations, and orbit-related experience. These papaers covered NASA, European, Russian, Japanese, Chinese, and Brazilian space programs and hardware.

Vibrational spectra from atomic fluctuations in dynamics simulations. I. Theory, limitations, and a sample application

NASA Astrophysics Data System (ADS)

Schmitz, Matthias; Tavan, Paul

2004-12-01

Hybrid molecular dynamics (MD) simulations, which combine density functional theory (DFT) descriptions of a molecule with a molecular mechanics (MM) modeling of its solvent environment, have opened the way towards accurate computations of solvation effects in the vibrational spectra of molecules. Recently, Wheeler et al. [ChemPhysChem 4, 382 (2002)] have suggested to compute these spectra from DFT/MM-MD trajectories by diagonalizing the covariance matrix of atomic fluctuations. This so-called principal mode analysis (PMA) allegedly can replace the well-established approaches, which are based on Fourier transform methods or on conventional normal mode analyses. By scrutinizing and revising the PMA approach we identify five conditions, which must be guaranteed if PMA is supposed to render exact vibrational frequencies. Besides specific choices of (a) coordinates and (b) coordinate systems, these conditions cover (c) a harmonic intramolecular potential, (d) a complete thermal equilibrium within the molecule, and (e) a molecular Hamiltonian independent of time. However, the PMA conditions [(c)-(d)] and [(c)-(e)] are generally violated in gas phase DFT-MD and liquid phase DFT/MM-MD trajectories, respectively. Based on a series of simple analytical model calculations and on the analysis of MD trajectories calculated for the formaldehyde molecule in the gas phase (DFT) and in liquid water (DFT/MM) we show that in both phases the violation of condition (d) can cause huge errors in PMA frequency computations, whereas the inevitable violations of conditions (c) and (e), the latter being generic to the liquid phase, imply systematic and sizable underestimates of the vibrational frequencies by PMA. We demonstrate that the huge errors, which are caused by an incomplete thermal equilibrium violating (d), can be avoided if one introduces mode-specific temperatures Tj and calculates the frequencies from a "generalized virial" (GV) expression instead from PMA. Concerning ways to additionally remove the remaining errors, which GV still shares with PMA, we refer to Paper II of this work [M. Schmitz and P. Tavan, J. Chem. Phys. 121, 12247 (2004)].

Large scale atomistic simulation of single-layer graphene growth on Ni(111) surface: molecular dynamics simulation based on a new generation of carbon-metal potential

NASA Astrophysics Data System (ADS)

Xu, Ziwei; Yan, Tianying; Liu, Guiwu; Qiao, Guanjun; Ding, Feng

2015-12-01

To explore the mechanism of graphene chemical vapor deposition (CVD) growth on a catalyst surface, a molecular dynamics (MD) simulation of carbon atom self-assembly on a Ni(111) surface based on a well-designed empirical reactive bond order potential was performed. We simulated single layer graphene with recorded size (up to 300 atoms per super-cell) and reasonably good quality by MD trajectories up to 15 ns. Detailed processes of graphene CVD growth, such as carbon atom dissolution and precipitation, formation of carbon chains of various lengths, polygons and small graphene domains were observed during the initial process of the MD simulation. The atomistic processes of typical defect healing, such as the transformation from a pentagon into a hexagon and from a pentagon-heptagon pair (5|7) to two adjacent hexagons (6|6), were revealed as well. The study also showed that higher temperature and longer annealing time are essential to form high quality graphene layers, which is in agreement with experimental reports and previous theoretical results.To explore the mechanism of graphene chemical vapor deposition (CVD) growth on a catalyst surface, a molecular dynamics (MD) simulation of carbon atom self-assembly on a Ni(111) surface based on a well-designed empirical reactive bond order potential was performed. We simulated single layer graphene with recorded size (up to 300 atoms per super-cell) and reasonably good quality by MD trajectories up to 15 ns. Detailed processes of graphene CVD growth, such as carbon atom dissolution and precipitation, formation of carbon chains of various lengths, polygons and small graphene domains were observed during the initial process of the MD simulation. The atomistic processes of typical defect healing, such as the transformation from a pentagon into a hexagon and from a pentagon-heptagon pair (5|7) to two adjacent hexagons (6|6), were revealed as well. The study also showed that higher temperature and longer annealing time are essential to form high quality graphene layers, which is in agreement with experimental reports and previous theoretical results. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06016h

How far in-silico computing meets real experiments. A study on the structure and dynamics of spin labeled vinculin tail protein by molecular dynamics simulations and EPR spectroscopy

PubMed Central

2013-01-01

Background Investigation of conformational changes in a protein is a prerequisite to understand its biological function. To explore these conformational changes in proteins we developed a strategy with the combination of molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy. The major goal of this work is to investigate how far computer simulations can meet the experiments. Methods Vinculin tail protein is chosen as a model system as conformational changes within the vinculin protein are believed to be important for its biological function at the sites of cell adhesion. MD simulations were performed on vinculin tail protein both in water and in vacuo environments. EPR experimental data is compared with those of the simulated data for corresponding spin label positions. Results The calculated EPR spectra from MD simulations trajectories of selected spin labelled positions are comparable to experimental EPR spectra. The results show that the information contained in the spin label mobility provides a powerful means of mapping protein folds and their conformational changes. Conclusions The results suggest the localization of dynamic and flexible regions of the vinculin tail protein. This study shows MD simulations can be used as a complementary tool to interpret experimental EPR data. PMID:23445506

Molecular Dynamics Simulation of Tau Peptides for the Investigation of Conformational Changes Induced by Specific Phosphorylation Patterns.

PubMed

Gandhi, Neha S; Kukic, Predrag; Lippens, Guy; Mancera, Ricardo L

2017-01-01

The Tau protein plays an important role due to its biomolecular interactions in neurodegenerative diseases. The lack of stable structure and various posttranslational modifications such as phosphorylation at various sites in the Tau protein pose a challenge for many experimental methods that are traditionally used to study protein folding and aggregation. Atomistic molecular dynamics (MD) simulations can help around deciphering relationship between phosphorylation and various intermediate and stable conformations of the Tau protein which occur on longer timescales. This chapter outlines protocols for the preparation, execution, and analysis of all-atom MD simulations of a 21-amino acid-long phosphorylated Tau peptide with the aim of generating biologically relevant structural and dynamic information. The simulations are done in explicit solvent and starting from nearly extended configurations of the peptide. The scaled MD method implemented in AMBER14 was chosen to achieve enhanced conformational sampling in addition to a conventional MD approach, thereby allowing the characterization of folding for such an intrinsically disordered peptide at 293 K. Emphasis is placed on the analysis of the simulation trajectories to establish correlations with NMR data (i.e., chemical shifts and NOEs). Finally, in-depth discussions are provided for commonly encountered problems.

Mapping multiple potential ATP binding sites on the matrix side of the bovine ADP/ATP carrier by the combined use of MD simulation and docking.

PubMed

Di Marino, Daniele; Oteri, Francesco; della Rocca, Blasco Morozzo; D'Annessa, Ilda; Falconi, Mattia

2012-06-01

The mitochondrial adenosine diphosphate/adenosine triphosphate (ADP/ATP) carrier-AAC-was crystallized in complex with its specific inhibitor carboxyatractyloside (CATR). The protein consists of a six-transmembrane helix bundle that defines the nucleotide translocation pathway, which is closed towards the matrix side due to sharp kinks in the odd-numbered helices. In this paper, we describe the interaction between the matrix side of the AAC transporter and the ATP(4-) molecule using carrier structures obtained through classical molecular dynamics simulation (MD) and a protein-ligand docking procedure. Fifteen structures were extracted from a previously published MD trajectory through clustering analysis, and 50 docking runs were carried out for each carrier conformation, for a total of 750 runs ("MD docking"). The results were compared to those from 750 docking runs performed on the X-ray structure ("X docking"). The docking procedure indicated the presence of a single interaction site in the X-ray structure that was conserved in the structures extracted from the MD trajectory. MD docking showed the presence of a second binding site that was not found in the X docking. The interaction strategy between the AAC transporter and the ATP(4-) molecule was analyzed by investigating the composition and 3D arrangement of the interaction pockets, together with the orientations of the substrate inside them. A relationship between sequence repeats and the ATP(4-) binding sites in the AAC carrier structure is proposed.

Variational Identification of Markovian Transition States

NASA Astrophysics Data System (ADS)

Martini, Linda; Kells, Adam; Covino, Roberto; Hummer, Gerhard; Buchete, Nicolae-Viorel; Rosta, Edina

2017-07-01

We present a method that enables the identification and analysis of conformational Markovian transition states from atomistic or coarse-grained molecular dynamics (MD) trajectories. Our algorithm is presented by using both analytical models and examples from MD simulations of the benchmark system helix-forming peptide Ala5 , and of larger, biomedically important systems: the 15-lipoxygenase-2 enzyme (15-LOX-2), the epidermal growth factor receptor (EGFR) protein, and the Mga2 fungal transcription factor. The analysis of 15-LOX-2 uses data generated exclusively from biased umbrella sampling simulations carried out at the hybrid ab initio density functional theory (DFT) quantum mechanics/molecular mechanics (QM/MM) level of theory. In all cases, our method automatically identifies the corresponding transition states and metastable conformations in a variationally optimal way, with the input of a set of relevant coordinates, by accurately reproducing the intrinsic slowest relaxation rate of each system. Our approach offers a general yet easy-to-implement analysis method that provides unique insight into the molecular mechanism and the rare but crucial (i.e., rate-limiting) transition states occurring along conformational transition paths in complex dynamical systems such as molecular trajectories.

Machine Learning of Accurate Energy-Conserving Molecular Force Fields

NASA Astrophysics Data System (ADS)

Chmiela, Stefan; Tkatchenko, Alexandre; Sauceda, Huziel; Poltavsky, Igor; Schütt, Kristof; Müller, Klaus-Robert; GDML Collaboration

Efficient and accurate access to the Born-Oppenheimer potential energy surface (PES) is essential for long time scale molecular dynamics (MD) simulations. Using conservation of energy - a fundamental property of closed classical and quantum mechanical systems - we develop an efficient gradient-domain machine learning (GDML) approach to construct accurate molecular force fields using a restricted number of samples from ab initio MD trajectories (AIMD). The GDML implementation is able to reproduce global potential-energy surfaces of intermediate-size molecules with an accuracy of 0.3 kcal/mol for energies and 1 kcal/mol/Å for atomic forces using only 1000 conformational geometries for training. We demonstrate this accuracy for AIMD trajectories of molecules, including benzene, toluene, naphthalene, malonaldehyde, ethanol, uracil, and aspirin. The challenge of constructing conservative force fields is accomplished in our work by learning in a Hilbert space of vector-valued functions that obey the law of energy conservation. The GDML approach enables quantitative MD simulations for molecules at a fraction of cost of explicit AIMD calculations, thereby allowing the construction of efficient force fields with the accuracy and transferability of high-level ab initio methods.

An Investigation of Molecular Docking and Molecular Dynamic Simulation on Imidazopyridines as B-Raf Kinase Inhibitors.

PubMed

Xie, Huiding; Li, Yupeng; Yu, Fang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-11-16

In the recent cancer treatment, B-Raf kinase is one of key targets. Nowadays, a group of imidazopyridines as B-Raf kinase inhibitors have been reported. In order to investigate the interaction between this group of inhibitors and B-Raf kinase, molecular docking, molecular dynamic (MD) simulation and binding free energy (ΔGbind) calculation were performed in this work. Molecular docking was carried out to identify the key residues in the binding site, and MD simulations were performed to determine the detail binding mode. The results obtained from MD simulation reveal that the binding site is stable during the MD simulations, and some hydrogen bonds (H-bonds) in MD simulations are different from H-bonds in the docking mode. Based on the obtained MD trajectories, ΔGbind was computed by using Molecular Mechanics Generalized Born Surface Area (MM-GBSA), and the obtained energies are consistent with the activities. An energetic analysis reveals that both electrostatic and van der Waals contributions are important to ΔGbind, and the unfavorable polar solvation contribution results in the instability of the inhibitor with the lowest activity. These results are expected to understand the binding between B-Raf and imidazopyridines and provide some useful information to design potential B-Raf inhibitors.

Molecular Dynamics Simulations of the 136 Unique Tetranucleotide Sequences of DNA Oligonucleotides. I. Research Design and Results on d(CpG) Steps

PubMed Central

Beveridge, David L.; Barreiro, Gabriela; Byun, K. Suzie; Case, David A.; Cheatham, Thomas E.; Dixit, Surjit B.; Giudice, Emmanuel; Lankas, Filip; Lavery, Richard; Maddocks, John H.; Osman, Roman; Seibert, Eleanore; Sklenar, Heinz; Stoll, Gautier; Thayer, Kelly M.; Varnai, Péter; Young, Matthew A.

2004-01-01

We describe herein a computationally intensive project aimed at carrying out molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide base sequences. This initiative was undertaken by an international collaborative effort involving nine research groups, the “Ascona B-DNA Consortium” (ABC). Calculations were carried out on the 136 cases imbedded in 39 DNA oligomers with repeating tetranucleotide sequences, capped on both ends by GC pairs and each having a total length of 15 nucleotide pairs. All MD simulations were carried out using a well-defined protocol, the AMBER suite of programs, and the parm94 force field. Phase I of the ABC project involves a total of ∼0.6 μs of simulation for systems containing ∼24,000 atoms. The resulting trajectories involve 600,000 coordinate sets and represent ∼400 gigabytes of data. In this article, the research design, details of the simulation protocol, informatics issues, and the organization of the results into a web-accessible database are described. Preliminary results from 15-ns MD trajectories are presented for the d(CpG) step in its 10 unique sequence contexts, and issues of stability and convergence, the extent of quasiergodic problems, and the possibility of long-lived conformational substates are discussed. PMID:15326025

Identification of the protein folding transition state from molecular dynamics trajectories

NASA Astrophysics Data System (ADS)

Muff, S.; Caflisch, A.

2009-03-01

The rate of protein folding is governed by the transition state so that a detailed characterization of its structure is essential for understanding the folding process. In vitro experiments have provided a coarse-grained description of the folding transition state ensemble (TSE) of small proteins. Atomistic details could be obtained by molecular dynamics (MD) simulations but it is not straightforward to extract the TSE directly from the MD trajectories, even for small peptides. Here, the structures in the TSE are isolated by the cut-based free-energy profile (cFEP) using the network whose nodes and links are configurations sampled by MD and direct transitions among them, respectively. The cFEP is a barrier-preserving projection that does not require arbitrarily chosen progress variables. First, a simple two-dimensional free-energy surface is used to illustrate the successful determination of the TSE by the cFEP approach and to explain the difficulty in defining boundary conditions of the Markov state model for an entropically stabilized free-energy minimum. The cFEP is then used to extract the TSE of a β-sheet peptide with a complex free-energy surface containing multiple basins and an entropic region. In contrast, Markov state models with boundary conditions defined by projected variables and conventional histogram-based free-energy profiles are not able to identify the TSE of the β-sheet peptide.

Integrated experimental and theoretical approach for the structural characterization of Hg2+ aqueous solutions

NASA Astrophysics Data System (ADS)

D'Angelo, Paola; Migliorati, Valentina; Mancini, Giordano; Barone, Vincenzo; Chillemi, Giovanni

2008-02-01

The structural and dynamic properties of the solvated Hg2+ ion in aqueous solution have been investigated by a combined experimental-theoretical approach employing x-ray absorption spectroscopy and molecular dynamics (MD) simulations. This method allows one to perform a quantitative analysis of the x-ray absorption near-edge structure (XANES) spectra of ionic solutions using a proper description of the thermal and structural fluctuations. XANES spectra have been computed starting from the MD trajectory, without carrying out any minimization in the structural parameter space. The XANES experimental data are accurately reproduced by a first-shell heptacoordinated cluster only if the second hydration shell is included in the calculations. These results confirm at the same time the existence of a sevenfold first hydration shell for the Hg2+ ion in aqueous solution and the reliability of the potentials used in the MD simulations. The combination of MD and XANES is found to be very helpful to get important new insights into the quantitative estimation of structural properties of disordered systems.

Multiple oxygen entry pathways in globin proteins revealed by intrinsic pathway identification method

NASA Astrophysics Data System (ADS)

Takayanagi, Masayoshi; Kurisaki, Ikuo; Nagaoka, Masataka

2015-12-01

Each subunit of human hemoglobin (HbA) stores an oxygen molecule (O2) in the binding site (BS) cavity near the heme group. The BS is buried in the interior of the subunit so that there is a debate over the O2 entry pathways from solvent to the BS; histidine gate or multiple pathways. To elucidate the O2 entry pathways, we executed ensemble molecular dynamics (MD) simulations of T-state tetramer HbA in high concentration O2 solvent to simulate spontaneous O2 entry from solvent into the BS. By analyzing 128 independent 8 ns MD trajectories by intrinsic pathway identification by clustering (IPIC) method, we found 141 and 425 O2 entry events into the BS of the α and β subunits, respectively. In both subunits, we found that multiple O2 entry pathways through inside cavities play a significant role for O2 entry process of HbA. The rate constants of O2 entry estimated from the MD trajectories correspond to the experimentally observed values. In addition, by analyzing monomer myoglobin, we verified that the high O2 concentration condition can reproduce the ratios of each multiple pathway in the one-tenth lower O2 concentration condition. These indicate the validity of the multiple pathways obtained in our MD simulations.

Dynamics and intramolecular ligand binding of DtxR studied by MD simulations and NMR spectroscopy

NASA Astrophysics Data System (ADS)

Yi, Myunggi; Bhattacharya, Nilakshee; Zhou, Huan-Xiang

2005-11-01

Diphtheria toxin repressor (DtxR) regulates the expression of the diphtheria toxin gene through intramolecular ligand binding (Wylie et al., Biochemistry 2005, 44:40-51). Protein dynamics is essential to the binding process of the Pro-rich (Pr) ligand to the C-terminal SH3 domain. We present MD and NMR results on the dynamics and ligand interactions of a Pr-SH3 construct of DtxR. NMR relaxation data (T1, T2, and NOE) showed that the Pr ligand is very flexible, suggesting that it undergoes binding/unbinding transitions. A 50-ns MD trajectory of the protein was used to calculate T1, T2, and NOE, reproducing the NMR results for the SH3 domain but not for the Pr segment. During the MD simulation, the ligand stayed bound to the SH3 domain; thus the simulation represented the bound state. The NMR data for the Pr-segment could be explained by assuming that they represented the average behavior of a fast binding/unbinding exchange. Though unbinding was not observed in the MD simulation, the simulation did show large fluctuations of a loop which forms part of the wall of the binding pocket. The fluctuations led to opening up of the binding pocket, thus weakening the interaction with the Pr segment and perhaps ultimately leading to ligand unbinding.

Single-Molecule Probing the Energy Landscape of Enzymatic Reaction and Non-Covalent Interactions

NASA Astrophysics Data System (ADS)

Lu, H. Peter; Hu, Dehong; Chen, Yu; Vorpagel, Erich R.

2002-03-01

We have applied single-molecule spectroscopy under physiological conditions to study the mechanisms and dynamics of T4 lysozyme enzymatic reactions, characterizing mode-specific protein conformational dynamics. Enzymatic reaction turnovers and the associated structure changes of individual protein molecules were observed simultaneously in real-time. The overall reaction rates were found to vary widely from molecule-to-molecule, and the initial non-specific binding of the enzyme to the substrate was seen to dominate this inhomogeneity. The reaction steps subsequent to the initial binding were found to have homogeneous rates. Molecular dynamics simulation has been applied to elucidate the mechanism and intermediate states of the single-molecule enzymatic reaction. Combining the analysis of single-molecule experimental trajectories, MD simulation trajectories, and statistical modeling, we have revealed the nature of multiple intermediate states involved in the active enzyme-substrate complex formation and the associated conformational change mechanism and dynamics.

Low-temperature protein dynamics: a simulation analysis of interprotein vibrations and the boson peak at 150 k.

PubMed

Kurkal-Siebert, Vandana; Smith, Jeremy C

2006-02-22

An understanding of low-frequency, collective protein dynamics at low temperatures can furnish valuable information on functional protein energy landscapes, on the origins of the protein glass transition and on protein-protein interactions. Here, molecular dynamics (MD) simulations and normal-mode analyses are performed on various models of crystalline myoglobin in order to characterize intra- and interprotein vibrations at 150 K. Principal component analysis of the MD trajectories indicates that the Boson peak, a broad peak in the dynamic structure factor centered at about approximately 2-2.5 meV, originates from approximately 10(2) collective, harmonic vibrations. An accurate description of the environment is found to be essential in reproducing the experimental Boson peak form and position. At lower energies other strong peaks are found in the calculated dynamic structure factor. Characterization of these peaks shows that they arise from harmonic vibrations of proteins relative to each other. These vibrations are likely to furnish valuable information on the physical nature of protein-protein interactions.

A Molecular Dynamics-Quantum Mechanics Theoretical Study of DNA-Mediated Charge Transport in Hydrated Ionic Liquids.

PubMed

Meng, Zhenyu; Kubar, Tomas; Mu, Yuguang; Shao, Fangwei

2018-05-08

Charge transport (CT) through biomolecules is of high significance in the research fields of biology, nanotechnology, and molecular devices. Inspired by our previous work that showed the binding of ionic liquid (IL) facilitated charge transport in duplex DNA, in silico simulation is a useful means to understand the microscopic mechanism of the facilitation phenomenon. Here molecular dynamics simulations (MD) of duplex DNA in water and hydrated ionic liquids were employed to explore the helical parameters. Principal component analysis was further applied to capture the subtle conformational changes of helical DNA upon different environmental impacts. Sequentially, CT rates were calculated by a QM/MM simulation of the flickering resonance model based upon MD trajectories. Herein, MD simulation illustrated that the binding of ionic liquids can restrain dynamic conformation and lower the on-site energy of the DNA base. Confined movement among the adjacent base pairs was highly related to the increase of electronic coupling among base pairs, which may lead DNA to a CT facilitated state. Sequentially combining MD and QM/MM analysis, the rational correlations among the binding modes, the conformational changes, and CT rates illustrated the facilitation effects from hydrated IL on DNA CT and supported a conformational-gating mechanism.

GPU-enabled molecular dynamics simulations of ankyrin kinase complex

NASA Astrophysics Data System (ADS)

Gautam, Vertika; Chong, Wei Lim; Wisitponchai, Tanchanok; Nimmanpipug, Piyarat; Zain, Sharifuddin M.; Rahman, Noorsaadah Abd.; Tayapiwatana, Chatchai; Lee, Vannajan Sanghiran

2014-10-01

The ankyrin repeat (AR) protein can be used as a versatile scaffold for protein-protein interactions. It has been found that the heterotrimeric complex between integrin-linked kinase (ILK), PINCH, and parvin is an essential signaling platform, serving as a convergence point for integrin and growth-factor signaling and regulating cell adhesion, spreading, and migration. Using ILK-AR with high affinity for the PINCH1 as our model system, we explored a structure-based computational protocol to probe and characterize binding affinity hot spots at protein-protein interfaces. In this study, the long time scale dynamics simulations with GPU accelerated molecular dynamics (MD) simulations in AMBER12 have been performed to locate the hot spots of protein-protein interaction by the analysis of the Molecular Mechanics-Poisson-Boltzmann Surface Area/Generalized Born Solvent Area (MM-PBSA/GBSA) of the MD trajectories. Our calculations suggest good binding affinity of the complex and also the residues critical in the binding.

METAGUI 3: A graphical user interface for choosing the collective variables in molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Giorgino, Toni; Laio, Alessandro; Rodriguez, Alex

2017-08-01

Molecular dynamics (MD) simulations allow the exploration of the phase space of biopolymers through the integration of equations of motion of their constituent atoms. The analysis of MD trajectories often relies on the choice of collective variables (CVs) along which the dynamics of the system is projected. We developed a graphical user interface (GUI) for facilitating the interactive choice of the appropriate CVs. The GUI allows: defining interactively new CVs; partitioning the configurations into microstates characterized by similar values of the CVs; calculating the free energies of the microstates for both unbiased and biased (metadynamics) simulations; clustering the microstates in kinetic basins; visualizing the free energy landscape as a function of a subset of the CVs used for the analysis. A simple mouse click allows one to quickly inspect structures corresponding to specific points in the landscape.

A parallel algorithm for step- and chain-growth polymerization in molecular dynamics.

PubMed

de Buyl, Pierre; Nies, Erik

2015-04-07

Classical Molecular Dynamics (MD) simulations provide insight into the properties of many soft-matter systems. In some situations, it is interesting to model the creation of chemical bonds, a process that is not part of the MD framework. In this context, we propose a parallel algorithm for step- and chain-growth polymerization that is based on a generic reaction scheme, works at a given intrinsic rate and produces continuous trajectories. We present an implementation in the ESPResSo++ simulation software and compare it with the corresponding feature in LAMMPS. For chain growth, our results are compared to the existing simulation literature. For step growth, a rate equation is proposed for the evolution of the crosslinker population that compares well to the simulations for low crosslinker functionality or for short times.

A parallel algorithm for step- and chain-growth polymerization in molecular dynamics

NASA Astrophysics Data System (ADS)

de Buyl, Pierre; Nies, Erik

2015-04-01

Classical Molecular Dynamics (MD) simulations provide insight into the properties of many soft-matter systems. In some situations, it is interesting to model the creation of chemical bonds, a process that is not part of the MD framework. In this context, we propose a parallel algorithm for step- and chain-growth polymerization that is based on a generic reaction scheme, works at a given intrinsic rate and produces continuous trajectories. We present an implementation in the ESPResSo++ simulation software and compare it with the corresponding feature in LAMMPS. For chain growth, our results are compared to the existing simulation literature. For step growth, a rate equation is proposed for the evolution of the crosslinker population that compares well to the simulations for low crosslinker functionality or for short times.

Precise determination of water exchanges on a mineral surface

DOE PAGES

Stack, Andrew G.; Borreguero, Jose M.; Prisk, Timothy R.; ...

2016-10-03

Solvent exchanges on solid surfaces and dissolved ions are a fundamental property important for understanding chemical reactions, but the rates of fast exchanges are poorly constrained. In this paper, we probed the diffusional motions of water adsorbed onto nanoparticles of the mineral barite (BaSO 4) using quasi-elastic neutron scattering (QENS) and classical molecular dynamics (MD) to reveal the complex dynamics of water exchange along mineral surfaces. QENS data as a function of temperature and momentum transfer (Q) were fit using scattering functions derived from MD trajectories. The simulations reproduce the dynamics measured in the experiments at ambient temperatures, but asmore » temperature is lowered the simulations overestimate slower motions. Decomposition of the MD-computed QENS intensity into contributions from adsorbed and unbound water shows that the majority of the signal arises from adsorbed species, although the dynamics of unbound water cannot be dismissed. The mean residence times of water on each of the four surface sites present on the barite {001} were calculated using MD: at room temperature the low barium site is 194 ps, whereas the high barium site contains two distributions of motions at 84 and 2.5 ps. These contrast to 13 ps residence time on both sulfate sites, with an additional surface diffusion exchange of 66 ps. Surface exchanges are similar to those of the aqueous ions calculated using the same force field: Ba aq 2+ is 208 ps and SO 4aq 2- is 5.8 ps. Finally, this work demonstrates how MD can be a reliable method to deconvolute solvent exchange reactions when quantitatively validated by QENS measurements.« less

Simulation of urea-induced protein unfolding: a lesson from bovine β-lactoglobulin.

PubMed

Eberini, Ivano; Emerson, Andrew; Sensi, Cristina; Ragona, Laura; Ricchiuto, Piero; Pedretti, Alessandro; Gianazza, Elisabetta; Tramontano, Anna

2011-09-01

To investigate the molecular mechanisms involved in the very initial stages of protein unfolding, we carried out one long (1 μs) simulation of bovine β-lactoglobulin (BLG) together with three (500 ns) supporting MD runs, in which the unfolding conditions were produced by adding the osmolyte urea to the simulated systems and/or by increasing the thermal energy raising the temperature from 300 to 350 K. BLG was chosen, since it is a well-characterized model protein, for which structural and folding properties have been widely investigated by X-ray and NMR. MD trajectories were analyzed not only in terms of standard progress variables, such as backbone H-bonds, gyration radius width, secondary structure elements, but also through the scrutiny of interactions and dynamical behavior of specific key residues previously pointed out and investigated by NMR and belonging to a well known hydrophobic cluster. MD trajectories simulated in different unfolding conditions suggest that urea destabilizes BLG structure weakening protein::protein hydrophobic interactions and the hydrogen bond network. The early unfolding events, better observed at higher temperature, affect both secondary and tertiary structure of the protein. Copyright © 2011 Elsevier Inc. All rights reserved.

Structural features that predict real-value fluctuations of globular proteins.

PubMed

Jamroz, Michal; Kolinski, Andrzej; Kihara, Daisuke

2012-05-01

It is crucial to consider dynamics for understanding the biological function of proteins. We used a large number of molecular dynamics (MD) trajectories of nonhomologous proteins as references and examined static structural features of proteins that are most relevant to fluctuations. We examined correlation of individual structural features with fluctuations and further investigated effective combinations of features for predicting the real value of residue fluctuations using the support vector regression (SVR). It was found that some structural features have higher correlation than crystallographic B-factors with fluctuations observed in MD trajectories. Moreover, SVR that uses combinations of static structural features showed accurate prediction of fluctuations with an average Pearson's correlation coefficient of 0.669 and a root mean square error of 1.04 Å. This correlation coefficient is higher than the one observed in predictions by the Gaussian network model (GNM). An advantage of the developed method over the GNMs is that the former predicts the real value of fluctuation. The results help improve our understanding of relationships between protein structure and fluctuation. Furthermore, the developed method provides a convienient practial way to predict fluctuations of proteins using easily computed static structural features of proteins. Copyright © 2012 Wiley Periodicals, Inc.

On the assumptions underlying milestoning.

PubMed

Vanden-Eijnden, Eric; Venturoli, Maddalena; Ciccotti, Giovanni; Elber, Ron

2008-11-07

Milestoning is a procedure to compute the time evolution of complicated processes such as barrier crossing events or long diffusive transitions between predefined states. Milestoning reduces the dynamics to transition events between intermediates (the milestones) and computes the local kinetic information to describe these transitions via short molecular dynamics (MD) runs between the milestones. The procedure relies on the ability to reinitialize MD trajectories on the milestones to get the right kinetic information about the transitions. It also rests on the assumptions that the transition events between successive milestones and the time lags between these transitions are statistically independent. In this paper, we analyze the validity of these assumptions. We show that sets of optimal milestones exist, i.e., sets such that successive transitions are indeed statistically independent. The proof of this claim relies on the results of transition path theory and uses the isocommittor surfaces of the reaction as milestones. For systems in the overdamped limit, we also obtain the probability distribution to reinitialize the MD trajectories on the milestones, and we discuss why this distribution is not available in closed form for systems with inertia. We explain why the time lags between transitions are not statistically independent even for optimal milestones, but we show that working with such milestones allows one to compute mean first passage times between milestones exactly. Finally, we discuss some practical implications of our results and we compare milestoning with Markov state models in view of our findings.

Cutoff size need not strongly influence molecular dynamics results for solvated polypeptides.

PubMed

Beck, David A C; Armen, Roger S; Daggett, Valerie

2005-01-18

The correct treatment of van der Waals and electrostatic nonbonded interactions in molecular force fields is essential for performing realistic molecular dynamics (MD) simulations of solvated polypeptides. The most computationally tractable treatment of nonbonded interactions in MD utilizes a spherical distance cutoff (typically, 8-12 A) to reduce the number of pairwise interactions. In this work, we assess three spherical atom-based cutoff approaches for use with all-atom explicit solvent MD: abrupt truncation, a CHARMM-style electrostatic shift truncation, and our own force-shifted truncation. The chosen system for this study is an end-capped 17-residue alanine-based alpha-helical peptide, selected because of its use in previous computational and experimental studies. We compare the time-averaged helical content calculated from these MD trajectories with experiment. We also examine the effect of varying the cutoff treatment and distance on energy conservation. We find that the abrupt truncation approach is pathological in its inability to conserve energy. The CHARMM-style shift truncation performs quite well but suffers from energetic instability. On the other hand, the force-shifted spherical cutoff method conserves energy, correctly predicts the experimental helical content, and shows convergence in simulation statistics as the cutoff is increased. This work demonstrates that by using proper and rigorous techniques, it is possible to correctly model polypeptide dynamics in solution with a spherical cutoff. The inherent computational advantage of spherical cutoffs over Ewald summation (and related) techniques is essential in accessing longer MD time scales.

An energy function for dynamics simulations of polypeptides in torsion angle space

NASA Astrophysics Data System (ADS)

Sartori, F.; Melchers, B.; Böttcher, H.; Knapp, E. W.

1998-05-01

Conventional simulation techniques to model the dynamics of proteins in atomic detail are restricted to short time scales. A simplified molecular description, in which high frequency motions with small amplitudes are ignored, can overcome this problem. In this protein model only the backbone dihedrals φ and ψ and the χi of the side chains serve as degrees of freedom. Bond angles and lengths are fixed at ideal geometry values provided by the standard molecular dynamics (MD) energy function CHARMM. In this work a Monte Carlo (MC) algorithm is used, whose elementary moves employ cooperative rotations in a small window of consecutive amide planes, leaving the polypeptide conformation outside of this window invariant. A single of these window MC moves generates local conformational changes only. But, the application of many such moves at different parts of the polypeptide backbone leads to global conformational changes. To account for the lack of flexibility in the protein model employed, the energy function used to evaluate conformational energies is split into sequentially neighbored and sequentially distant contributions. The sequentially neighbored part is represented by an effective (φ,ψ)-torsion potential. It is derived from MD simulations of a flexible model dipeptide using a conventional MD energy function. To avoid exaggeration of hydrogen bonding strengths, the electrostatic interactions involving hydrogen atoms are scaled down at short distances. With these adjustments of the energy function, the rigid polypeptide model exhibits the same equilibrium distributions as obtained by conventional MD simulation with a fully flexible molecular model. Also, the same temperature dependence of the stability and build-up of α helices of 18-alanine as found in MD simulations is observed using the adapted energy function for MC simulations. Analyses of transition frequencies demonstrate that also dynamical aspects of MD trajectories are faithfully reproduced. Finally, it is demonstrated that even for high temperature unfolded polypeptides the MC simulation is more efficient by a factor of 10 than conventional MD simulations.

Slow dynamics of a protein backbone in molecular dynamics simulation revealed by time-structure based independent component analysis

NASA Astrophysics Data System (ADS)

Naritomi, Yusuke; Fuchigami, Sotaro

2013-12-01

We recently proposed the method of time-structure based independent component analysis (tICA) to examine the slow dynamics involved in conformational fluctuations of a protein as estimated by molecular dynamics (MD) simulation [Y. Naritomi and S. Fuchigami, J. Chem. Phys. 134, 065101 (2011)]. Our previous study focused on domain motions of the protein and examined its dynamics by using rigid-body domain analysis and tICA. However, the protein changes its conformation not only through domain motions but also by various types of motions involving its backbone and side chains. Some of these motions might occur on a slow time scale: we hypothesize that if so, we could effectively detect and characterize them using tICA. In the present study, we investigated slow dynamics of the protein backbone using MD simulation and tICA. The selected target protein was lysine-, arginine-, ornithine-binding protein (LAO), which comprises two domains and undergoes large domain motions. MD simulation of LAO in explicit water was performed for 1 μs, and the obtained trajectory of Cα atoms in the backbone was analyzed by tICA. This analysis successfully provided us with slow modes for LAO that represented either domain motions or local movements of the backbone. Further analysis elucidated the atomic details of the suggested local motions and confirmed that these motions truly occurred on the expected slow time scale.

pyPcazip: A PCA-based toolkit for compression and analysis of molecular simulation data

NASA Astrophysics Data System (ADS)

Shkurti, Ardita; Goni, Ramon; Andrio, Pau; Breitmoser, Elena; Bethune, Iain; Orozco, Modesto; Laughton, Charles A.

The biomolecular simulation community is currently in need of novel and optimised software tools that can analyse and process, in reasonable timescales, the large generated amounts of molecular simulation data. In light of this, we have developed and present here pyPcazip: a suite of software tools for compression and analysis of molecular dynamics (MD) simulation data. The software is compatible with trajectory file formats generated by most contemporary MD engines such as AMBER, CHARMM, GROMACS and NAMD, and is MPI parallelised to permit the efficient processing of very large datasets. pyPcazip is a Unix based open-source software (BSD licenced) written in Python.

Virtual substitution scan via single-step free energy perturbation.

PubMed

Chiang, Ying-Chih; Wang, Yi

2016-02-05

With the rapid expansion of our computing power, molecular dynamics (MD) simulations ranging from hundreds of nanoseconds to microseconds or even milliseconds have become increasingly common. The majority of these long trajectories are obtained from plain (vanilla) MD simulations, where no enhanced sampling or free energy calculation method is employed. To promote the 'recycling' of these trajectories, we developed the Virtual Substitution Scan (VSS) toolkit as a plugin of the open-source visualization and analysis software VMD. Based on the single-step free energy perturbation (sFEP) method, VSS enables the user to post-process a vanilla MD trajectory for a fast free energy scan of substituting aryl hydrogens by small functional groups. Dihedrals of the functional groups are sampled explicitly in VSS, which improves the performance of the calculation and is found particularly important for certain groups. As a proof-of-concept demonstration, we employ VSS to compute the solvation free energy change upon substituting the hydrogen of a benzene molecule by 12 small functional groups frequently considered in lead optimization. Additionally, VSS is used to compute the relative binding free energy of four selected ligands of the T4 lysozyme. Overall, the computational cost of VSS is only a fraction of the corresponding multi-step FEP (mFEP) calculation, while its results agree reasonably well with those of mFEP, indicating that VSS offers a promising tool for rapid free energy scan of small functional group substitutions. This article is protected by copyright. All rights reserved. © 2016 Wiley Periodicals, Inc.

Searching for protein binding sites from Molecular Dynamics simulations and paramagnetic fragment-based NMR studies.

PubMed

Bernini, Andrea; Henrici De Angelis, Lucia; Morandi, Edoardo; Spiga, Ottavia; Santucci, Annalisa; Assfalg, Michael; Molinari, Henriette; Pillozzi, Serena; Arcangeli, Annarosa; Niccolai, Neri

2014-03-01

Hotspot delineation on protein surfaces represents a fundamental step for targeting protein-protein interfaces. Disruptors of protein-protein interactions can be designed provided that the sterical features of binding pockets, including the transient ones, can be defined. Molecular Dynamics, MD, simulations have been used as a reliable framework for identifying transient pocket openings on the protein surface. Accessible surface area and intramolecular H-bond involvement of protein backbone amides are proposed as descriptors for characterizing binding pocket occurrence and evolution along MD trajectories. TEMPOL induced paramagnetic perturbations on (1)H-(15)N HSQC signals of protein backbone amides have been analyzed as a fragment-based search for surface hotspots, in order to validate MD predicted pockets. This procedure has been applied to CXCL12, a small chemokine responsible for tumor progression and proliferation. From combined analysis of MD data and paramagnetic profiles, two CXCL12 sites suitable for the binding of small molecules were identified. One of these sites is the already well characterized CXCL12 region involved in the binding to CXCR4 receptor. The other one is a transient pocket predicted by Molecular Dynamics simulations, which could not be observed from static analysis of CXCL12 PDB structures. The present results indicate how TEMPOL, instrumental in identifying this transient pocket, can be a powerful tool to delineate minor conformations which can be highly relevant in dynamic discovery of antitumoral drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Conformational analysis of GT1B ganglioside and its interaction with botulinum neurotoxin type B: a study by molecular modeling and molecular dynamics.

PubMed

Venkateshwari, Sureshkumar; Veluraja, Kasinadar

2012-01-01

The conformational property of oligosaccharide GT1B in aqueous environment was studied by molecular dynamics (MD) simulation using all-atom model. Based on the trajectory analysis, three prominent conformational models were proposed for GT1B. Direct and water-mediated hydrogen bonding interactions stabilize these structures. The molecular modeling and 15 ns MD simulation of the Botulinum Neuro Toxin/B (BoNT/B) - GT1B complex revealed that BoNT/B can accommodate the GT1B in the single binding mode. Least mobility was seen for oligo-GT1B in the binding pocket. The bound conformation of GT1B obtained from the MD simulation of the BoNT/B-GT1B complex bear a close conformational similarity with the crystal structure of BoNT/A-GT1B complex. The mobility noticed for Arg 1268 in the dynamics was accounted for its favorable interaction with terminal NeuNAc. The internal NeuNAc1 tends to form 10 hydrogen bonds with BoNT/B, hence specifying this particular site as a crucial space for the therapeutic design that can restrict the pathogenic activity of BoNT/B.

MDWeb and MDMoby: an integrated web-based platform for molecular dynamics simulations.

PubMed

Hospital, Adam; Andrio, Pau; Fenollosa, Carles; Cicin-Sain, Damjan; Orozco, Modesto; Gelpí, Josep Lluís

2012-05-01

MDWeb and MDMoby constitute a web-based platform to help access to molecular dynamics (MD) in the standard and high-throughput regime. The platform provides tools to prepare systems from PDB structures mimicking the procedures followed by human experts. It provides inputs and can send simulations for three of the most popular MD packages (Amber, NAMD and Gromacs). Tools for analysis of trajectories, either provided by the user or retrieved from our MoDEL database (http://mmb.pcb.ub.es/MoDEL) are also incorporated. The platform has two ways of access, a set of web-services based on the BioMoby framework (MDMoby), programmatically accessible and a web portal (MDWeb). http://mmb.irbbarcelona.org/MDWeb; additional information and methodology details can be found at the web site ( http://mmb.irbbarcelona.org/MDWeb/help.php)

Probing the hydrogen equilibrium and kinetics in zeolite imidazolate frameworks via molecular dynamics and quasi-elastic neutron scattering experiments.

PubMed

Pantatosaki, Evangelia; Jobic, Hervé; Kolokolov, Daniil I; Karmakar, Shilpi; Biniwale, Rajesh; Papadopoulos, George K

2013-01-21

The problem of simulating processes involving equilibria and dynamics of guest sorbates within zeolitic imidazolate frameworks (ZIF) by means of molecular dynamics (MD) computer experiments is of growing importance because of the promising role of ZIFs as molecular "traps" for clean energy applications. A key issue for validating such an atomistic modeling attempt is the possibility of comparing the MD results, with real experiments being able to capture analogous space and time scales to the ones pertained to the computer experiments. In the present study, this prerequisite is fulfilled through the quasi-elastic neutron scattering technique (QENS) for measuring self-diffusivity, by elaborating the incoherent scattering signal of hydrogen nuclei. QENS and MD experiments were performed in parallel to probe the hydrogen motion, for the first time in ZIF members. The predicted and measured dynamics behaviors show considerable concentration variation of the hydrogen self-diffusion coefficient in the two topologically different ZIF pore networks of this study, the ZIF-3 and ZIF-8. Modeling options such as the flexibility of the entire matrix versus a rigid framework version, the mobility of the imidazolate ligand, and the inclusion of quantum mechanical effects in the potential functions were examined in detail for the sorption thermodynamics and kinetics of hydrogen and also of deuterium, by employing MD combined with Widom averaging towards studying phase equilibria. The latter methodology ensures a rigorous and efficient way for post-processing the dynamics trajectory, thereby avoiding stochastic moves via Monte Carlo simulation, over the large number of configurational degrees of freedom a nonrigid framework encompasses.

Trajectory NG: portable, compressed, general molecular dynamics trajectories.

PubMed

Spångberg, Daniel; Larsson, Daniel S D; van der Spoel, David

2011-10-01

We present general algorithms for the compression of molecular dynamics trajectories. The standard ways to store MD trajectories as text or as raw binary floating point numbers result in very large files when efficient simulation programs are used on supercomputers. Our algorithms are based on the observation that differences in atomic coordinates/velocities, in either time or space, are generally smaller than the absolute values of the coordinates/velocities. Also, it is often possible to store values at a lower precision. We apply several compression schemes to compress the resulting differences further. The most efficient algorithms developed here use a block sorting algorithm in combination with Huffman coding. Depending on the frequency of storage of frames in the trajectory, either space, time, or combinations of space and time differences are usually the most efficient. We compare the efficiency of our algorithms with each other and with other algorithms present in the literature for various systems: liquid argon, water, a virus capsid solvated in 15 mM aqueous NaCl, and solid magnesium oxide. We perform tests to determine how much precision is necessary to obtain accurate structural and dynamic properties, as well as benchmark a parallelized implementation of the algorithms. We obtain compression ratios (compared to single precision floating point) of 1:3.3-1:35 depending on the frequency of storage of frames and the system studied.

Theoretical restrictions on longest implicit time scales in Markov state models of biomolecular dynamics

NASA Astrophysics Data System (ADS)

Sinitskiy, Anton V.; Pande, Vijay S.

2018-01-01

Markov state models (MSMs) have been widely used to analyze computer simulations of various biomolecular systems. They can capture conformational transitions much slower than an average or maximal length of a single molecular dynamics (MD) trajectory from the set of trajectories used to build the MSM. A rule of thumb claiming that the slowest implicit time scale captured by an MSM should be comparable by the order of magnitude to the aggregate duration of all MD trajectories used to build this MSM has been known in the field. However, this rule has never been formally proved. In this work, we present analytical results for the slowest time scale in several types of MSMs, supporting the above rule. We conclude that the slowest implicit time scale equals the product of the aggregate sampling and four factors that quantify: (1) how much statistics on the conformational transitions corresponding to the longest implicit time scale is available, (2) how good the sampling of the destination Markov state is, (3) the gain in statistics from using a sliding window for counting transitions between Markov states, and (4) a bias in the estimate of the implicit time scale arising from finite sampling of the conformational transitions. We demonstrate that in many practically important cases all these four factors are on the order of unity, and we analyze possible scenarios that could lead to their significant deviation from unity. Overall, we provide for the first time analytical results on the slowest time scales captured by MSMs. These results can guide further practical applications of MSMs to biomolecular dynamics and allow for higher computational efficiency of simulations.

Model-free estimation of the effective correlation time for C–H bond reorientation in amphiphilic bilayers: {sup 1}H–{sup 13}C solid-state NMR and MD simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferreira, Tiago Mendes, E-mail: tiago.ferreira@fkem1.lu.se; Physical Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund; Ollila, O. H. Samuli

2015-01-28

Molecular dynamics (MD) simulations give atomically detailed information on structure and dynamics in amphiphilic bilayer systems on timescales up to about 1 μs. The reorientational dynamics of the C–H bonds is conventionally verified by measurements of {sup 13}C or {sup 2}H nuclear magnetic resonance (NMR) longitudinal relaxation rates R{sub 1}, which are more sensitive to motional processes with correlation times close to the inverse Larmor frequency, typically around 1-10 ns on standard NMR instrumentation, and are thus less sensitive to the 10-1000 ns timescale motion that can be observed in the MD simulations. We propose an experimental procedure for atomicallymore » resolved model-free estimation of the C–H bond effective reorientational correlation time τ{sub e}, which includes contributions from the entire range of all-atom MD timescales and that can be calculated directly from the MD trajectories. The approach is based on measurements of {sup 13}C R{sub 1} and R{sub 1ρ} relaxation rates, as well as {sup 1}H−{sup 13}C dipolar couplings, and is applicable to anisotropic liquid crystalline lipid or surfactant systems using a conventional solid-state NMR spectrometer and samples with natural isotopic composition. The procedure is demonstrated on a fully hydrated lamellar phase of 1-palmitoyl-2-oleoyl-phosphatidylcholine, yielding values of τ{sub e} from 0.1 ns for the methyl groups in the choline moiety and at the end of the acyl chains to 3 ns for the g{sub 1} methylene group of the glycerol backbone. MD simulations performed with a widely used united-atom force-field reproduce the τ{sub e}-profile of the major part of the acyl chains but underestimate the dynamics of the glycerol backbone and adjacent molecular segments. The measurement of experimental τ{sub e}-profiles can be used to study subtle effects on C–H bond reorientational motions in anisotropic liquid crystals, as well as to validate the C–H bond reorientation dynamics predicted in MD simulations of amphiphilic bilayers such as lipid membranes.« less

MDAnalysis: a toolkit for the analysis of molecular dynamics simulations.

PubMed

Michaud-Agrawal, Naveen; Denning, Elizabeth J; Woolf, Thomas B; Beckstein, Oliver

2011-07-30

MDAnalysis is an object-oriented library for structural and temporal analysis of molecular dynamics (MD) simulation trajectories and individual protein structures. It is written in the Python language with some performance-critical code in C. It uses the powerful NumPy package to expose trajectory data as fast and efficient NumPy arrays. It has been tested on systems of millions of particles. Many common file formats of simulation packages including CHARMM, Gromacs, Amber, and NAMD and the Protein Data Bank format can be read and written. Atoms can be selected with a syntax similar to CHARMM's powerful selection commands. MDAnalysis enables both novice and experienced programmers to rapidly write their own analytical tools and access data stored in trajectories in an easily accessible manner that facilitates interactive explorative analysis. MDAnalysis has been tested on and works for most Unix-based platforms such as Linux and Mac OS X. It is freely available under the GNU General Public License from http://mdanalysis.googlecode.com. Copyright © 2011 Wiley Periodicals, Inc.

Design of Quiet Rotorcraft Approach Trajectories: Verification Phase

NASA Technical Reports Server (NTRS)

Padula, Sharon L.

2010-01-01

Flight testing that is planned for October 2010 will provide an opportunity to evaluate rotorcraft trajectory optimization techniques. The flight test will involve a fully instrumented MD-902 helicopter, which will be flown over an array of microphones. In this work, the helicopter approach trajectory is optimized via a multiobjective genetic algorithm to improve community noise, passenger comfort, and pilot acceptance. Previously developed optimization strategies are modified to accommodate new helicopter data and to increase pilot acceptance. This paper describes the MD-902 trajectory optimization plus general optimization strategies and modifications that are needed to reduce the uncertainty in noise predictions. The constraints that are imposed by the flight test conditions and characteristics of the MD-902 helicopter limit the testing possibilities. However, the insights that will be gained through this research will prove highly valuable.

vmdICE: a plug-in for rapid evaluation of molecular dynamics simulations using VMD.

PubMed

Knapp, Bernhard; Lederer, Nadja; Omasits, Ulrich; Schreiner, Wolfgang

2010-12-01

Molecular dynamics (MD) is a powerful in silico method to investigate the interactions between biomolecules. It solves Newton's equations of motion for atoms over a specified period of time and yields a trajectory file, containing the different spatial arrangements of atoms during the simulation. The movements and energies of each single atom are recorded. For evaluating of these simulation trajectories with regard to biomedical implications, several methods are available. Three well-known ones are the root mean square deviation (RMSD), the root mean square fluctuation (RMSF) and solvent accessible surface area (SASA). Herein, we present a novel plug-in for the software "visual molecular dynamics" (VMD) that allows an interactive 3D representation of RMSD, RMSF, and SASA, directly on the molecule. On the one hand, our plug-in is easy to handle for inexperienced users, and on the other hand, it provides a fast and flexible graphical impression of the spatial dynamics of a system for experts in the field. © 2010 Wiley Periodicals, Inc.

Implementation of 3D spatial indexing and compression in a large-scale molecular dynamics simulation database for rapid atomic contact detection.

PubMed

Toofanny, Rudesh D; Simms, Andrew M; Beck, David A C; Daggett, Valerie

2011-08-10

Molecular dynamics (MD) simulations offer the ability to observe the dynamics and interactions of both whole macromolecules and individual atoms as a function of time. Taken in context with experimental data, atomic interactions from simulation provide insight into the mechanics of protein folding, dynamics, and function. The calculation of atomic interactions or contacts from an MD trajectory is computationally demanding and the work required grows exponentially with the size of the simulation system. We describe the implementation of a spatial indexing algorithm in our multi-terabyte MD simulation database that significantly reduces the run-time required for discovery of contacts. The approach is applied to the Dynameomics project data. Spatial indexing, also known as spatial hashing, is a method that divides the simulation space into regular sized bins and attributes an index to each bin. Since, the calculation of contacts is widely employed in the simulation field, we also use this as the basis for testing compression of data tables. We investigate the effects of compression of the trajectory coordinate tables with different options of data and index compression within MS SQL SERVER 2008. Our implementation of spatial indexing speeds up the calculation of contacts over a 1 nanosecond (ns) simulation window by between 14% and 90% (i.e., 1.2 and 10.3 times faster). For a 'full' simulation trajectory (51 ns) spatial indexing reduces the calculation run-time between 31 and 81% (between 1.4 and 5.3 times faster). Compression resulted in reduced table sizes but resulted in no significant difference in the total execution time for neighbour discovery. The greatest compression (~36%) was achieved using page level compression on both the data and indexes. The spatial indexing scheme significantly decreases the time taken to calculate atomic contacts and could be applied to other multidimensional neighbor discovery problems. The speed up enables on-the-fly calculation and visualization of contacts and rapid cross simulation analysis for knowledge discovery. Using page compression for the atomic coordinate tables and indexes saves ~36% of disk space without any significant decrease in calculation time and should be considered for other non-transactional databases in MS SQL SERVER 2008.

Implementation of 3D spatial indexing and compression in a large-scale molecular dynamics simulation database for rapid atomic contact detection

PubMed Central

2011-01-01

Background Molecular dynamics (MD) simulations offer the ability to observe the dynamics and interactions of both whole macromolecules and individual atoms as a function of time. Taken in context with experimental data, atomic interactions from simulation provide insight into the mechanics of protein folding, dynamics, and function. The calculation of atomic interactions or contacts from an MD trajectory is computationally demanding and the work required grows exponentially with the size of the simulation system. We describe the implementation of a spatial indexing algorithm in our multi-terabyte MD simulation database that significantly reduces the run-time required for discovery of contacts. The approach is applied to the Dynameomics project data. Spatial indexing, also known as spatial hashing, is a method that divides the simulation space into regular sized bins and attributes an index to each bin. Since, the calculation of contacts is widely employed in the simulation field, we also use this as the basis for testing compression of data tables. We investigate the effects of compression of the trajectory coordinate tables with different options of data and index compression within MS SQL SERVER 2008. Results Our implementation of spatial indexing speeds up the calculation of contacts over a 1 nanosecond (ns) simulation window by between 14% and 90% (i.e., 1.2 and 10.3 times faster). For a 'full' simulation trajectory (51 ns) spatial indexing reduces the calculation run-time between 31 and 81% (between 1.4 and 5.3 times faster). Compression resulted in reduced table sizes but resulted in no significant difference in the total execution time for neighbour discovery. The greatest compression (~36%) was achieved using page level compression on both the data and indexes. Conclusions The spatial indexing scheme significantly decreases the time taken to calculate atomic contacts and could be applied to other multidimensional neighbor discovery problems. The speed up enables on-the-fly calculation and visualization of contacts and rapid cross simulation analysis for knowledge discovery. Using page compression for the atomic coordinate tables and indexes saves ~36% of disk space without any significant decrease in calculation time and should be considered for other non-transactional databases in MS SQL SERVER 2008. PMID:21831299

Using Wavelet Analysis To Assist in Identification of Significant Events in Molecular Dynamics Simulations.

PubMed

Heidari, Zahra; Roe, Daniel R; Galindo-Murillo, Rodrigo; Ghasemi, Jahan B; Cheatham, Thomas E

2016-07-25

Long time scale molecular dynamics (MD) simulations of biological systems are becoming increasingly commonplace due to the availability of both large-scale computational resources and significant advances in the underlying simulation methodologies. Therefore, it is useful to investigate and develop data mining and analysis techniques to quickly and efficiently extract the biologically relevant information from the incredible amount of generated data. Wavelet analysis (WA) is a technique that can quickly reveal significant motions during an MD simulation. Here, the application of WA on well-converged long time scale (tens of μs) simulations of a DNA helix is described. We show how WA combined with a simple clustering method can be used to identify both the physical and temporal locations of events with significant motion in MD trajectories. We also show that WA can not only distinguish and quantify the locations and time scales of significant motions, but by changing the maximum time scale of WA a more complete characterization of these motions can be obtained. This allows motions of different time scales to be identified or ignored as desired.

Quantum clustering and network analysis of MD simulation trajectories to probe the conformational ensembles of protein-ligand interactions.

PubMed

Bhattacharyya, Moitrayee; Vishveshwara, Saraswathi

2011-07-01

In this article, we present a novel application of a quantum clustering (QC) technique to objectively cluster the conformations, sampled by molecular dynamics simulations performed on different ligand bound structures of the protein. We further portray each conformational population in terms of dynamically stable network parameters which beautifully capture the ligand induced variations in the ensemble in atomistic detail. The conformational populations thus identified by the QC method and verified by network parameters are evaluated for different ligand bound states of the protein pyrrolysyl-tRNA synthetase (DhPylRS) from D. hafniense. The ligand/environment induced re-distribution of protein conformational ensembles forms the basis for understanding several important biological phenomena such as allostery and enzyme catalysis. The atomistic level characterization of each population in the conformational ensemble in terms of the re-orchestrated networks of amino acids is a challenging problem, especially when the changes are minimal at the backbone level. Here we demonstrate that the QC method is sensitive to such subtle changes and is able to cluster MD snapshots which are similar at the side-chain interaction level. Although we have applied these methods on simulation trajectories of a modest time scale (20 ns each), we emphasize that our methodology provides a general approach towards an objective clustering of large-scale MD simulation data and may be applied to probe multistate equilibria at higher time scales, and to problems related to protein folding for any protein or protein-protein/RNA/DNA complex of interest with a known structure.

Benchmarking all-atom simulations using hydrogen exchange

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skinner, John J.; Yu, Wookyung; Gichana, Elizabeth K.

We are now able to fold small proteins reversibly to their native structures [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517–520] using long-time molecular dynamics (MD) simulations. Our results indicate that modern force fields can reproduce the energy surface near the native structure. In this paper, to test how well the force fields recapitulate the other regions of the energy surface, MD trajectories for a variant of protein G are compared with data from site-resolved hydrogen exchange (HX) and other biophysical measurements. Because HX monitors the breaking of individual H-bonds, this experimental technique identifies the stability andmore » H-bond content of excited states, thus enabling quantitative comparison with the simulations. Contrary to experimental findings of a cooperative, all-or-none unfolding process, the simulated denatured state ensemble, on average, is highly collapsed with some transient or persistent native 2° structure. The MD trajectories of this protein G variant and other small proteins exhibit excessive intramolecular H-bonding even for the most expanded conformations, suggesting that the force fields require improvements in describing H-bonding and backbone hydration. Finally and moreover, these comparisons provide a general protocol for validating the ability of simulations to accurately capture rare structural fluctuations.« less

Benchmarking all-atom simulations using hydrogen exchange

DOE PAGES

Skinner, John J.; Yu, Wookyung; Gichana, Elizabeth K.; ...

2014-10-27

We are now able to fold small proteins reversibly to their native structures [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517–520] using long-time molecular dynamics (MD) simulations. Our results indicate that modern force fields can reproduce the energy surface near the native structure. In this paper, to test how well the force fields recapitulate the other regions of the energy surface, MD trajectories for a variant of protein G are compared with data from site-resolved hydrogen exchange (HX) and other biophysical measurements. Because HX monitors the breaking of individual H-bonds, this experimental technique identifies the stability andmore » H-bond content of excited states, thus enabling quantitative comparison with the simulations. Contrary to experimental findings of a cooperative, all-or-none unfolding process, the simulated denatured state ensemble, on average, is highly collapsed with some transient or persistent native 2° structure. The MD trajectories of this protein G variant and other small proteins exhibit excessive intramolecular H-bonding even for the most expanded conformations, suggesting that the force fields require improvements in describing H-bonding and backbone hydration. Finally and moreover, these comparisons provide a general protocol for validating the ability of simulations to accurately capture rare structural fluctuations.« less

Assessing an ensemble docking-based virtual screening strategy for kinase targets by considering protein flexibility.

PubMed

Tian, Sheng; Sun, Huiyong; Pan, Peichen; Li, Dan; Zhen, Xuechu; Li, Youyong; Hou, Tingjun

2014-10-27

In this study, to accommodate receptor flexibility, based on multiple receptor conformations, a novel ensemble docking protocol was developed by using the naïve Bayesian classification technique, and it was evaluated in terms of the prediction accuracy of docking-based virtual screening (VS) of three important targets in the kinase family: ALK, CDK2, and VEGFR2. First, for each target, the representative crystal structures were selected by structural clustering, and the capability of molecular docking based on each representative structure to discriminate inhibitors from non-inhibitors was examined. Then, for each target, 50 ns molecular dynamics (MD) simulations were carried out to generate an ensemble of the conformations, and multiple representative structures/snapshots were extracted from each MD trajectory by structural clustering. On average, the representative crystal structures outperform the representative structures extracted from MD simulations in terms of the capabilities to separate inhibitors from non-inhibitors. Finally, by using the naïve Bayesian classification technique, an integrated VS strategy was developed to combine the prediction results of molecular docking based on different representative conformations chosen from crystal structures and MD trajectories. It was encouraging to observe that the integrated VS strategy yields better performance than the docking-based VS based on any single rigid conformation. This novel protocol may provide an improvement over existing strategies to search for more diverse and promising active compounds for a target of interest.

Path Similarity Analysis: A Method for Quantifying Macromolecular Pathways

PubMed Central

Seyler, Sean L.; Kumar, Avishek; Thorpe, M. F.; Beckstein, Oliver

2015-01-01

Diverse classes of proteins function through large-scale conformational changes and various sophisticated computational algorithms have been proposed to enhance sampling of these macromolecular transition paths. Because such paths are curves in a high-dimensional space, it has been difficult to quantitatively compare multiple paths, a necessary prerequisite to, for instance, assess the quality of different algorithms. We introduce a method named Path Similarity Analysis (PSA) that enables us to quantify the similarity between two arbitrary paths and extract the atomic-scale determinants responsible for their differences. PSA utilizes the full information available in 3N-dimensional configuration space trajectories by employing the Hausdorff or Fréchet metrics (adopted from computational geometry) to quantify the degree of similarity between piecewise-linear curves. It thus completely avoids relying on projections into low dimensional spaces, as used in traditional approaches. To elucidate the principles of PSA, we quantified the effect of path roughness induced by thermal fluctuations using a toy model system. Using, as an example, the closed-to-open transitions of the enzyme adenylate kinase (AdK) in its substrate-free form, we compared a range of protein transition path-generating algorithms. Molecular dynamics-based dynamic importance sampling (DIMS) MD and targeted MD (TMD) and the purely geometric FRODA (Framework Rigidity Optimized Dynamics Algorithm) were tested along with seven other methods publicly available on servers, including several based on the popular elastic network model (ENM). PSA with clustering revealed that paths produced by a given method are more similar to each other than to those from another method and, for instance, that the ENM-based methods produced relatively similar paths. PSA applied to ensembles of DIMS MD and FRODA trajectories of the conformational transition of diphtheria toxin, a particularly challenging example, showed that the geometry-based FRODA occasionally sampled the pathway space of force field-based DIMS MD. For the AdK transition, the new concept of a Hausdorff-pair map enabled us to extract the molecular structural determinants responsible for differences in pathways, namely a set of conserved salt bridges whose charge-charge interactions are fully modelled in DIMS MD but not in FRODA. PSA has the potential to enhance our understanding of transition path sampling methods, validate them, and to provide a new approach to analyzing conformational transitions. PMID:26488417

A study of internal energy relaxation in shocks using molecular dynamics based models

NASA Astrophysics Data System (ADS)

Li, Zheng; Parsons, Neal; Levin, Deborah A.

2015-10-01

Recent potential energy surfaces (PESs) for the N2 + N and N2 + N2 systems are used in molecular dynamics (MD) to simulate rates of vibrational and rotational relaxations for conditions that occur in hypersonic flows. For both chemical systems, it is found that the rotational relaxation number increases with the translational temperature and decreases as the rotational temperature approaches the translational temperature. The vibrational relaxation number is observed to decrease with translational temperature and approaches the rotational relaxation number in the high temperature region. The rotational and vibrational relaxation numbers are generally larger in the N2 + N2 system. MD-quasi-classical trajectory (QCT) with the PESs is also used to calculate the V-T transition cross sections, the collision cross section, and the dissociation cross section for each collision pair. Direct simulation Monte Carlo (DSMC) results for hypersonic flow over a blunt body with the total collision cross section from MD/QCT simulations, Larsen-Borgnakke with new relaxation numbers, and the N2 dissociation rate from MD/QCT show a profile with a decreased translational temperature and a rotational temperature close to vibrational temperature. The results demonstrate that many of the physical models employed in DSMC should be revised as fundamental potential energy surfaces suitable for high temperature conditions become available.

Detecting coupled collective motions in protein by independent subspace analysis

NASA Astrophysics Data System (ADS)

Sakuraba, Shun; Joti, Yasumasa; Kitao, Akio

2010-11-01

Protein dynamics evolves in a high-dimensional space, comprising aharmonic, strongly correlated motional modes. Such correlation often plays an important role in analyzing protein function. In order to identify significantly correlated collective motions, here we employ independent subspace analysis based on the subspace joint approximate diagonalization of eigenmatrices algorithm for the analysis of molecular dynamics (MD) simulation trajectories. From the 100 ns MD simulation of T4 lysozyme, we extract several independent subspaces in each of which collective modes are significantly correlated, and identify the other modes as independent. This method successfully detects the modes along which long-tailed non-Gaussian probability distributions are obtained. Based on the time cross-correlation analysis, we identified a series of events among domain motions and more localized motions in the protein, indicating the connection between the functionally relevant phenomena which have been independently revealed by experiments.

Ultrafast fragmentation dynamics of triply charged carbon dioxide: Vibrational-mode-dependent molecular bond breakage

NASA Astrophysics Data System (ADS)

Yang, HongJiang; Wang, Enliang; Dong, WenXiu; Gong, Maomao; Shen, Zhenjie; Tang, Yaguo; Shan, Xu; Chen, Xiangjun

2018-05-01

The a b i n i t i o molecular dynamics (MD) simulations using an atom-centered density matrix propagation method have been carried out to investigate the fragmentation of the ground-state triply charged carbon dioxide, CO23 +→C+ + Oa+ + Ob+ . Ten thousands of trajectories have been simulated. By analyzing the momentum correlation of the final fragments, it is demonstrated that the sequential fragmentation dominates in the three-body dissociation, consistent with our experimental observations which were performed by electron collision at impact energy of 1500 eV. Furthermore, the MD simulations allow us to have detailed insight into the ultrafast evolution of the molecular bond breakage at a very early stage, within several tens of femtoseconds, and the result shows that the initial nuclear vibrational mode plays a decisive role in switching the dissociation pathways.

Molecular dynamics simulation of highly charged proteins: Comparison of the particle-particle particle-mesh and reaction field methods for the calculation of electrostatic interactions

PubMed Central

Gargallo, Raimundo; Hünenberger, Philippe H.; Avilés, Francesc X.; Oliva, Baldomero

2003-01-01

Molecular dynamics (MD) simulations of the activation domain of porcine procarboxypeptidase B (ADBp) were performed to examine the effect of using the particle-particle particle-mesh (P3M) or the reaction field (RF) method for calculating electrostatic interactions in simulations of highly charged proteins. Several structural, thermodynamic, and dynamic observables were derived from the MD trajectories, including estimated entropies and solvation free energies and essential dynamics (ED). The P3M method leads to slightly higher atomic positional fluctuations and deviations from the crystallographic structure, along with somewhat lower values of the total energy and solvation free energy. However, the ED analysis of the system leads to nearly identical results for both simulations. Because of the strong similarity between the results, both methods appear well suited for the simulation of highly charged globular proteins in explicit solvent. However, the lower computational demand of the RF method in the present implementation represents a clear advantage over the P3M method. PMID:14500874

Dynamics and Kinetics Study of "In-Water" Chemical Reactions by Enhanced Sampling of Reactive Trajectories.

PubMed

Zhang, Jun; Yang, Y Isaac; Yang, Lijiang; Gao, Yi Qin

2015-11-12

High potential energy barriers and engagement of solvent coordinates set challenges for in silico studies of chemical reactions, and one is quite commonly limited to study reactions along predefined reaction coordinate(s). A systematic protocol, QM/MM MD simulations using enhanced sampling of reactive trajectories (ESoRT), is established to quantitatively study chemical transitions in complex systems. A number of trajectories for Claisen rearrangement in water and toluene were collected and analyzed, respectively. Evidence was found that the bond making and breaking during this reaction are concerted processes in solutions, preferentially through a chairlike configuration. Water plays an important dynamic role that helps stabilize the transition sate, and the dipole-dipole interaction between water and the solute also lowers the transition barrier. The calculated rate coefficient is consistent with the experimental measurement. Compared with water, the reaction pathway in toluene is "narrower" and the reaction rate is slower by almost three orders of magnitude due to the absence of proper interactions to stabilize the transition state. This study suggests that the "in-water" nature of the Claisen rearrangement in aqueous solution influences its thermodynamics, kinetics, as well as dynamics.

Direct Prediction of EPR Spectra from Lipid Bilayers: Understanding Structure and Dynamics in Biological Membranes.

PubMed

Catte, Andrea; White, Gaye F; Wilson, Mark R; Oganesyan, Vasily S

2018-06-02

Of the many biophysical techniques now being brought to bear on studies of membranes, electron paramagnetic resonance (EPR) of nitroxide spin probes was the first to provide information about both mobility and ordering in lipid membranes. Here, we report the first prediction of variable temperature EPR spectra of model lipid bilayers in the presence and absence of cholesterol from the results of large scale fully atomistic molecular dynamics (MD) simulations. Three types of structurally different spin probes were employed in order to study different parts of the bilayer. Our results demonstrate very good agreement with experiment and thus confirm the accuracy of the latest lipid force fields. The atomic resolution of the simulations allows the interpretation of the molecular motions and interactions in terms of their impact on the sensitive EPR line shapes. Direct versus indirect effects of cholesterol on the dynamics of spin probes are analysed. Given the complexity of structural organisation in lipid bilayers, the advantage of using a combined MD-EPR simulation approach is two-fold. Firstly, prediction of EPR line shapes directly from MD trajectories of actual phospholipid structures allows unambiguous interpretation of EPR spectra of biological membranes in terms of complex motions. Secondly, such an approach provides an ultimate test bed for the up-to-date MD simulation models employed in the studies of biological membranes, an area that currently attracts great attention. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations.

PubMed

Ge, Yushu; van der Kamp, Marc; Malaisree, Maturos; Liu, Dan; Liu, Yi; Mulholland, Adrian J

2017-11-01

Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.

Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Ge, Yushu; van der Kamp, Marc; Malaisree, Maturos; Liu, Dan; Liu, Yi; Mulholland, Adrian J.

2017-11-01

Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.

Reaction and relaxation at surface hotspots: using molecular dynamics and the energy-grained master equation to describe diamond etching.

PubMed

Glowacki, David R; Rodgers, W J; Shannon, Robin; Robertson, Struan H; Harvey, Jeremy N

2017-04-28

The extent to which vibrational energy transfer dynamics can impact reaction outcomes beyond the gas phase remains an active research question. Molecular dynamics (MD) simulations are the method of choice for investigating such questions; however, they can be extremely expensive, and therefore it is worth developing cheaper models that are capable of furnishing reasonable results. This paper has two primary aims. First, we investigate the competition between energy relaxation and reaction at 'hotspots' that form on the surface of diamond during the chemical vapour deposition process. To explore this, we developed an efficient reactive potential energy surface by fitting an empirical valence bond model to higher-level ab initio electronic structure theory. We then ran 160 000 NVE trajectories on a large slab of diamond, and the results are in reasonable agreement with experiment: they suggest that energy dissipation from surface hotspots is complete within a few hundred femtoseconds, but that a small fraction of CH 3 does in fact undergo dissociation prior to the onset of thermal equilibrium. Second, we developed and tested a general procedure to formulate and solve the energy-grained master equation (EGME) for surface chemistry problems. The procedure we outline splits the diamond slab into system and bath components, and then evaluates microcanonical transition-state theory rate coefficients in the configuration space of the system atoms. Energy transfer from the system to the bath is estimated using linear response theory from a single long MD trajectory, and used to parametrize an energy transfer function which can be input into the EGME. Despite the number of approximations involved, the surface EGME results are in reasonable agreement with the NVE MD simulations, but considerably cheaper. The results are encouraging, because they offer a computationally tractable strategy for investigating non-equilibrium reaction dynamics at surfaces for a broader range of systems.This article is part of the themed issue 'Theoretical and computational studies of non-equilibrium and non-statistical dynamics in the gas phase, in the condensed phase and at interfaces'. © 2017 The Authors.

Reaction and relaxation at surface hotspots: using molecular dynamics and the energy-grained master equation to describe diamond etching

PubMed Central

Rodgers, W. J.; Shannon, Robin; Robertson, Struan H.; Harvey, Jeremy N.

2017-01-01

The extent to which vibrational energy transfer dynamics can impact reaction outcomes beyond the gas phase remains an active research question. Molecular dynamics (MD) simulations are the method of choice for investigating such questions; however, they can be extremely expensive, and therefore it is worth developing cheaper models that are capable of furnishing reasonable results. This paper has two primary aims. First, we investigate the competition between energy relaxation and reaction at ‘hotspots’ that form on the surface of diamond during the chemical vapour deposition process. To explore this, we developed an efficient reactive potential energy surface by fitting an empirical valence bond model to higher-level ab initio electronic structure theory. We then ran 160 000 NVE trajectories on a large slab of diamond, and the results are in reasonable agreement with experiment: they suggest that energy dissipation from surface hotspots is complete within a few hundred femtoseconds, but that a small fraction of CH3 does in fact undergo dissociation prior to the onset of thermal equilibrium. Second, we developed and tested a general procedure to formulate and solve the energy-grained master equation (EGME) for surface chemistry problems. The procedure we outline splits the diamond slab into system and bath components, and then evaluates microcanonical transition-state theory rate coefficients in the configuration space of the system atoms. Energy transfer from the system to the bath is estimated using linear response theory from a single long MD trajectory, and used to parametrize an energy transfer function which can be input into the EGME. Despite the number of approximations involved, the surface EGME results are in reasonable agreement with the NVE MD simulations, but considerably cheaper. The results are encouraging, because they offer a computationally tractable strategy for investigating non-equilibrium reaction dynamics at surfaces for a broader range of systems. This article is part of the themed issue ‘Theoretical and computational studies of non-equilibrium and non-statistical dynamics in the gas phase, in the condensed phase and at interfaces’. PMID:28320908

In situ data analytics and indexing of protein trajectories.

PubMed

Johnston, Travis; Zhang, Boyu; Liwo, Adam; Crivelli, Silvia; Taufer, Michela

2017-06-15

The transition toward exascale computing will be accompanied by a performance dichotomy. Computational peak performance will rapidly increase; I/O performance will either grow slowly or be completely stagnant. Essentially, the rate at which data are generated will grow much faster than the rate at which data can be read from and written to the disk. MD simulations will soon face the I/O problem of efficiently writing to and reading from disk on the next generation of supercomputers. This article targets MD simulations at the exascale and proposes a novel technique for in situ data analysis and indexing of MD trajectories. Our technique maps individual trajectories' substructures (i.e., α-helices, β-strands) to metadata frame by frame. The metadata captures the conformational properties of the substructures. The ensemble of metadata can be used for automatic, strategic analysis within a trajectory or across trajectories, without manually identify those portions of trajectories in which critical changes take place. We demonstrate our technique's effectiveness by applying it to 26.3k helices and 31.2k strands from 9917 PDB proteins and by providing three empirical case studies. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Five-year growth trajectories of kindergarten children with learning difficulties in mathematics.

PubMed

Morgan, Paul L; Farkas, George; Qiong Wu

2009-01-01

The investigators used data from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K) to estimate whether and to what extent the timing and persistence of mathematics difficulties (MD) in kindergarten predicted children's first through fifth grade math growth trajectories. Results indicated that children persistently displaying MD (i.e., those experiencing MD in both fall and spring of kindergarten) had the lowest subsequent growth rates, children with MD in spring only had the second-lowest growth rates, and children with MD in the fall only (and who had thus recovered from their MD by the spring of kindergarten) had the next-lowest growth rates. The children who did not have MD in either fall or spring of kindergarten had the highest growth rates. These results were observed prior to and after statistical control for additional variables. They indicate that measuring the timing and persistence of kindergarten children's mathematics learning difficulties may help identify those most at risk for failing to become mathematically proficient during elementary school.

Slow dynamics in protein fluctuations revealed by time-structure based independent component analysis: The case of domain motions

NASA Astrophysics Data System (ADS)

Naritomi, Yusuke; Fuchigami, Sotaro

2011-02-01

Protein dynamics on a long time scale was investigated using all-atom molecular dynamics (MD) simulation and time-structure based independent component analysis (tICA). We selected the lysine-, arginine-, ornithine-binding protein (LAO) as a target protein and focused on its domain motions in the open state. A MD simulation of the LAO in explicit water was performed for 600 ns, in which slow and large-amplitude domain motions of the LAO were observed. After extracting domain motions by rigid-body domain analysis, the tICA was applied to the obtained rigid-body trajectory, yielding slow modes of the LAO's domain motions in order of decreasing time scale. The slowest mode detected by the tICA represented not a closure motion described by a largest-amplitude mode determined by the principal component analysis but a twist motion with a time scale of tens of nanoseconds. The slow dynamics of the LAO were well described by only the slowest mode and were characterized by transitions between two basins. The results show that tICA is promising for describing and analyzing slow dynamics of proteins.

Slow dynamics in protein fluctuations revealed by time-structure based independent component analysis: the case of domain motions.

PubMed

Naritomi, Yusuke; Fuchigami, Sotaro

2011-02-14

Protein dynamics on a long time scale was investigated using all-atom molecular dynamics (MD) simulation and time-structure based independent component analysis (tICA). We selected the lysine-, arginine-, ornithine-binding protein (LAO) as a target protein and focused on its domain motions in the open state. A MD simulation of the LAO in explicit water was performed for 600 ns, in which slow and large-amplitude domain motions of the LAO were observed. After extracting domain motions by rigid-body domain analysis, the tICA was applied to the obtained rigid-body trajectory, yielding slow modes of the LAO's domain motions in order of decreasing time scale. The slowest mode detected by the tICA represented not a closure motion described by a largest-amplitude mode determined by the principal component analysis but a twist motion with a time scale of tens of nanoseconds. The slow dynamics of the LAO were well described by only the slowest mode and were characterized by transitions between two basins. The results show that tICA is promising for describing and analyzing slow dynamics of proteins.

Multiple-time-stepping generalized hybrid Monte Carlo methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Escribano, Bruno, E-mail: bescribano@bcamath.org; Akhmatskaya, Elena; IKERBASQUE, Basque Foundation for Science, E-48013 Bilbao

2015-01-01

Performance of the generalized shadow hybrid Monte Carlo (GSHMC) method [1], which proved to be superior in sampling efficiency over its predecessors [2–4], molecular dynamics and hybrid Monte Carlo, can be further improved by combining it with multi-time-stepping (MTS) and mollification of slow forces. We demonstrate that the comparatively simple modifications of the method not only lead to better performance of GSHMC itself but also allow for beating the best performed methods, which use the similar force splitting schemes. In addition we show that the same ideas can be successfully applied to the conventional generalized hybrid Monte Carlo method (GHMC).more » The resulting methods, MTS-GHMC and MTS-GSHMC, provide accurate reproduction of thermodynamic and dynamical properties, exact temperature control during simulation and computational robustness and efficiency. MTS-GHMC uses a generalized momentum update to achieve weak stochastic stabilization to the molecular dynamics (MD) integrator. MTS-GSHMC adds the use of a shadow (modified) Hamiltonian to filter the MD trajectories in the HMC scheme. We introduce a new shadow Hamiltonian formulation adapted to force-splitting methods. The use of such Hamiltonians improves the acceptance rate of trajectories and has a strong impact on the sampling efficiency of the method. Both methods were implemented in the open-source MD package ProtoMol and were tested on a water and a protein systems. Results were compared to those obtained using a Langevin Molly (LM) method [5] on the same systems. The test results demonstrate the superiority of the new methods over LM in terms of stability, accuracy and sampling efficiency. This suggests that putting the MTS approach in the framework of hybrid Monte Carlo and using the natural stochasticity offered by the generalized hybrid Monte Carlo lead to improving stability of MTS and allow for achieving larger step sizes in the simulation of complex systems.« less

Error assessment in molecular dynamics trajectories using computed NMR chemical shifts.

PubMed

Koes, David R; Vries, John K

2017-01-01

Accurate chemical shifts for the atoms in molecular mechanics (MD) trajectories can be obtained from quantum mechanical (QM) calculations that depend solely on the coordinates of the atoms in the localized regions surrounding atoms of interest. If these coordinates are correct and the sample size is adequate, the ensemble average of these chemical shifts should be equal to the chemical shifts obtained from NMR spectroscopy. If this is not the case, the coordinates must be incorrect. We have utilized this fact to quantify the errors associated with the backbone atoms in MD simulations of proteins. A library of regional conformers containing 169,499 members was constructed from 6 model proteins. The chemical shifts associated with the backbone atoms in each of these conformers was obtained from QM calculations using density functional theory at the B3LYP level with a 6-311+G(2d,p) basis set. Chemical shifts were assigned to each backbone atom in each MD simulation frame using a template matching approach. The ensemble average of these chemical shifts was compared to chemical shifts from NMR spectroscopy. A large systematic error was identified that affected the 1 H atoms of the peptide bonds involved in hydrogen bonding with water molecules or peptide backbone atoms. This error was highly sensitive to changes in electrostatic parameters. Smaller errors affecting the 13 C a and 15 N atoms were also detected. We believe these errors could be useful as metrics for comparing the force-fields and parameter sets used in MD simulation because they are directly tied to errors in atomic coordinates.

Changes in conformational dynamics of basic side chains upon protein–DNA association

PubMed Central

Esadze, Alexandre; Chen, Chuanying; Zandarashvili, Levani; Roy, Sourav; Pettitt, B. Montgometry; Iwahara, Junji

2016-01-01

Basic side chains play major roles in recognition of nucleic acids by proteins. However, dynamic properties of these positively charged side chains are not well understood. In this work, we studied changes in conformational dynamics of basic side chains upon protein–DNA association for the zinc-finger protein Egr-1. By nuclear magnetic resonance (NMR) spectroscopy, we characterized the dynamics of all side-chain cationic groups in the free protein and in the complex with target DNA. Our NMR order parameters indicate that the arginine guanidino groups interacting with DNA bases are strongly immobilized, forming rigid interfaces. Despite the strong short-range electrostatic interactions, the majority of the basic side chains interacting with the DNA phosphates exhibited high mobility, forming dynamic interfaces. In particular, the lysine side-chain amino groups exhibited only small changes in the order parameters upon DNA-binding. We found a similar trend in the molecular dynamics (MD) simulations for the free Egr-1 and the Egr-1–DNA complex. Using the MD trajectories, we also analyzed side-chain conformational entropy. The interfacial arginine side chains exhibited substantial entropic loss upon binding to DNA, whereas the interfacial lysine side chains showed relatively small changes in conformational entropy. These data illustrate different dynamic characteristics of the interfacial arginine and lysine side chains. PMID:27288446

Multiple loop conformations of peptides predicted by molecular dynamics simulations are compatible with nuclear magnetic resonance.

PubMed

Carstens, Heiko; Renner, Christian; Milbradt, Alexander G; Moroder, Luis; Tavan, Paul

2005-03-29

The affinity and selectivity of protein-protein interactions can be fine-tuned by varying the size, flexibility, and amino acid composition of involved surface loops. As a model for such surface loops, we study the conformational landscape of an octapeptide, whose flexibility is chemically steered by a covalent ring closure integrating an azobenzene dye into and by a disulfide bridge additionally constraining the peptide backbone. Because the covalently integrated azobenzene dyes can be switched by light between a bent cis state and an elongated trans state, six cyclic peptide models of strongly different flexibilities are obtained. The conformational states of these peptide models are sampled by NMR and by unconstrained molecular dynamics (MD) simulations. Prototypical conformations and the free-energy landscapes in the high-dimensional space spanned by the phi/psi angles at the peptide backbone are obtained by clustering techniques from the MD trajectories. Multiple open-loop conformations are shown to be predicted by MD particularly in the very flexible cases and are shown to comply with the NMR data despite the fact that such open-loop conformations are missing in the refined NMR structures.

Solvent effects on the properties of hyperbranched polythiophenes.

PubMed

Torras, Juan; Zanuy, David; Aradilla, David; Alemán, Carlos

2016-09-21

The structural and electronic properties of all-thiophene dendrimers and dendrons in solution have been evaluated using very different theoretical approaches based on quantum mechanical (QM) and hybrid QM/molecular mechanics (MM) methodologies: (i) calculations on minimum energy conformations using an implicit solvation model in combination with density functional theory (DFT) or time-dependent DFT (TD-DFT) methods; (ii) hybrid QM/MM calculations, in which the solute and solvent molecules are represented at the DFT level as point charges, respectively, on snapshots extracted from classical molecular dynamics (MD) simulations using explicit solvent molecules, and (iii) QM/MM-MD trajectories in which the solute is described at the DFT or TD-DFT level and the explicit solvent molecules are represented using classical force-fields. Calculations have been performed in dichloromethane, tetrahydrofuran and dimethylformamide. A comparison of the results obtained using the different approaches with the available experimental data indicates that the incorporation of effects associated with both the conformational dynamics of the dendrimer and the explicit solvent molecules is strictly necessary to satisfactorily reproduce the properties of the investigated systems. Accordingly, QM/MM-MD simulations are able to capture such effects providing a reliable description of electronic properties-conformational flexibility relationships in all-Th dendrimers.

The Caenorhabditis elegans DAF-12 nuclear receptor: structure, dynamics, and interaction with ligands.

PubMed

Alvarez, Lautaro D; Mañez, Pau Arroyo; Estrin, Darío A; Burton, Gerardo

2012-07-01

A structure for the ligand binding domain (LBD) of the DAF-12 receptor from Caenorhabditis elegans was obtained from the X-ray crystal structure of the receptor LBD from Strongyloides stercoralis bound to (25R)-Δ(7)-dafachronic acid (DA) (pdb:3GYU). The model was constructed in the presence of the ligand using a combination of Modeller, Autodock, and molecular dynamics (MD) programs, and then its dynamical behavior was studied by MD. A strong ligand binding mode (LBM) was found, with the three arginines in the ligand binding pocket (LBP) contacting the C-26 carboxylate group of the DA. The quality of the ceDAF-12 model was then evaluated by constructing several ligand systems for which the experimental activity is known. Thus, the dynamical behavior of the ceDAF-12 complex with the more active (25S)-Δ(7)-DA showed two distinct binding modes, one of them being energetically more favorable compared with the 25R isomer. Then the effect of the Arg564Cys and Arg598Met mutations on the (25R)-Δ(7)-DA binding was analyzed. The MD simulations showed that in the first case the complex was unstable, consistent with the lack of transactivation activity of (25R)-Δ(7)-DA in this mutant. Instead, in the case of the Arg598Met mutant, known to produce a partial loss of activity, our model predicted smaller effects on the LBM with a more stable MD trajectory. The model also showed that removal of the C-25 methyl does not impede the simultaneous strong interaction of the carboxylate with the three arginines, predicting that 27-nor-DAs are putative ceDAF-12 ligands. Copyright © 2012 Wiley Periodicals, Inc.

Learning probabilistic models of hydrogen bond stability from molecular dynamics simulation trajectories.

PubMed

Chikalov, Igor; Yao, Peggy; Moshkov, Mikhail; Latombe, Jean-Claude

2011-02-15

Hydrogen bonds (H-bonds) play a key role in both the formation and stabilization of protein structures. They form and break while a protein deforms, for instance during the transition from a non-functional to a functional state. The intrinsic strength of an individual H-bond has been studied from an energetic viewpoint, but energy alone may not be a very good predictor. This paper describes inductive learning methods to train protein-independent probabilistic models of H-bond stability from molecular dynamics (MD) simulation trajectories of various proteins. The training data contains 32 input attributes (predictors) that describe an H-bond and its local environment in a conformation c and the output attribute is the probability that the H-bond will be present in an arbitrary conformation of this protein achievable from c within a time duration Δ. We model dependence of the output variable on the predictors by a regression tree. Several models are built using 6 MD simulation trajectories containing over 4000 distinct H-bonds (millions of occurrences). Experimental results demonstrate that such models can predict H-bond stability quite well. They perform roughly 20% better than models based on H-bond energy alone. In addition, they can accurately identify a large fraction of the least stable H-bonds in a conformation. In most tests, about 80% of the 10% H-bonds predicted as the least stable are actually among the 10% truly least stable. The important attributes identified during the tree construction are consistent with previous findings. We use inductive learning methods to build protein-independent probabilistic models to study H-bond stability, and demonstrate that the models perform better than H-bond energy alone.

Event Detection and Sub-state Discovery from Bio-molecular Simulations Using Higher-Order Statistics: Application To Enzyme Adenylate Kinase

PubMed Central

Ramanathan, Arvind; Savol, Andrej J.; Agarwal, Pratul K.; Chennubhotla, Chakra S.

2012-01-01

Biomolecular simulations at milli-second and longer timescales can provide vital insights into functional mechanisms. Since post-simulation analyses of such large trajectory data-sets can be a limiting factor in obtaining biological insights, there is an emerging need to identify key dynamical events and relating these events to the biological function online, that is, as simulations are progressing. Recently, we have introduced a novel computational technique, quasi-anharmonic analysis (QAA) (PLoS One 6(1): e15827), for partitioning the conformational landscape into a hierarchy of functionally relevant sub-states. The unique capabilities of QAA are enabled by exploiting anharmonicity in the form of fourth-order statistics for characterizing atomic fluctuations. In this paper, we extend QAA for analyzing long time-scale simulations online. In particular, we present HOST4MD - a higher-order statistical toolbox for molecular dynamics simulations, which (1) identifies key dynamical events as simulations are in progress, (2) explores potential sub-states and (3) identifies conformational transitions that enable the protein to access those sub-states. We demonstrate HOST4MD on micro-second time-scale simulations of the enzyme adenylate kinase in its apo state. HOST4MD identifies several conformational events in these simulations, revealing how the intrinsic coupling between the three sub-domains (LID, CORE and NMP) changes during the simulations. Further, it also identifies an inherent asymmetry in the opening/closing of the two binding sites. We anticipate HOST4MD will provide a powerful and extensible framework for detecting biophysically relevant conformational coordinates from long time-scale simulations. PMID:22733562

Current status and future challenges in T-cell receptor/peptide/MHC molecular dynamics simulations.

PubMed

Knapp, Bernhard; Demharter, Samuel; Esmaielbeiki, Reyhaneh; Deane, Charlotte M

2015-11-01

The interaction between T-cell receptors (TCRs) and major histocompatibility complex (MHC)-bound epitopes is one of the most important processes in the adaptive human immune response. Several hypotheses on TCR triggering have been proposed. Many of them involve structural and dynamical adjustments in the TCR/peptide/MHC interface. Molecular Dynamics (MD) simulations are a computational technique that is used to investigate structural dynamics at atomic resolution. Such simulations are used to improve understanding of signalling on a structural level. Here we review how MD simulations of the TCR/peptide/MHC complex have given insight into immune system reactions not achievable with current experimental methods. Firstly, we summarize methods of TCR/peptide/MHC complex modelling and TCR/peptide/MHC MD trajectory analysis methods. Then we classify recently published simulations into categories and give an overview of approaches and results. We show that current studies do not come to the same conclusions about TCR/peptide/MHC interactions. This discrepancy might be caused by too small sample sizes or intrinsic differences between each interaction process. As computational power increases future studies will be able to and should have larger sample sizes, longer runtimes and additional parts of the immunological synapse included. © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Computational Design of Apolipoprotein E4 Inhibitors for Alzheimer's Disease Therapy from Traditional Chinese Medicine

PubMed Central

Huang, Hung-Jin; Chen, Hsin-Yi; Lee, Cheng-Chun

2014-01-01

Apolipoprotein E4 (Apo E4) is the major genetic risk factor in the causation of Alzheimer's disease (AD). In this study we utilize virtual screening of the world's largest traditional Chinese medicine (TCM) database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD) simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB) penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors. PMID:24967370

Principal component and clustering analysis on molecular dynamics data of the ribosomal L11·23S subdomain.

PubMed

Wolf, Antje; Kirschner, Karl N

2013-02-01

With improvements in computer speed and algorithm efficiency, MD simulations are sampling larger amounts of molecular and biomolecular conformations. Being able to qualitatively and quantitatively sift these conformations into meaningful groups is a difficult and important task, especially when considering the structure-activity paradigm. Here we present a study that combines two popular techniques, principal component (PC) analysis and clustering, for revealing major conformational changes that occur in molecular dynamics (MD) simulations. Specifically, we explored how clustering different PC subspaces effects the resulting clusters versus clustering the complete trajectory data. As a case example, we used the trajectory data from an explicitly solvated simulation of a bacteria's L11·23S ribosomal subdomain, which is a target of thiopeptide antibiotics. Clustering was performed, using K-means and average-linkage algorithms, on data involving the first two to the first five PC subspace dimensions. For the average-linkage algorithm we found that data-point membership, cluster shape, and cluster size depended on the selected PC subspace data. In contrast, K-means provided very consistent results regardless of the selected subspace. Since we present results on a single model system, generalization concerning the clustering of different PC subspaces of other molecular systems is currently premature. However, our hope is that this study illustrates a) the complexities in selecting the appropriate clustering algorithm, b) the complexities in interpreting and validating their results, and c) by combining PC analysis with subsequent clustering valuable dynamic and conformational information can be obtained.

Molecular dynamics simulation of three plastic additives' diffusion in polyethylene terephthalate.

PubMed

Li, Bo; Wang, Zhi-Wei; Lin, Qin-Bao; Hu, Chang-Ying

2017-06-01

Accurate diffusion coefficient data of additives in a polymer are of paramount importance for estimating the migration of the additives over time. This paper shows how this diffusion coefficient can be estimated for three plastic additives [2-(2'-hydroxy-5'-methylphenyl) (UV-P), 2,6-di-tert-butyl-4-methylphenol (BHT) and di-(2-ethylhexyl) phthalate (DEHP)] in polyethylene terephthalate (PET) using the molecular dynamics (MD) simulation method. MD simulations were performed at temperatures of 293-433 K. The diffusion coefficient was calculated through the Einstein relationship connecting the data of mean-square displacement at different times. Comparison of the diffusion coefficients simulated by the MD simulation technique, predicted by the Piringer model and experiments, showed that, except for a few samples, the MD-simulated values were in agreement with the experimental values within one order of magnitude. Furthermore, the diffusion process for additives is discussed in detail, and four factors - the interaction energy between additive molecules and PET, fractional free volume, molecular shape and size, and self-diffusion of the polymer - are proposed to illustrate the microscopic diffusion mechanism. The movement trajectories of additives in PET cell models suggested that the additive molecules oscillate slowly rather than hopping for a long time. Occasionally, when a sufficiently large hole was created adjacently, the molecule could undergo spatial motion by jumping into the free-volume hole and consequently start a continuous oscillation and hop. The results indicate that MD simulation is a useful approach for predicting the microstructure and diffusion coefficient of plastic additives, and help to estimate the migration level of additives from PET packaging.

Structured water in polyelectrolyte dendrimers: Understanding small angle neutron scattering results through atomistic simulation

NASA Astrophysics Data System (ADS)

Wu, Bin; Kerkeni, Boutheïna; Egami, Takeshi; Do, Changwoo; Liu, Yun; Wang, Yongmei; Porcar, Lionel; Hong, Kunlun; Smith, Sean C.; Liu, Emily L.; Smith, Gregory S.; Chen, Wei-Ren

2012-04-01

Based on atomistic molecular dynamics (MD) simulations, the small angle neutron scattering (SANS) intensity behavior of a single generation-4 polyelectrolyte polyamidoamine starburst dendrimer is investigated at different levels of molecular protonation. The SANS form factor, P(Q), and Debye autocorrelation function, γ(r), are calculated from the equilibrium MD trajectory based on a mathematical approach proposed in this work. The consistency found in comparison against previously published experimental findings (W.-R. Chen, L. Porcar, Y. Liu, P. D. Butler, and L. J. Magid, Macromolecules 40, 5887 (2007)) leads to a link between the neutron scattering experiment and MD computation, and fresh perspectives. The simulations enable scattering calculations of not only the hydrocarbons but also the contribution from the scattering length density fluctuations caused by structured, confined water within the dendrimer. Based on our computational results, we explore the validity of using radius of gyration RG for microstructure characterization of a polyelectrolyte dendrimer from the scattering perspective.

Do homologous thermophilic-mesophilic proteins exhibit similar structures and dynamics at optimal growth temperatures? A molecular dynamics simulation study.

PubMed

Basu, Sohini; Sen, Srikanta

2013-02-25

Structure and dynamics both are known to be important for the activity of a protein. A fundamental question is whether a thermophilic protein and its mesophilic homologue exhibit similar dynamics at their respective optimal growth temperatures. We have addressed this question by performing molecular dynamics (MD) simulations of a natural mesophilic-thermophilic homologue pair at their respective optimal growth temperatures to compare their structural, dynamical, and solvent properties. The MD simulations were done in explicit aqueous solvent under periodic boundary and constant pressure and temperature (CPT) conditions and continued for 10.0 ns using the same protocol for the two proteins, excepting the temperatures. The trajectories were analyzed to compare the properties of the two proteins. Results indicated that the dynamical behaviors of the two proteins at the respective optimal growth temperatures were remarkably similar. For the common residues in the thermophilic protein, the rms fluctuations have a general trend to be slightly higher compared to that in the mesophilic counterpart. Lindemann parameter values indicated that only a few residues exhibited solid-like dynamics while the protein as a whole appeared as a molten globule in each case. Interestingly, the water-water interaction was found to be strikingly similar in spite of the difference in temperatures while, the protein-water interaction was significantly different in the two simulations.

How Kinetics within the Unfolded State Affects Protein Folding: an Analysis Based on Markov State Models and an Ultra-Long MD Trajectory

PubMed Central

Deng, Nan-jie; Dai, Wei

2013-01-01

Understanding how kinetics in the unfolded state affects protein folding is a fundamentally important yet less well-understood issue. Here we employ three different models to analyze the unfolded landscape and folding kinetics of the miniprotein Trp-cage. The first is a 208 μs explicit solvent molecular dynamics (MD) simulation from D. E. Shaw Research containing tens of folding events. The second is a Markov state model (MSM-MD) constructed from the same ultra-long MD simulation; MSM-MD can be used to generate thousands of folding events. The third is a Markov state model built from temperature replica exchange MD simulations in implicit solvent (MSM-REMD). All the models exhibit multiple folding pathways, and there is a good correspondence between the folding pathways from direct MD and those computed from the MSMs. The unfolded populations interconvert rapidly between extended and collapsed conformations on time scales ≤ 40 ns, compared with the folding time of ≈ 5 μs. The folding rates are independent of where the folding is initiated from within the unfolded ensemble. About 90 % of the unfolded states are sampled within the first 40 μs of the ultra-long MD trajectory, which on average explores ~27 % of the unfolded state ensemble between consecutive folding events. We clustered the folding pathways according to structural similarity into “tubes”, and kinetically partitioned the unfolded state into populations that fold along different tubes. From our analysis of the simulations and a simple kinetic model, we find that when the mixing within the unfolded state is comparable to or faster than folding, the folding waiting times for all the folding tubes are similar and the folding kinetics is essentially single exponential despite the presence of heterogeneous folding paths with non-uniform barriers. When the mixing is much slower than folding, different unfolded populations fold independently leading to non-exponential kinetics. A kinetic partition of the Trp-cage unfolded state is constructed which reveals that different unfolded populations have almost the same probability to fold along any of the multiple folding paths. We are investigating whether the results for the kinetics in the unfolded state of the twenty-residue Trp-cage is representative of larger single domain proteins. PMID:23705683

Changes in conformational dynamics of basic side chains upon protein-DNA association.

PubMed

Esadze, Alexandre; Chen, Chuanying; Zandarashvili, Levani; Roy, Sourav; Pettitt, B Montgometry; Iwahara, Junji

2016-08-19

Basic side chains play major roles in recognition of nucleic acids by proteins. However, dynamic properties of these positively charged side chains are not well understood. In this work, we studied changes in conformational dynamics of basic side chains upon protein-DNA association for the zinc-finger protein Egr-1. By nuclear magnetic resonance (NMR) spectroscopy, we characterized the dynamics of all side-chain cationic groups in the free protein and in the complex with target DNA. Our NMR order parameters indicate that the arginine guanidino groups interacting with DNA bases are strongly immobilized, forming rigid interfaces. Despite the strong short-range electrostatic interactions, the majority of the basic side chains interacting with the DNA phosphates exhibited high mobility, forming dynamic interfaces. In particular, the lysine side-chain amino groups exhibited only small changes in the order parameters upon DNA-binding. We found a similar trend in the molecular dynamics (MD) simulations for the free Egr-1 and the Egr-1-DNA complex. Using the MD trajectories, we also analyzed side-chain conformational entropy. The interfacial arginine side chains exhibited substantial entropic loss upon binding to DNA, whereas the interfacial lysine side chains showed relatively small changes in conformational entropy. These data illustrate different dynamic characteristics of the interfacial arginine and lysine side chains. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Exact milestoning

PubMed Central

Bello-Rivas, Juan M.; Elber, Ron

2015-01-01

A new theory and an exact computer algorithm for calculating kinetics and thermodynamic properties of a particle system are described. The algorithm avoids trapping in metastable states, which are typical challenges for Molecular Dynamics (MD) simulations on rough energy landscapes. It is based on the division of the full space into Voronoi cells. Prior knowledge or coarse sampling of space points provides the centers of the Voronoi cells. Short time trajectories are computed between the boundaries of the cells that we call milestones and are used to determine fluxes at the milestones. The flux function, an essential component of the new theory, provides a complete description of the statistical mechanics of the system at the resolution of the milestones. We illustrate the accuracy and efficiency of the exact Milestoning approach by comparing numerical results obtained on a model system using exact Milestoning with the results of long trajectories and with a solution of the corresponding Fokker-Planck equation. The theory uses an equation that resembles the approximate Milestoning method that was introduced in 2004 [A. K. Faradjian and R. Elber, J. Chem. Phys. 120(23), 10880-10889 (2004)]. However, the current formulation is exact and is still significantly more efficient than straightforward MD simulations on the system studied. PMID:25747056

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bello-Rivas, Juan M.; Elber, Ron; Department of Chemistry, University of Texas at Austin, Austin, Texas 78712

A new theory and an exact computer algorithm for calculating kinetics and thermodynamic properties of a particle system are described. The algorithm avoids trapping in metastable states, which are typical challenges for Molecular Dynamics (MD) simulations on rough energy landscapes. It is based on the division of the full space into Voronoi cells. Prior knowledge or coarse sampling of space points provides the centers of the Voronoi cells. Short time trajectories are computed between the boundaries of the cells that we call milestones and are used to determine fluxes at the milestones. The flux function, an essential component of themore » new theory, provides a complete description of the statistical mechanics of the system at the resolution of the milestones. We illustrate the accuracy and efficiency of the exact Milestoning approach by comparing numerical results obtained on a model system using exact Milestoning with the results of long trajectories and with a solution of the corresponding Fokker-Planck equation. The theory uses an equation that resembles the approximate Milestoning method that was introduced in 2004 [A. K. Faradjian and R. Elber, J. Chem. Phys. 120(23), 10880-10889 (2004)]. However, the current formulation is exact and is still significantly more efficient than straightforward MD simulations on the system studied.« less

ATP Hydrolysis Induced Conformational Changes in the Vitamin B12 Transporter BtuCD Revealed by MD Simulations

PubMed Central

Pan, Chao; Weng, Jingwei; Wang, Wenning

2016-01-01

ATP binding cassette (ABC) transporters utilize the energy of ATP hydrolysis to uni-directionally transport substrates across cell membrane. ATP hydrolysis occurs at the nucleotide-binding domain (NBD) dimer interface of ABC transporters, whereas substrate translocation takes place at the translocation pathway between the transmembrane domains (TMDs), which is more than 30 angstroms away from the NBD dimer interface. This raises the question of how the hydrolysis energy released at NBDs is “transmitted” to trigger the conformational changes at TMDs. Using molecular dynamics (MD) simulations, we studied the post-hydrolysis state of the vitamin B12 importer BtuCD. Totally 3-μs MD trajectories demonstrate a predominantly asymmetric arrangement of the NBD dimer interface, with the ADP-bound site disrupted and the ATP-bound site preserved in most of the trajectories. TMDs response to ATP hydrolysis by separation of the L-loops and opening of the cytoplasmic gate II, indicating that hydrolysis of one ATP could facilitate substrate translocation by opening the cytoplasmic end of translocation pathway. It was also found that motions of the L-loops and the cytoplasmic gate II are coupled with each other through a contiguous interaction network involving a conserved Asn83 on the extended stretch preceding TM3 helix plus the cytoplasmic end of TM2/6/7 helix bundle. These findings entail a TMD-NBD communication mechanism for type II ABC importers. PMID:27870912

Molecular Dynamics Study of Nitrogen-Pyramidalized Bicyclic β-Proline Oligomers: Length-Dependent Convergence to Organized Structures.

PubMed

Otani, Yuko; Watanabe, Satoshi; Ohwada, Tomohiko; Kitao, Akio

2017-01-12

In this study, the solution structures of the homooligomers of a conformationally constrained bicyclic proline-type β-amino acid were studied by means of molecular dynamics (MD) calculations in explicit methanol and water using the umbrella sampling method. The ratio of trans-amide and cis-amide was estimated by NMR and the rotational barrier of the amide of acetylated bicyclic amino acid monomer was estimated by two-dimensional (2D) exchange spectroscopy (EXSY) or line-shape analysis. A bias potential was introduced with respect to the amide torsion angle ω to enhance conformational exchange including isomerization of amide bonds by lowering the rotation energy barrier. After determination of reweighting parameters to best reproduce the experimental results of the monomer amide, the free energy profile around the amide torsion angle ω was obtained from the MD trajectory by reweighting of the biased probability density. The MD simulation results support the existence of invertomers of nitrogen-pyramidalized amide. Furthermore, extended structures with a high fraction of trans-amide conformation appear to be increasingly stabilized as the oligomer is elongated, both in methanol and in water. Our conformational analysis of natural and non-natural tertiary-amide-based peptide oligomers indicates that these oligomers preferentially adopt a limited number of conformations.

Calculations of the free energy of interaction of the c-Fos-c-Jun coiled coil: effects of the solvation model and the inclusion of polarization effects.

PubMed

Zuo, Zhili; Gandhi, Neha S; Mancera, Ricardo L

2010-12-27

The leucine zipper region of activator protein-1 (AP-1) comprises the c-Jun and c-Fos proteins and constitutes a well-known coiled coil protein-protein interaction motif. We have used molecular dynamics (MD) simulations in conjunction with the molecular mechanics/Poisson-Boltzmann generalized-Born surface area [MM/PB(GB)SA] methods to predict the free energy of interaction of these proteins. In particular, the influence of the choice of solvation model, protein force field, and water potential on the stability and dynamic properties of the c-Fos-c-Jun complex were investigated. Use of the AMBER polarizable force field ff02 in combination with the polarizable POL3 water potential was found to result in increased stability of the c-Fos-c-Jun complex. MM/PB(GB)SA calculations revealed that MD simulations using the POL3 water potential give the lowest predicted free energies of interaction compared to other nonpolarizable water potentials. In addition, the calculated absolute free energy of binding was predicted to be closest to the experimental value using the MM/GBSA method with independent MD simulation trajectories using the POL3 water potential and the polarizable ff02 force field, while all other binding affinities were overestimated.

Anharmonic resonance absorption of short laser pulses in clusters: A molecular dynamics simulation study

NASA Astrophysics Data System (ADS)

Mahalik, S. S.; Kundu, M.

2016-12-01

Linear resonance (LR) absorption of an intense 800 nm laser light in a nano-cluster requires a long laser pulse >100 fs when Mie-plasma frequency ( ω M ) of electrons in the expanding cluster matches the laser frequency (ω). For a short duration of the pulse, the condition for LR is not satisfied. In this case, it was shown by a model and particle-in-cell (PIC) simulations [Phys. Rev. Lett. 96, 123401 (2006)] that electrons absorb laser energy by anharmonic resonance (AHR) when the position-dependent frequency Ω [ r ( t ) ] of an electron in the self-consistent anharmonic potential of the cluster satisfies Ω [ r ( t ) ] = ω . However, AHR remains to be a debate and still obscure in multi-particle plasma simulations. Here, we identify AHR mechanism in a laser driven cluster using molecular dynamics (MD) simulations. By analyzing the trajectory of each MD electron and extracting its Ω [ r ( t ) ] in the self-generated anharmonic plasma potential, it is found that electron is outer ionized only when AHR is met. An anharmonic oscillator model, introduced here, brings out most of the features of MD electrons while passing the AHR. Thus, we not only bridge the gap between PIC simulations, analytical models, and MD calculations for the first time but also unequivocally prove that AHR process is a universal dominant collisionless mechanism of absorption in the short pulse regime or in the early time of longer pulses in clusters.

pKa values in proteins determined by electrostatics applied to molecular dynamics trajectories.

PubMed

Meyer, Tim; Knapp, Ernst-Walter

2015-06-09

For a benchmark set of 194 measured pKa values in 13 proteins, electrostatic energy computations are performed in which pKa values are computed by solving the Poisson-Boltzmann equation. In contrast to the previous approach of Karlsberg(+) (KB(+)) that essentially used protein crystal structures with variations in their side chain conformations, the present approach (KB2(+)MD) uses protein conformations from four molecular dynamics (MD) simulations of 10 ns each. These MD simulations are performed with different specific but fixed protonation patterns, selected to sample the conformational space for the different protonation patterns faithfully. The root-mean-square deviation between computed and measured pKa values (pKa RMSD) is shown to be reduced from 1.17 pH units using KB(+) to 0.96 pH units using KB2(+)MD. The pKa RMSD can be further reduced to 0.79 pH units, if each conformation is energy-minimized with a dielectric constant of εmin = 4 prior to calculating the electrostatic energy. The electrostatic energy expressions upon which the computations are based have been reformulated such that they do not involve terms that mix protein and solvent environment contributions and no thermodynamic cycle is needed. As a consequence, conformations of the titratable residues can be treated independently in the protein and solvent environments. In addition, the energy terms used here avoid the so-called intrinsic pKa and can therefore be interpreted without reference to arbitrary protonation states and conformations.

Assessment of amide I spectroscopic maps for a gas-phase peptide using IR-UV double-resonance spectroscopy and density functional theory calculations

NASA Astrophysics Data System (ADS)

Carr, J. K.; Zabuga, A. V.; Roy, S.; Rizzo, T. R.; Skinner, J. L.

2014-06-01

The spectroscopy of amide I vibrations has become a powerful tool for exploring protein structure and dynamics. To help with spectral interpretation, it is often useful to perform molecular dynamics (MD) simulations. To connect spectroscopic experiments to simulations in an efficient manner, several researchers have proposed "maps," which relate observables in classical MD simulations to quantum spectroscopic variables. It can be difficult to discern whether errors in the theoretical results (compared to experiment) arise from inaccuracies in the MD trajectories or in the maps themselves. In this work, we evaluate spectroscopic maps independently from MD simulations by comparing experimental and theoretical spectra for a single conformation of the α-helical model peptide Ac-Phe-(Ala)5-Lys-H+ in the gas phase. Conformation-specific experimental spectra are obtained for the unlabeled peptide and for several singly and doubly 13C-labeled variants using infrared-ultraviolet double-resonance spectroscopy, and these spectra are found to be well-modeled by density functional theory (DFT) calculations at the B3LYP/6-31G** level. We then compare DFT results for the deuterated and 13C18O-labeled peptide with those from spectroscopic maps developed and used previously by the Skinner group. We find that the maps are typically accurate to within a few cm-1 for both frequencies and couplings, having larger errors only for the frequencies of terminal amides.

Assessment of amide I spectroscopic maps for a gas-phase peptide using IR-UV double-resonance spectroscopy and density functional theory calculations

PubMed Central

Carr, J. K.; Zabuga, A. V.; Roy, S.; Rizzo, T. R.; Skinner, J. L.

2014-01-01

The spectroscopy of amide I vibrations has become a powerful tool for exploring protein structure and dynamics. To help with spectral interpretation, it is often useful to perform molecular dynamics (MD) simulations. To connect spectroscopic experiments to simulations in an efficient manner, several researchers have proposed “maps,” which relate observables in classical MD simulations to quantum spectroscopic variables. It can be difficult to discern whether errors in the theoretical results (compared to experiment) arise from inaccuracies in the MD trajectories or in the maps themselves. In this work, we evaluate spectroscopic maps independently from MD simulations by comparing experimental and theoretical spectra for a single conformation of the α-helical model peptide Ac-Phe-(Ala)5-Lys-H+ in the gas phase. Conformation-specific experimental spectra are obtained for the unlabeled peptide and for several singly and doubly 13C-labeled variants using infrared-ultraviolet double-resonance spectroscopy, and these spectra are found to be well-modeled by density functional theory (DFT) calculations at the B3LYP/6-31G** level. We then compare DFT results for the deuterated and 13C18O-labeled peptide with those from spectroscopic maps developed and used previously by the Skinner group. We find that the maps are typically accurate to within a few cm−1 for both frequencies and couplings, having larger errors only for the frequencies of terminal amides. PMID:24929378

Ligand Selectivity Mechanism and Conformational Changes in Guanine Riboswitch by Molecular Dynamics Simulations and Free Energy Calculations.

PubMed

Hu, Guodong; Ma, Aijing; Wang, Jihua

2017-04-24

Riboswitches regulate gene expression through direct and specific interactions with small metabolite molecules. Binding of a ligand to its RNA target is high selectivity and affinity and induces conformational changes of the RNA's secondary and tertiary structure. The structural difference of two purine riboswitches aptamers is caused by only one single mutation, where cytosine 74 in the guanine riboswitch is corresponding to a uracil 74 in adenine riboswitch. Here we employed molecular dynamics (MD) simulation, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and thermodynamic integration computational methodologies to evaluate the energetic and conformational changes of ligands binding to purine riboswitches. The snapshots used in MM-PBSA calculation were extracted from ten 50 ns MD simulation trajectories for each complex. These free energy results are in consistent with the experimental data and rationalize the selectivity of the riboswitches for different ligands. In particular, it is found that the loss in binding free energy upon mutation is mainly electrostatic in guanine (GUA) and riboswitch complex. Furthermore, new hydrogen bonds are found in mutated complexes. To reveal the conformational properties of guanine riboswitch, we performed a total of 6 μs MD simulations in both the presence and the absence of the ligand GUA. The MD simulations suggest that the conformation of guanine riboswitch depends on the distance of two groups in the binding pocket of ligand. The conformation is in a close conformation when U51-A52 is close to C74-U75.

Refined method for predicting electrochemical windows of ionic liquids and experimental validation studies.

PubMed

Zhang, Yong; Shi, Chaojun; Brennecke, Joan F; Maginn, Edward J

2014-06-12

A combined classical molecular dynamics (MD) and ab initio MD (AIMD) method was developed for the calculation of electrochemical windows (ECWs) of ionic liquids. In the method, the liquid phase of ionic liquid is explicitly sampled using classical MD. The electrochemical window, estimated by the energy difference between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), is calculated at the density functional theory (DFT) level based on snapshots obtained from classical MD trajectories. The snapshots were relaxed using AIMD and quenched to their local energy minima, which assures that the HOMO/LUMO calculations are based on stable configurations on the same potential energy surface. The new procedure was applied to a group of ionic liquids for which the ECWs were also experimentally measured in a self-consistent manner. It was found that the predicted ECWs not only agree with the experimental trend very well but also the values are quantitatively accurate. The proposed method provides an efficient way to compare ECWs of ionic liquids in the same context, which has been difficult in experiments or simulation due to the fact that ECW values sensitively depend on experimental setup and conditions.

Event detection and sub-state discovery from biomolecular simulations using higher-order statistics: application to enzyme adenylate kinase.

PubMed

Ramanathan, Arvind; Savol, Andrej J; Agarwal, Pratul K; Chennubhotla, Chakra S

2012-11-01

Biomolecular simulations at millisecond and longer time-scales can provide vital insights into functional mechanisms. Because post-simulation analyses of such large trajectory datasets can be a limiting factor in obtaining biological insights, there is an emerging need to identify key dynamical events and relating these events to the biological function online, that is, as simulations are progressing. Recently, we have introduced a novel computational technique, quasi-anharmonic analysis (QAA) (Ramanathan et al., PLoS One 2011;6:e15827), for partitioning the conformational landscape into a hierarchy of functionally relevant sub-states. The unique capabilities of QAA are enabled by exploiting anharmonicity in the form of fourth-order statistics for characterizing atomic fluctuations. In this article, we extend QAA for analyzing long time-scale simulations online. In particular, we present HOST4MD--a higher-order statistical toolbox for molecular dynamics simulations, which (1) identifies key dynamical events as simulations are in progress, (2) explores potential sub-states, and (3) identifies conformational transitions that enable the protein to access those sub-states. We demonstrate HOST4MD on microsecond timescale simulations of the enzyme adenylate kinase in its apo state. HOST4MD identifies several conformational events in these simulations, revealing how the intrinsic coupling between the three subdomains (LID, CORE, and NMP) changes during the simulations. Further, it also identifies an inherent asymmetry in the opening/closing of the two binding sites. We anticipate that HOST4MD will provide a powerful and extensible framework for detecting biophysically relevant conformational coordinates from long time-scale simulations. Copyright © 2012 Wiley Periodicals, Inc.

Long-time atomistic simulations with the Parallel Replica Dynamics method

NASA Astrophysics Data System (ADS)

Perez, Danny

Molecular Dynamics (MD) -- the numerical integration of atomistic equations of motion -- is a workhorse of computational materials science. Indeed, MD can in principle be used to obtain any thermodynamic or kinetic quantity, without introducing any approximation or assumptions beyond the adequacy of the interaction potential. It is therefore an extremely powerful and flexible tool to study materials with atomistic spatio-temporal resolution. These enviable qualities however come at a steep computational price, hence limiting the system sizes and simulation times that can be achieved in practice. While the size limitation can be efficiently addressed with massively parallel implementations of MD based on spatial decomposition strategies, allowing for the simulation of trillions of atoms, the same approach usually cannot extend the timescales much beyond microseconds. In this article, we discuss an alternative parallel-in-time approach, the Parallel Replica Dynamics (ParRep) method, that aims at addressing the timescale limitation of MD for systems that evolve through rare state-to-state transitions. We review the formal underpinnings of the method and demonstrate that it can provide arbitrarily accurate results for any definition of the states. When an adequate definition of the states is available, ParRep can simulate trajectories with a parallel speedup approaching the number of replicas used. We demonstrate the usefulness of ParRep by presenting different examples of materials simulations where access to long timescales was essential to access the physical regime of interest and discuss practical considerations that must be addressed to carry out these simulations. Work supported by the United States Department of Energy (U.S. DOE), Office of Science, Office of Basic Energy Sciences, Materials Sciences and Engineering Division.

Hydration free energies of cyanide and hydroxide ions from molecular dynamics simulations with accurate force fields

USGS Publications Warehouse

Lee, M.W.; Meuwly, M.

2013-01-01

The evaluation of hydration free energies is a sensitive test to assess force fields used in atomistic simulations. We showed recently that the vibrational relaxation times, 1D- and 2D-infrared spectroscopies for CN(-) in water can be quantitatively described from molecular dynamics (MD) simulations with multipolar force fields and slightly enlarged van der Waals radii for the C- and N-atoms. To validate such an approach, the present work investigates the solvation free energy of cyanide in water using MD simulations with accurate multipolar electrostatics. It is found that larger van der Waals radii are indeed necessary to obtain results close to the experimental values when a multipolar force field is used. For CN(-), the van der Waals ranges refined in our previous work yield hydration free energy between -72.0 and -77.2 kcal mol(-1), which is in excellent agreement with the experimental data. In addition to the cyanide ion, we also study the hydroxide ion to show that the method used here is readily applicable to similar systems. Hydration free energies are found to sensitively depend on the intermolecular interactions, while bonded interactions are less important, as expected. We also investigate in the present work the possibility of applying the multipolar force field in scoring trajectories generated using computationally inexpensive methods, which should be useful in broader parametrization studies with reduced computational resources, as scoring is much faster than the generation of the trajectories.

Controlling protein molecular dynamics: How to accelerate folding while preserving the native state

NASA Astrophysics Data System (ADS)

Jensen, Christian H.; Nerukh, Dmitry; Glen, Robert C.

2008-12-01

The dynamics of peptides and proteins generated by classical molecular dynamics (MD) is described by using a Markov model. The model is built by clustering the trajectory into conformational states and estimating transition probabilities between the states. Assuming that it is possible to influence the dynamics of the system by varying simulation parameters, we show how to use the Markov model to determine the parameter values that preserve the folded state of the protein and at the same time, reduce the folding time in the simulation. We investigate this by applying the method to two systems. The first system is an imaginary peptide described by given transition probabilities with a total folding time of 1μs. We find that only small changes in the transition probabilities are needed to accelerate (or decelerate) the folding. This implies that folding times for slowly folding peptides and proteins calculated using MD cannot be meaningfully compared to experimental results. The second system is a four residue peptide valine-proline-alanine-leucine in water. We control the dynamics of the transitions by varying the temperature and the atom masses. The simulation results show that it is possible to find the combinations of parameter values that accelerate the dynamics and at the same time preserve the native state of the peptide. A method for accelerating larger systems without performing simulations for the whole folding process is outlined.

Stabilities and Dynamics of Protein Folding Nuclei by Molecular Dynamics Simulation

NASA Astrophysics Data System (ADS)

Song, Yong-Shun; Zhou, Xin; Zheng, Wei-Mou; Wang, Yan-Ting

2017-07-01

To understand how the stabilities of key nuclei fragments affect protein folding dynamics, we simulate by molecular dynamics (MD) simulation in aqueous solution four fragments cut out of a protein G, including one α-helix (seqB: KVFKQYAN), two β-turns (seqA: LNGKTLKG and seqC: YDDATKTF), and one β-strand (seqD: DGEWTYDD). The Markov State Model clustering method combined with the coarse-grained conformation letters method are employed to analyze the data sampled from 2-μs equilibrium MD simulation trajectories. We find that seqA and seqB have more stable structures than their native structures which become metastable when cut out of the protein structure. As expected, seqD alone is flexible and does not have a stable structure. Throughout our simulations, the native structure of seqC is stable but cannot be reached if starting from a structure other than the native one, implying a funnel-shape free energy landscape of seqC in aqueous solution. All the above results suggest that different nuclei have different formation dynamics during protein folding, which may have a major contribution to the hierarchy of protein folding dynamics. Supported by the National Basic Research Program of China under Grant No. 2013CB932804, the National Natural Science Foundation of China under Grant No. 11421063, and the CAS Biophysics Interdisciplinary Innovation Team Project

Web-4D-QSAR: A web-based application to generate 4D-QSAR descriptors.

PubMed

Ataide Martins, João Paulo; Rougeth de Oliveira, Marco Antônio; Oliveira de Queiroz, Mário Sérgio

2018-06-05

A web-based application is developed to generate 4D-QSAR descriptors using the LQTA-QSAR methodology, based on molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package. The LQTAGrid module calculates the intermolecular interaction energies at each grid point, considering probes and all aligned conformations resulting from MD simulations. These interaction energies are the independent variables or descriptors employed in a QSAR analysis. A friendly front end web interface, built using the Django framework and Python programming language, integrates all steps of the LQTA-QSAR methodology in a way that is transparent to the user, and in the backend, GROMACS and LQTAGrid are executed to generate 4D-QSAR descriptors to be used later in the process of QSAR model building. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Gro2mat: a package to efficiently read gromacs output in MATLAB.

PubMed

Dien, Hung; Deane, Charlotte M; Knapp, Bernhard

2014-07-30

Molecular dynamics (MD) simulations are a state-of-the-art computational method used to investigate molecular interactions at atomic scale. Interaction processes out of experimental reach can be monitored using MD software, such as Gromacs. Here, we present the gro2mat package that allows fast and easy access to Gromacs output files from Matlab. Gro2mat enables direct parsing of the most common Gromacs output formats including the binary xtc-format. No openly available Matlab parser currently exists for this format. The xtc reader is orders of magnitudes faster than other available pdb/ascii workarounds. Gro2mat is especially useful for scientists with an interest in quick prototyping of new mathematical and statistical approaches for Gromacs trajectory analyses. © 2014 Wiley Periodicals, Inc. Copyright © 2014 Wiley Periodicals, Inc.

On the Dynamical Behavior of the Cysteine Dioxygenase-l-Cysteine Complex in the Presence of Free Dioxygen and l-Cysteine.

PubMed

Pietra, Francesco

2017-11-01

In this work, viable models of cysteine dioxygenase (CDO) and its complex with l-cysteine dianion were built for the first time, under strict adherence to the crystal structure from X-ray diffraction studies, for all atom molecular dynamics (MD). Based on the CHARMM36 FF, the active site, featuring an octahedral dummy Fe(II) model, allowed us observing water exchange, which would have escaped attention with the more popular bonded models. Free dioxygen (O 2 ) and l-cysteine, added at the active site, could be observed being expelled toward the solvating medium under Random Accelerated Molecular Dynamics (RAMD) along major and minor pathways. Correspondingly, free dioxygen (O 2 ), added to the solvating medium, could be observed to follow the same above pathways in getting to the active site under unbiased MD. For the bulky l-cysteine, 600 ns of trajectory were insufficient for protein penetration, and the molecule was stuck at the protein borders. These models pave the way to free energy studies of ligand associations, devised to better clarify how this cardinal enzyme behaves in human metabolism. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Locally enhanced sampling molecular dynamics study of the dioxygen transport in human cytoglobin.

PubMed

Orlowski, Slawomir; Nowak, Wieslaw

2007-07-01

Cytoglobin (Cyg)--a new member of the vertebrate heme globin family--is expressed in many tissues of the human body but its physiological role is still unclear. It may deliver oxygen under hypoxia, serve as a scavenger of reactive species or be involved in collagen synthesis. This protein is usually six-coordinated and binds oxygen by a displacement of the distal HisE7 imidazole. In this paper, the results of 60 ns molecular dynamics (MD) simulations of dioxygen diffusion inside Cyg matrix are discussed. In addition to a classical MD trajectory, an approximate Locally Enhanced Sampling (LES) method has been employed. Classical diffusion paths were carefully analyzed, five cavities in dynamical structures were determined and at least four distinct ligand exit paths were identified. The most probable exit/entry path is connected with a large tunnel present in Cyg. Several residues that are perhaps critical for kinetics of small gaseous diffusion were discovered. A comparison of gaseous ligand transport in Cyg and in the most studied heme protein myoglobin is presented. Implications of efficient oxygen transport found in Cyg to its possible physiological role are discussed.

Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations.

PubMed

Chen, Jianzhong; Yang, Maoyou; Hu, Guodong; Shi, Shuhua; Yi, Changhong; Zhang, Qinggang

2009-10-01

The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method combined with molecular dynamics (MD) simulations were used to investigate the functional role of protonation in human immunodeficiency virus type 1 (HIV-1) protease complexed with the inhibitor BEA369. Our results demonstrate that protonation of two aspartic acids (Asp25/Asp25') has a strong influence on the dynamics behavior of the complex, the binding free energy of BEA369, and inhibitor-residue interactions. Relative binding free energies calculated using the MM-PBSA method show that protonation of Asp25 results in the strongest binding of BEA369 to HIV-1 protease. Inhibitor-residue interactions computed by the theory of free energy decomposition also indicate that protonation of Asp25 has the most favorable effect on binding of BEA369. In addition, hydrogen-bond analysis based on the trajectories of the MD simulations shows that protonation of Asp25 strongly influences the water-mediated link of a conserved water molecule, Wat301. We expect that the results of this study will contribute significantly to binding calculations for BEA369, and to the design of high affinity inhibitors.

Investigation of Inhibition Mechanism of Chemokine Receptor CCR5 by Micro-second Molecular Dynamics Simulations.

PubMed

Salmas, Ramin Ekhteiari; Yurtsever, Mine; Durdagi, Serdar

2015-08-24

Chemokine receptor 5 (CCR5) belongs to G protein coupled receptors (GPCRs) and plays an important role in treatment of human immunodeficiency virus (HIV) infection since HIV uses CCR5 protein as a co-receptor. Recently, the crystal structure of CCR5-bound complex with an approved anti-retroviral drug (maroviroc) was resolved. During the crystallization procedure, amino acid residues (i.e., Cys224, Arg225, Asn226 and Glu227) at the third intra-cellular loop were replaced by the rubredoxin for stability reasons. In the current study, we aimed to understand the impact of the incorporated rubredoxin on the conformations of TM domains of the target protein. For this reason, rubredoxin was deleted from the crystal structure and the missing amino acids were engineered. The resultant structure was subjected to long (μs) molecular dynamics (MD) simulations to shed light into the inhibitory mechanism. The derived model structure displayed a significant deviation in the cytoplasmic domain of TM5 and IC3 in the absence of rubredoxin. The principal component analyses (PCA) and MD trajectory analyses revealed important structural and dynamical differences at apo and holo forms of the CCR5.

On the non-stationary generalized Langevin equation

NASA Astrophysics Data System (ADS)

Meyer, Hugues; Voigtmann, Thomas; Schilling, Tanja

2017-12-01

In molecular dynamics simulations and single molecule experiments, observables are usually measured along dynamic trajectories and then averaged over an ensemble ("bundle") of trajectories. Under stationary conditions, the time-evolution of such averages is described by the generalized Langevin equation. By contrast, if the dynamics is not stationary, it is not a priori clear which form the equation of motion for an averaged observable has. We employ the formalism of time-dependent projection operator techniques to derive the equation of motion for a non-equilibrium trajectory-averaged observable as well as for its non-stationary auto-correlation function. The equation is similar in structure to the generalized Langevin equation but exhibits a time-dependent memory kernel as well as a fluctuating force that implicitly depends on the initial conditions of the process. We also derive a relation between this memory kernel and the autocorrelation function of the fluctuating force that has a structure similar to a fluctuation-dissipation relation. In addition, we show how the choice of the projection operator allows us to relate the Taylor expansion of the memory kernel to data that are accessible in MD simulations and experiments, thus allowing us to construct the equation of motion. As a numerical example, the procedure is applied to Brownian motion initialized in non-equilibrium conditions and is shown to be consistent with direct measurements from simulations.

Extending molecular simulation time scales: Parallel in time integrations for high-level quantum chemistry and complex force representations

NASA Astrophysics Data System (ADS)

Bylaska, Eric J.; Weare, Jonathan Q.; Weare, John H.

2013-08-01

Parallel in time simulation algorithms are presented and applied to conventional molecular dynamics (MD) and ab initio molecular dynamics (AIMD) models of realistic complexity. Assuming that a forward time integrator, f (e.g., Verlet algorithm), is available to propagate the system from time ti (trajectory positions and velocities xi = (ri, vi)) to time ti + 1 (xi + 1) by xi + 1 = fi(xi), the dynamics problem spanning an interval from t0…tM can be transformed into a root finding problem, F(X) = [xi - f(x(i - 1)]i = 1, M = 0, for the trajectory variables. The root finding problem is solved using a variety of root finding techniques, including quasi-Newton and preconditioned quasi-Newton schemes that are all unconditionally convergent. The algorithms are parallelized by assigning a processor to each time-step entry in the columns of F(X). The relation of this approach to other recently proposed parallel in time methods is discussed, and the effectiveness of various approaches to solving the root finding problem is tested. We demonstrate that more efficient dynamical models based on simplified interactions or coarsening time-steps provide preconditioners for the root finding problem. However, for MD and AIMD simulations, such preconditioners are not required to obtain reasonable convergence and their cost must be considered in the performance of the algorithm. The parallel in time algorithms developed are tested by applying them to MD and AIMD simulations of size and complexity similar to those encountered in present day applications. These include a 1000 Si atom MD simulation using Stillinger-Weber potentials, and a HCl + 4H2O AIMD simulation at the MP2 level. The maximum speedup (serial execution time/parallel execution time) obtained by parallelizing the Stillinger-Weber MD simulation was nearly 3.0. For the AIMD MP2 simulations, the algorithms achieved speedups of up to 14.3. The parallel in time algorithms can be implemented in a distributed computing environment using very slow transmission control protocol/Internet protocol networks. Scripts written in Python that make calls to a precompiled quantum chemistry package (NWChem) are demonstrated to provide an actual speedup of 8.2 for a 2.5 ps AIMD simulation of HCl + 4H2O at the MP2/6-31G* level. Implemented in this way these algorithms can be used for long time high-level AIMD simulations at a modest cost using machines connected by very slow networks such as WiFi, or in different time zones connected by the Internet. The algorithms can also be used with programs that are already parallel. Using these algorithms, we are able to reduce the cost of a MP2/6-311++G(2d,2p) simulation that had reached its maximum possible speedup in the parallelization of the electronic structure calculation from 32 s/time step to 6.9 s/time step.

Extending molecular simulation time scales: Parallel in time integrations for high-level quantum chemistry and complex force representations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bylaska, Eric J.; Weare, Jonathan Q.; Weare, John H.

2013-08-21

Parallel in time simulation algorithms are presented and applied to conventional molecular dynamics (MD) and ab initio molecular dynamics (AIMD) models of realistic complexity. Assuming that a forward time integrator, f , (e.g. Verlet algorithm) is available to propagate the system from time ti (trajectory positions and velocities xi = (ri; vi)) to time ti+1 (xi+1) by xi+1 = fi(xi), the dynamics problem spanning an interval from t0 : : : tM can be transformed into a root finding problem, F(X) = [xi - f (x(i-1)]i=1;M = 0, for the trajectory variables. The root finding problem is solved using amore » variety of optimization techniques, including quasi-Newton and preconditioned quasi-Newton optimization schemes that are all unconditionally convergent. The algorithms are parallelized by assigning a processor to each time-step entry in the columns of F(X). The relation of this approach to other recently proposed parallel in time methods is discussed and the effectiveness of various approaches to solving the root finding problem are tested. We demonstrate that more efficient dynamical models based on simplified interactions or coarsening time-steps provide preconditioners for the root finding problem. However, for MD and AIMD simulations such preconditioners are not required to obtain reasonable convergence and their cost must be considered in the performance of the algorithm. The parallel in time algorithms developed are tested by applying them to MD and AIMD simulations of size and complexity similar to those encountered in present day applications. These include a 1000 Si atom MD simulation using Stillinger-Weber potentials, and a HCl+4H2O AIMD simulation at the MP2 level. The maximum speedup obtained by parallelizing the Stillinger-Weber MD simulation was nearly 3.0. For the AIMD MP2 simulations the algorithms achieved speedups of up to 14.3. The parallel in time algorithms can be implemented in a distributed computing environment using very slow TCP/IP networks. Scripts written in Python that make calls to a precompiled quantum chemistry package (NWChem) are demonstrated to provide an actual speedup of 8.2 for a 2.5 ps AIMD simulation of HCl+4H2O at the MP2/6-31G* level. Implemented in this way these algorithms can be used for long time high-level AIMD simulations at a modest cost using machines connected by very slow networks such as WiFi, or in different time zones connected by the Internet. The algorithms can also be used with programs that are already parallel. By using these algorithms we are able to reduce the cost of a MP2/6-311++G(2d,2p) simulation that had reached its maximum possible speedup in the parallelization of the electronic structure calculation from 32 seconds per time step to 6.9 seconds per time step.« less

Extending molecular simulation time scales: Parallel in time integrations for high-level quantum chemistry and complex force representations.

PubMed

Bylaska, Eric J; Weare, Jonathan Q; Weare, John H

2013-08-21

Parallel in time simulation algorithms are presented and applied to conventional molecular dynamics (MD) and ab initio molecular dynamics (AIMD) models of realistic complexity. Assuming that a forward time integrator, f (e.g., Verlet algorithm), is available to propagate the system from time ti (trajectory positions and velocities xi = (ri, vi)) to time ti + 1 (xi + 1) by xi + 1 = fi(xi), the dynamics problem spanning an interval from t0[ellipsis (horizontal)]tM can be transformed into a root finding problem, F(X) = [xi - f(x(i - 1)]i = 1, M = 0, for the trajectory variables. The root finding problem is solved using a variety of root finding techniques, including quasi-Newton and preconditioned quasi-Newton schemes that are all unconditionally convergent. The algorithms are parallelized by assigning a processor to each time-step entry in the columns of F(X). The relation of this approach to other recently proposed parallel in time methods is discussed, and the effectiveness of various approaches to solving the root finding problem is tested. We demonstrate that more efficient dynamical models based on simplified interactions or coarsening time-steps provide preconditioners for the root finding problem. However, for MD and AIMD simulations, such preconditioners are not required to obtain reasonable convergence and their cost must be considered in the performance of the algorithm. The parallel in time algorithms developed are tested by applying them to MD and AIMD simulations of size and complexity similar to those encountered in present day applications. These include a 1000 Si atom MD simulation using Stillinger-Weber potentials, and a HCl + 4H2O AIMD simulation at the MP2 level. The maximum speedup (serial execution/timeparallel execution time) obtained by parallelizing the Stillinger-Weber MD simulation was nearly 3.0. For the AIMD MP2 simulations, the algorithms achieved speedups of up to 14.3. The parallel in time algorithms can be implemented in a distributed computing environment using very slow transmission control protocol/Internet protocol networks. Scripts written in Python that make calls to a precompiled quantum chemistry package (NWChem) are demonstrated to provide an actual speedup of 8.2 for a 2.5 ps AIMD simulation of HCl + 4H2O at the MP2/6-31G* level. Implemented in this way these algorithms can be used for long time high-level AIMD simulations at a modest cost using machines connected by very slow networks such as WiFi, or in different time zones connected by the Internet. The algorithms can also be used with programs that are already parallel. Using these algorithms, we are able to reduce the cost of a MP2/6-311++G(2d,2p) simulation that had reached its maximum possible speedup in the parallelization of the electronic structure calculation from 32 s/time step to 6.9 s/time step.

Molecular dynamics simulations of cis-trans isomerization for a proline-containing tripeptide in solution

NASA Astrophysics Data System (ADS)

Wan, Shun Zhou; Wang, Cun Xin; Xu, Ying Wu; Shi, Yun Yu

1996-11-01

The cis-trans isomerization of X-Pro (X is Pro or any other residue) often plays a rate-limiting role in protein folding. In order to study the dynamic properties of X-Pro in water, we have analyzed the trajectory data obtained from constrained molecular dynamics (MD) simulations of a tripeptide Phe-Pro-Ala in solution. Via calculation of autocorrelation functions and their corresponding spectral densities, we have found that the structural fluctuations of the solute are affected by the motions of various degrees of freedom, and the solvent dynamic behavior is bimodal rather than exponential or Gaussian. In addition, according to the energy and torque analysis, we suggest that both the anti/endo and the syn/endo could be the possible transition state for the cis-trans isomerization of the tripeptide.

The solution structures of the cucumber mosaic virus and tomato aspermy virus coat proteins explored with molecular dynamics simulations.

PubMed

Gellért, Akos; Balázs, Ervin

2010-02-26

The three-dimensional structures of two cucumovirus coat proteins (CP), namely Cucumber mosaic virus (CMV) and Tomato aspermy virus (TAV), were explored by molecular dynamics (MD) simulations. The N-terminal domain and the C-terminal tail of the CPs proved to be intrinsically unstructured protein regions in aqueous solution. The N-terminal alpha-helix had a partially unrolled conformation. The thermal factor analysis of the CP loop regions demonstrated that the CMV CP had more flexible loop regions than the TAV CP. The principal component analysis (PCA) of the MD trajectories showed that the first three eigenvectors represented the three main conformational motions in the CPs. The first motion components with the highest variance contribution described an opening movement between the hinge and the N-terminal domain of both CPs. The second eigenvector showed a closing motion, while the third eigenvector represented crosswise conformational fluctuations. These new findings, together with previous results, suggest that the hinge region of CPs plays a central role in the recognition and binding of viral RNA. Copyright 2009 Elsevier Inc. All rights reserved.

A polarizable QM/MM approach to the molecular dynamics of amide groups solvated in water

NASA Astrophysics Data System (ADS)

Schwörer, Magnus; Wichmann, Christoph; Tavan, Paul

2016-03-01

The infrared (IR) spectra of polypeptides are dominated by the so-called amide bands. Because they originate from the strongly polar and polarizable amide groups (AGs) making up the backbone, their spectral positions sensitively depend on the local electric fields. Aiming at accurate computations of these IR spectra by molecular dynamics (MD) simulations, which derive atomic forces from a hybrid quantum and molecular mechanics (QM/MM) Hamiltonian, here we consider the effects of solvation in bulk liquid water on the amide bands of the AG model compound N-methyl-acetamide (NMA). As QM approach to NMA we choose grid-based density functional theory (DFT). For the surrounding MM water, we develop, largely based on computations, a polarizable molecular mechanics (PMM) model potential called GP6P, which features six Gaussian electrostatic sources (one induced dipole, five static partial charge distributions) and, therefore, avoids spurious distortions of the DFT electron density in hybrid DFT/PMM simulations. Bulk liquid GP6P is shown to have favorable properties at the thermodynamic conditions of the parameterization and beyond. Lennard-Jones (LJ) parameters of the DFT fragment NMA are optimized by comparing radial distribution functions in the surrounding GP6P liquid with reference data obtained from a "first-principles" DFT-MD simulation. Finally, IR spectra of NMA in GP6P water are calculated from extended DFT/PMM-MD trajectories, in which the NMA is treated by three different DFT functionals (BP, BLYP, B3LYP). Method-specific frequency scaling factors are derived from DFT-MD simulations of isolated NMA. The DFT/PMM-MD simulations with GP6P and with the optimized LJ parameters then excellently predict the effects of aqueous solvation and deuteration observed in the IR spectra of NMA. As a result, the methods required to accurately compute such spectra by DFT/PMM-MD also for larger peptides in aqueous solution are now at hand.

A polarizable QM/MM approach to the molecular dynamics of amide groups solvated in water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwörer, Magnus; Wichmann, Christoph; Tavan, Paul, E-mail: tavan@physik.uni-muenchen.de

2016-03-21

The infrared (IR) spectra of polypeptides are dominated by the so-called amide bands. Because they originate from the strongly polar and polarizable amide groups (AGs) making up the backbone, their spectral positions sensitively depend on the local electric fields. Aiming at accurate computations of these IR spectra by molecular dynamics (MD) simulations, which derive atomic forces from a hybrid quantum and molecular mechanics (QM/MM) Hamiltonian, here we consider the effects of solvation in bulk liquid water on the amide bands of the AG model compound N-methyl-acetamide (NMA). As QM approach to NMA we choose grid-based density functional theory (DFT). Formore » the surrounding MM water, we develop, largely based on computations, a polarizable molecular mechanics (PMM) model potential called GP6P, which features six Gaussian electrostatic sources (one induced dipole, five static partial charge distributions) and, therefore, avoids spurious distortions of the DFT electron density in hybrid DFT/PMM simulations. Bulk liquid GP6P is shown to have favorable properties at the thermodynamic conditions of the parameterization and beyond. Lennard-Jones (LJ) parameters of the DFT fragment NMA are optimized by comparing radial distribution functions in the surrounding GP6P liquid with reference data obtained from a “first-principles” DFT-MD simulation. Finally, IR spectra of NMA in GP6P water are calculated from extended DFT/PMM-MD trajectories, in which the NMA is treated by three different DFT functionals (BP, BLYP, B3LYP). Method-specific frequency scaling factors are derived from DFT-MD simulations of isolated NMA. The DFT/PMM-MD simulations with GP6P and with the optimized LJ parameters then excellently predict the effects of aqueous solvation and deuteration observed in the IR spectra of NMA. As a result, the methods required to accurately compute such spectra by DFT/PMM-MD also for larger peptides in aqueous solution are now at hand.« less

Correlations between dynamics and atomic structures in Cu64.5Zr35.5 metallic glass

NASA Astrophysics Data System (ADS)

Wang, C. Z.; Zhang, Y.; Zhang, F.; Mendelev, M. I.; Kramer, M. J.; Ho, K. M.

2015-03-01

The atomic structure of Cu-Zr metallic glasses (MGs) has been widely accepted to be heterogeneous and dominated by icosahedral short range order (ISRO). However, the correlations between dynamics and atomic structures in Cu-Zr MGs remain an enigma. Using molecular dynamics (MD) simulations, we investigated the correlations between dynamics and atomic structures in Cu64.5Zr35.5 MG. The atomic structures are characterized using ISRO and the Bergman-type medium range order (BMRO). The simulation and analysis results show that the majority of the mobile atoms are not involved in ISRO or BMRO, indicating that the dynamical heterogeneity has a strong correlation to structural heterogeneity. Moreover, we found that the localized soft vibration modes below 1.0 THz are mostly concentrated on the mobile atoms. The diffusion was studied using the atomic trajectory collected in an extended time interval of 1.2 μs at 700 K in MD simulations. It was found that the long range diffusion in MGs is highly heterogeneous, which is confined to the liquid-like regions and strongly avoids the ISRO and the Bergman-type MRO. All These results clearly demonstrate strong correlations between dynamics (in terms of dynamical heterogeneity and diffusion) and atomic structures in Cu64.5Zr35.5 MGs. This work was supported by the U.S. Department of Energy, Basic Energy Sciences, Division of Materials Science and Engineering under the Contract No. DE-AC02-07CH11358.

Traversing the folding pathway of proteins using temperature-aided cascade molecular dynamics with conformation-dependent charges.

PubMed

Jani, Vinod; Sonavane, Uddhavesh; Joshi, Rajendra

2016-07-01

Protein folding is a multi-micro second time scale event and involves many conformational transitions. Crucial conformational transitions responsible for biological functions of biomolecules are difficult to capture using current state-of-the-art molecular dynamics (MD) simulations. Protein folding, being a stochastic process, witnesses these transitions as rare events. Many new methodologies have been proposed for observing these rare events. In this work, a temperature-aided cascade MD is proposed as a technique for studying the conformational transitions. Folding studies for Engrailed homeodomain and Immunoglobulin domain B of protein A have been carried out. Using this methodology, the unfolded structures with RMSD of 20 Å were folded to a structure with RMSD of 2 Å. Three sets of cascade MD runs were carried out using implicit solvation, explicit solvation, and charge updation scheme. In the charge updation scheme, charges based on the conformation obtained are calculated and are updated in the topology file. In all the simulations, the structure of 2 Å was reached within a few nanoseconds using these methods. Umbrella sampling has been performed using snapshots from the temperature-aided cascade MD simulation trajectory to build an entire conformational transition pathway. The advantage of the method is that the possible pathways for a particular reaction can be explored within a short duration of simulation time and the disadvantage is that the knowledge of the start and end state is required. The charge updation scheme adds the polarization effects in the force fields. This improves the electrostatic interaction among the atoms, which may help the protein to fold faster.

Assessment of amide I spectroscopic maps for a gas-phase peptide using IR-UV double-resonance spectroscopy and density functional theory calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carr, J. K.; Roy, S.; Skinner, J. L.

2014-06-14

The spectroscopy of amide I vibrations has become a powerful tool for exploring protein structure and dynamics. To help with spectral interpretation, it is often useful to perform molecular dynamics (MD) simulations. To connect spectroscopic experiments to simulations in an efficient manner, several researchers have proposed “maps,” which relate observables in classical MD simulations to quantum spectroscopic variables. It can be difficult to discern whether errors in the theoretical results (compared to experiment) arise from inaccuracies in the MD trajectories or in the maps themselves. In this work, we evaluate spectroscopic maps independently from MD simulations by comparing experimental andmore » theoretical spectra for a single conformation of the α-helical model peptide Ac-Phe-(Ala){sub 5}-Lys-H{sup +} in the gas phase. Conformation-specific experimental spectra are obtained for the unlabeled peptide and for several singly and doubly {sup 13}C-labeled variants using infrared-ultraviolet double-resonance spectroscopy, and these spectra are found to be well-modeled by density functional theory (DFT) calculations at the B3LYP/6-31G** level. We then compare DFT results for the deuterated and {sup 13}C{sup 18}O-labeled peptide with those from spectroscopic maps developed and used previously by the Skinner group. We find that the maps are typically accurate to within a few cm{sup −1} for both frequencies and couplings, having larger errors only for the frequencies of terminal amides.« less

Microcanonical molecular simulations of methane hydrate nucleation and growth: evidence that direct nucleation to sI hydrate is among the multiple nucleation pathways.

PubMed

Zhang, Zhengcai; Walsh, Matthew R; Guo, Guang-Jun

2015-04-14

The results of six high-precision constant energy molecular dynamics (MD) simulations initiated from methane-water systems equilibrated at 80 MPa and 250 K indicate that methane hydrates can nucleate via multiple pathways. Five trajectories nucleate to an amorphous solid. One trajectory nucleates to a structure-I hydrate template with long-range order which spans the simulation box across periodic boundaries despite the presence of several defects. While experimental and simulation data for hydrate nucleation with different time- and length-scales suggest that there may exist multiple pathways for nucleation, including metastable intermediates and the direct formation of the globally-stable phase, this work provides the most compelling evidence that direct formation to the globally stable crystalline phase is one of the multiple pathways available for hydrate nucleation.

Patterns of cranial ontogeny in lacertid lizards: morphological and allometric disparity.

PubMed

Urošević, A; Ljubisavljević, K; Ivanović, A

2013-02-01

We explored the ontogenetic dynamics of the morphological and allometric disparity in the cranium shapes of twelve lacertid lizard species. The analysed species (Darevskia praticola, Dinarolacerta mosorensis, Iberolacerta horvathi, Lacerta agilis, L. trilineata, L. viridis, Podarcis erhardii, P. melisellensis, P. muralis, P. sicula, P. taurica and Zootoca vivipara) can be classified into different ecomorphs: terrestrial lizards that inhabit vegetated habitats (habitats with lush or sparse vegetation), saxicolous and shrub-climbing lizards. We observed that there was an overall increase in the morphological disparity (MD) during the ontogeny of the lacertid lizards. The ventral cranium, which is involved in the mechanics of jaw movement and feeding, showed higher levels of MD, an ontogenetic shift in the morphospace planes and more variable allometric patterns than more conserved dorsal crania. With respect to ecology, the allometric trajectories of the shrub-climbing species tended to cluster together, whereas the allometric trajectories of the saxicolous species were highly dispersed. Our results indicate that the ontogenetic patterns of morphological and allometric disparity in the lacertid lizards are modified by ecology and functional constraints and that the identical mechanisms that lead to intraspecific morphological variation also produce morphological divergence at higher taxonomic levels. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

Molecular dynamics simulations show altered secondary structure of clawless in binary complex with DNA providing insights into aristaless-clawless-DNA ternary complex formation.

PubMed

Kachhap, Sangita; Priyadarshini, Pragya; Singh, Balvinder

2017-05-01

Aristaless (Al) and clawless (Cll) homeodomains that are involved in leg development in Drosophila melanogaster are known to bind cooperatively to 5'-(T/C)TAATTAA(T/A)(T/A)G-3' DNA sequence, but the mechanism of their binding to DNA is unknown. Molecular dynamics (MD) studies have been carried out on binary, ternary, and reconstructed protein-DNA complexes involving Al, Cll, and DNA along with binding free energy analysis of these complexes. Analysis of MD trajectories of Cll-3A01, binary complex reveals that C-terminal end of helixIII of Cll, unwind in the absence of Al and remains so in reconstructed ternary complex, Cll-3A01-Al. In addition, this change in secondary structure of Cll does not allow it to form protein-protein interactions with Al in the ternary reconstructed complex. However, secondary structure of Cll and its interactions are maintained in other reconstructed ternary complex, Al-3A01-Cll where Cll binds to Al-3A01, binary complex to form ternary complex. These interactions as observed during MD simulations compare well with those observed in ternary crystal structure. Thus, this study highlights the role of helixIII of Cll and protein-protein interactions while proposing likely mechanism of recognition in ternary complex, Al-Cll-DNA.

Analysis of 15N-1H NMR relaxation in proteins by a combined experimental and molecular dynamics simulation approach: picosecond-nanosecond dynamics of the Rho GTPase binding domain of plexin-B1 in the dimeric state indicates allosteric pathways.

PubMed

Zerbetto, Mirco; Anderson, Ross; Bouguet-Bonnet, Sabine; Rech, Mariano; Zhang, Liqun; Meirovitch, Eva; Polimeno, Antonino; Buck, Matthias

2013-01-10

We investigate picosecond–nanosecond dynamics of the Rho-GTPase Binding Domain (RBD) of plexin-B1, which plays a key role in plexin-mediated cell signaling. Backbone 15N relaxation data of the dimeric RBD are analyzed with the model-free (MF) method, and with the slowly relaxing local structure/molecular dynamics (SRLS-MD) approach. Independent analysis of the MD trajectories, based on the MF paradigm, is also carried out. MF is a widely popular and simple method, SRLS is a general approach, and SRLS-MD is an integrated approach we developed recently. Corresponding parameters from the RBD dimer, a previously studied RBD monomer mutant, and the previously studied complex of the latter with the GTPase Rac1, are compared. The L2, L3, and L4 loops of the plexin-B1 RBD are involved in interactions with other plexin domains, GTPase binding, and RBD dimerization, respectively. Peptide groups in the loops of both the monomeric and dimeric RBD are found to experience weak and moderately asymmetric local ordering centered approximately at the C(i–1)(α)–C(i)(α) axes, and nanosecond backbone motion. Peptide groups in the α-helices and the β-strands of the dimer (the β-strands of the monomer) experience strong and highly asymmetric local ordering centered approximately at the C(i–1)(α)–C(i)(α) axes (N–H bonds). N–H fluctuations occur on the picosecond time scale. An allosteric pathway for GTPase binding, providing new insights into plexin function, is delineated.

Formulation of improved basis sets for the study of polymer dynamics through diffusion theory methods.

PubMed

Gaspari, Roberto; Rapallo, Arnaldo

2008-06-28

In this work a new method is proposed for the choice of basis functions in diffusion theory (DT) calculations. This method, named hybrid basis approach (HBA), combines the two previously adopted long time sorting procedure (LTSP) and maximum correlation approximation (MCA) techniques; the first emphasizing contributions from the long time dynamics, the latter being based on the local correlations along the chain. In order to fulfill this task, the HBA procedure employs a first order basis set corresponding to a high order MCA one and generates upper order approximations according to LTSP. A test of the method is made first on a melt of cis-1,4-polyisoprene decamers where HBA and LTSP are compared in terms of efficiency. Both convergence properties and numerical stability are improved by the use of the HBA basis set whose performance is evaluated on local dynamics, by computing the correlation times of selected bond vectors along the chain, and on global ones, through the eigenvalues of the diffusion operator L. Further use of the DT with a HBA basis set has been made on a 71-mer of syndiotactic trans-1,2-polypentadiene in toluene solution, whose dynamical properties have been computed with a high order calculation and compared to the "numerical experiment" provided by the molecular dynamics (MD) simulation in explicit solvent. The necessary equilibrium averages have been obtained by a vacuum trajectory of the chain where solvent effects on conformational properties have been reproduced with a proper screening of the nonbonded interactions, corresponding to a definite value of the mean radius of gyration of the polymer in vacuum. Results show a very good agreement between DT calculations and the MD numerical experiment. This suggests a further use of DT methods with the necessary input quantities obtained by the only knowledge of some experimental values, i.e., the mean radius of gyration of the chain and the viscosity of the solution, and by a suitable vacuum trajectory, with great savings in computational time required. This offers a theoretical bridge between the experimental static and dynamical properties of polymers.

Maternal depression and infant development: theory and current evidence.

PubMed

Miklush, Lisa; Connelly, Cynthia D

2013-01-01

Maternal depression (MD) is a condition that has wide-ranging effects on the woman, her family, and the broader global society. It is generally agreed that MD is associated with untoward effects on the developmental trajectory of offspring. The aim of this article is to review the historical and theoretical underpinnings informing current thought linking MD with infant development, and to highlight some of the neuroendocrine and epigenetic processes related to MD and its sequelae. A broad understanding of the association between MD and infant developmental outcomes can inform nursing care of the childbearing family.

A Model Comparison for Characterizing Protein Motions from Structure

NASA Astrophysics Data System (ADS)

David, Charles; Jacobs, Donald

2011-10-01

A comparative study is made using three computational models that characterize native state dynamics starting from known protein structures taken from four distinct SCOP classifications. A geometrical simulation is performed, and the results are compared to the elastic network model and molecular dynamics. The essential dynamics is quantified by a direct analysis of a mode subspace constructed from ANM and a principal component analysis on both the FRODA and MD trajectories using root mean square inner product and principal angles. Relative subspace sizes and overlaps are visualized using the projection of displacement vectors on the model modes. Additionally, a mode subspace is constructed from PCA on an exemplar set of X-ray crystal structures in order to determine similarly with respect to the generated ensembles. Quantitative analysis reveals there is significant overlap across the three model subspaces and the model independent subspace. These results indicate that structure is the key determinant for native state dynamics.

Molecular modeling studies of substrate binding by penicillin acylase.

PubMed

Chilov, G G; Stroganov, O V; Svedas, V K

2008-01-01

Molecular modeling has revealed intimate details of the mechanism of binding of natural substrate, penicillin G (PG), in the penicillin acylase active center and solved questions raised by analysis of available X-ray structures, mimicking Michaelis complex, which substantially differ in the binding pattern of the PG leaving group. Three MD trajectories were launched, starting from PDB complexes of the inactive mutant enzyme with PG (1FXV) and native penicillin acylase with sluggishly hydrolyzed substrate analog penicillin G sulfoxide (1GM9), or from the complex obtained by PG docking. All trajectories converged to a similar PG binding mode, which represented the near-to-attack conformation, consistent with chemical criteria of how reactive Michaelis complex should look. Simulated dynamic structure of the enzyme-substrate complex differed significantly from 1FXV, resembling rather 1GM9; however, additional contacts with residues bG385, bS386, and bN388 have been found, which were missing in X-ray structures. Combination of molecular docking and molecular dynamics also clarified the nature of extremely effective phenol binding in the hydrophobic pocket of penicillin acylase, which lacked proper explanation from crystallographic experiments. Alternative binding modes of phenol were probed, and corresponding trajectories converged to a single binding pattern characterized by a hydrogen bond between the phenol hydroxyl and the main chain oxygen of bS67, which was not evident from the crystal structure. Observation of the trajectory, in which phenol moved from its steady bound to pre-dissociation state, mapped the consequence of molecular events governing the conformational transitions in a coil region a143-a146 coupled to substrate binding and release of the reaction products. The current investigation provided information on dynamics of the conformational transitions accompanying substrate binding and significance of poorly structured and flexible regions in maintaining catalytic framework.

Post-processing interstitialcy diffusion from molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Bhardwaj, U.; Bukkuru, S.; Warrier, M.

2016-01-01

An algorithm to rigorously trace the interstitialcy diffusion trajectory in crystals is developed. The algorithm incorporates unsupervised learning and graph optimization which obviate the need to input extra domain specific information depending on crystal or temperature of the simulation. The algorithm is implemented in a flexible framework as a post-processor to molecular dynamics (MD) simulations. We describe in detail the reduction of interstitialcy diffusion into known computational problems of unsupervised clustering and graph optimization. We also discuss the steps, computational efficiency and key components of the algorithm. Using the algorithm, thermal interstitialcy diffusion from low to near-melting point temperatures is studied. We encapsulate the algorithms in a modular framework with functionality to calculate diffusion coefficients, migration energies and other trajectory properties. The study validates the algorithm by establishing the conformity of output parameters with experimental values and provides detailed insights for the interstitialcy diffusion mechanism. The algorithm along with the help of supporting visualizations and analysis gives convincing details and a new approach to quantifying diffusion jumps, jump-lengths, time between jumps and to identify interstitials from lattice atoms.

Post-processing interstitialcy diffusion from molecular dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhardwaj, U., E-mail: haptork@gmail.com; Bukkuru, S.; Warrier, M.

2016-01-15

An algorithm to rigorously trace the interstitialcy diffusion trajectory in crystals is developed. The algorithm incorporates unsupervised learning and graph optimization which obviate the need to input extra domain specific information depending on crystal or temperature of the simulation. The algorithm is implemented in a flexible framework as a post-processor to molecular dynamics (MD) simulations. We describe in detail the reduction of interstitialcy diffusion into known computational problems of unsupervised clustering and graph optimization. We also discuss the steps, computational efficiency and key components of the algorithm. Using the algorithm, thermal interstitialcy diffusion from low to near-melting point temperatures ismore » studied. We encapsulate the algorithms in a modular framework with functionality to calculate diffusion coefficients, migration energies and other trajectory properties. The study validates the algorithm by establishing the conformity of output parameters with experimental values and provides detailed insights for the interstitialcy diffusion mechanism. The algorithm along with the help of supporting visualizations and analysis gives convincing details and a new approach to quantifying diffusion jumps, jump-lengths, time between jumps and to identify interstitials from lattice atoms. -- Graphical abstract:.« less

Examining Summer Laboratory Research Apprenticeships for High School Students as a Factor in Entry to MD/PhD Programs at Matriculation

ERIC Educational Resources Information Center

Tai, Robert H.; Kong, Xiaoqing; Mitchell, Claire E.; Dabney, Katherine P.; Read, Daniel M.; Jeffe, Donna B.; Andriole, Dorothy A.; Wathington, Heather D.

2017-01-01

Do summer laboratory research apprenticeships during high school have an impact on entry into MD/PhD programs? Apart from the nearly decade-long span of time between high school and matriculation into an MD/PhD program, young people have many life-shaping experiences that presumably impact their education and career trajectories. This quantitative…

Decoding the Role of Water Dynamics in Ligand-Protein Unbinding: CRF1R as a Test Case.

PubMed

Bortolato, Andrea; Deflorian, Francesca; Weiss, Dahlia R; Mason, Jonathan S

2015-09-28

The residence time of a ligand-protein complex is a crucial aspect in determining biological effect in vivo. Despite its importance, the prediction of ligand koff still remains challenging for modern computational chemistry. We have developed aMetaD, a fast and generally applicable computational protocol to predict ligand-protein unbinding events using a molecular dynamics (MD) method based on adiabatic-bias MD and metadynamics. This physics-based, fully flexible, and pose-dependent ligand scoring function evaluates the maximum energy (RTscore) required to move the ligand from the bound-state energy basin to the next. Unbinding trajectories are automatically analyzed and translated into atomic solvation factor (SF) values representing the water dynamics during the unbinding event. This novel computational protocol was initially tested on two M3 muscarinic receptor and two adenosine A2A receptor antagonists and then evaluated on a test set of 12 CRF1R ligands. The resulting RTscores were used successfully to classify ligands with different residence times. Additionally, the SF analysis was used to detect key differences in the degree of accessibility to water molecules during the predicted ligand unbinding events. The protocol provides actionable working hypotheses that are applicable in a drug discovery program for the rational optimization of ligand binding kinetics.

Atomistic Simulations of High-intensity XFEL Pulses on Diffractive Imaging of Nano-sized System Dynamics

NASA Astrophysics Data System (ADS)

Ho, Phay; Knight, Christopher; Bostedt, Christoph; Young, Linda; Tegze, Miklos; Faigel, Gyula

2016-05-01

We have developed a large-scale atomistic computational method based on a combined Monte Carlo and Molecular Dynamics (MC/MD) method to simulate XFEL-induced radiation damage dynamics of complex materials. The MD algorithm is used to propagate the trajectories of electrons, ions and atoms forward in time and the quantum nature of interactions with an XFEL pulse is accounted for by a MC method to calculate probabilities of electronic transitions. Our code has good scalability with MPI/OpenMP parallelization, and it has been run on Mira, a petascale system at the Argonne Leardership Computing Facility, with particle number >50 million. Using this code, we have examined the impact of high-intensity 8-keV XFEL pulses on the x-ray diffraction patterns of argon clusters. The obtained patterns show strong pulse parameter dependence, providing evidence of significant lattice rearrangement and diffuse scattering. Real-space electronic reconstruction was performed using phase retrieval methods. We found that the structure of the argon cluster can be recovered with atomic resolution even in the presence of considerable radiation damage. This work was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, Chemical Sciences, Geosciences, and Biosciences Division.

Artificial neural networks for efficient clustering of conformational ensembles and their potential for medicinal chemistry.

PubMed

Pandini, Alessandro; Fraccalvieri, Domenico; Bonati, Laura

2013-01-01

The biological function of proteins is strictly related to their molecular flexibility and dynamics: enzymatic activity, protein-protein interactions, ligand binding and allosteric regulation are important mechanisms involving protein motions. Computational approaches, such as Molecular Dynamics (MD) simulations, are now routinely used to study the intrinsic dynamics of target proteins as well as to complement molecular docking approaches. These methods have also successfully supported the process of rational design and discovery of new drugs. Identification of functionally relevant conformations is a key step in these studies. This is generally done by cluster analysis of the ensemble of structures in the MD trajectory. Recently Artificial Neural Network (ANN) approaches, in particular methods based on Self-Organising Maps (SOMs), have been reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data-mining problems. In the specific case of conformational analysis, SOMs have been successfully used to compare multiple ensembles of protein conformations demonstrating a potential in efficiently detecting the dynamic signatures central to biological function. Moreover, examples of the use of SOMs to address problems relevant to other stages of the drug-design process, including clustering of docking poses, have been reported. In this contribution we review recent applications of ANN algorithms in analysing conformational and structural ensembles and we discuss their potential in computer-based approaches for medicinal chemistry.

Extending molecular simulation time scales: Parallel in time integrations for high-level quantum chemistry and complex force representations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bylaska, Eric J., E-mail: Eric.Bylaska@pnnl.gov; Weare, Jonathan Q., E-mail: weare@uchicago.edu; Weare, John H., E-mail: jweare@ucsd.edu

2013-08-21

Parallel in time simulation algorithms are presented and applied to conventional molecular dynamics (MD) and ab initio molecular dynamics (AIMD) models of realistic complexity. Assuming that a forward time integrator, f (e.g., Verlet algorithm), is available to propagate the system from time t{sub i} (trajectory positions and velocities x{sub i} = (r{sub i}, v{sub i})) to time t{sub i+1} (x{sub i+1}) by x{sub i+1} = f{sub i}(x{sub i}), the dynamics problem spanning an interval from t{sub 0}…t{sub M} can be transformed into a root finding problem, F(X) = [x{sub i} − f(x{sub (i−1})]{sub i} {sub =1,M} = 0, for themore » trajectory variables. The root finding problem is solved using a variety of root finding techniques, including quasi-Newton and preconditioned quasi-Newton schemes that are all unconditionally convergent. The algorithms are parallelized by assigning a processor to each time-step entry in the columns of F(X). The relation of this approach to other recently proposed parallel in time methods is discussed, and the effectiveness of various approaches to solving the root finding problem is tested. We demonstrate that more efficient dynamical models based on simplified interactions or coarsening time-steps provide preconditioners for the root finding problem. However, for MD and AIMD simulations, such preconditioners are not required to obtain reasonable convergence and their cost must be considered in the performance of the algorithm. The parallel in time algorithms developed are tested by applying them to MD and AIMD simulations of size and complexity similar to those encountered in present day applications. These include a 1000 Si atom MD simulation using Stillinger-Weber potentials, and a HCl + 4H{sub 2}O AIMD simulation at the MP2 level. The maximum speedup ((serial execution time)/(parallel execution time) ) obtained by parallelizing the Stillinger-Weber MD simulation was nearly 3.0. For the AIMD MP2 simulations, the algorithms achieved speedups of up to 14.3. The parallel in time algorithms can be implemented in a distributed computing environment using very slow transmission control protocol/Internet protocol networks. Scripts written in Python that make calls to a precompiled quantum chemistry package (NWChem) are demonstrated to provide an actual speedup of 8.2 for a 2.5 ps AIMD simulation of HCl + 4H{sub 2}O at the MP2/6-31G* level. Implemented in this way these algorithms can be used for long time high-level AIMD simulations at a modest cost using machines connected by very slow networks such as WiFi, or in different time zones connected by the Internet. The algorithms can also be used with programs that are already parallel. Using these algorithms, we are able to reduce the cost of a MP2/6-311++G(2d,2p) simulation that had reached its maximum possible speedup in the parallelization of the electronic structure calculation from 32 s/time step to 6.9 s/time step.« less

In silico FRET from simulated dye dynamics

NASA Astrophysics Data System (ADS)

Hoefling, Martin; Grubmüller, Helmut

2013-03-01

Single molecule fluorescence resonance energy transfer (smFRET) experiments probe molecular distances on the nanometer scale. In such experiments, distances are recorded from FRET transfer efficiencies via the Förster formula, E=1/(1+(). The energy transfer however also depends on the mutual orientation of the two dyes used as distance reporter. Since this information is typically inaccessible in FRET experiments, one has to rely on approximations, which reduce the accuracy of these distance measurements. A common approximation is an isotropic and uncorrelated dye orientation distribution. To assess the impact of such approximations, we present the algorithms and implementation of a computational toolkit for the simulation of smFRET on the basis of molecular dynamics (MD) trajectory ensembles. In this study, the dye orientation dynamics, which are used to determine dynamic FRET efficiencies, are extracted from MD simulations. In a subsequent step, photons and bursts are generated using a Monte Carlo algorithm. The application of the developed toolkit on a poly-proline system demonstrated good agreement between smFRET simulations and experimental results and therefore confirms our computational method. Furthermore, it enabled the identification of the structural basis of measured heterogeneity. The presented computational toolkit is written in Python, available as open-source, applicable to arbitrary systems and can easily be extended and adapted to further problems. Catalogue identifier: AENV_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AENV_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GPLv3, the bundled SIMD friendly Mersenne twister implementation [1] is provided under the SFMT-License. No. of lines in distributed program, including test data, etc.: 317880 No. of bytes in distributed program, including test data, etc.: 54774217 Distribution format: tar.gz Programming language: Python, Cython, C (ANSI C99). Computer: Any (see memory requirements). Operating system: Any OS with CPython distribution (e.g. Linux, MacOSX, Windows). Has the code been vectorised or parallelized?: Yes, in Ref. [2], 4 CPU cores were used. RAM: About 700MB per process for the simulation setup in Ref. [2]. Classification: 16.1, 16.7, 23. External routines: Calculation of Rκ2-trajectories from GROMACS [3] MD trajectories requires the GromPy Python module described in Ref. [4] or a GROMACS 4.6 installation. The md2fret program uses a standard Python interpreter (CPython) v2.6+ and < v3.0 as well as the NumPy module. The analysis examples require the Matplotlib Python module. Nature of problem: Simulation and interpretation of single molecule FRET experiments. Solution method: Combination of force-field based molecular dynamics (MD) simulating the dye dynamics and Monte Carlo sampling to obtain photon statistics of FRET kinetics. Additional comments: !!!!! The distribution file for this program is over 50 Mbytes and therefore is not delivered directly when download or Email is requested. Instead a html file giving details of how the program can be obtained is sent. !!!!! Running time: A single run in Ref. [2] takes about 10 min on a Quad Core Intel Xeon CPU W3520 2.67GHz with 6GB physical RAM References: [1] M. Saito, M. Matsumoto, SIMD-oriented fast Mersenne twister: a 128-bit pseudorandom number generator, in: A. Keller, S. Heinrich, H. Niederreiter (Eds.), Monte Carlo and Quasi-Monte Carlo Methods 2006, Springer; Berlin, Heidelberg, 2008, pp. 607-622. [2] M. Hoefling, N. Lima, D. Hänni, B. Schuler, C. A. M. Seidel, H. Grubmüller, Structural heterogeneity and quantitative FRET efficiency distributions of polyprolines through a hybrid atomistic simulation and Monte Carlo approach, PLoS ONE 6 (5) (2011) e19791. [3] D. V. D. Spoel, E. Lindahl, B. Hess, G. Groenhof, A. E. Mark, H. J. C. Berendsen, GROMACS: fast, flexible, and free., J Comput Chem 26 (16) (2005) 1701-1718. [4] R. Pool, A. Feenstra, M. Hoefling, R. Schulz, J. C. Smith, J. Heringa, Enabling grand-canonical Monte Carlo: Extending the flexibility of gromacs through the GromPy Python interface module, Journal of Chemical Theory and Computation 33 (12) (2012) 1207-1214.

Molecular dynamics simulation of phosphorylated KID post-translational modification.

PubMed

Chen, Hai-Feng

2009-08-05

Kinase-inducible domain (KID) as transcriptional activator can stimulate target gene expression in signal transduction by associating with KID interacting domain (KIX). NMR spectra suggest that apo-KID is an unstructured protein. After post-translational modification by phosphorylation, KID undergoes a transition from disordered to well folded protein upon binding to KIX. However, the mechanism of folding coupled to binding is poorly understood. To get an insight into the mechanism, we have performed ten trajectories of explicit-solvent molecular dynamics (MD) for both bound and apo phosphorylated KID (pKID). Ten MD simulations are sufficient to capture the average properties in the protein folding and unfolding. Room-temperature MD simulations suggest that pKID becomes more rigid and stable upon the KIX-binding. Kinetic analysis of high-temperature MD simulations shows that bound pKID and apo-pKID unfold via a three-state and a two-state process, respectively. Both kinetics and free energy landscape analyses indicate that bound pKID folds in the order of KIX access, initiation of pKID tertiary folding, folding of helix alpha(B), folding of helix alpha(A), completion of pKID tertiary folding, and finalization of pKID-KIX binding. Our data show that the folding pathways of apo-pKID are different from the bound state: the foldings of helices alpha(A) and alpha(B) are swapped. Here we also show that Asn139, Asp140 and Leu141 with large Phi-values are key residues in the folding of bound pKID. Our results are in good agreement with NMR experimental observations and provide significant insight into the general mechanisms of binding induced protein folding and other conformational adjustment in post-translational modification.

Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations.

PubMed

Hou, Tingjun; Wang, Junmei; Li, Youyong; Wang, Wei

2011-01-24

The Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) methods calculate binding free energies for macromolecules by combining molecular mechanics calculations and continuum solvation models. To systematically evaluate the performance of these methods, we report here an extensive study of 59 ligands interacting with six different proteins. First, we explored the effects of the length of the molecular dynamics (MD) simulation, ranging from 400 to 4800 ps, and the solute dielectric constant (1, 2, or 4) on the binding free energies predicted by MM/PBSA. The following three important conclusions could be observed: (1) MD simulation length has an obvious impact on the predictions, and longer MD simulation is not always necessary to achieve better predictions. (2) The predictions are quite sensitive to the solute dielectric constant, and this parameter should be carefully determined according to the characteristics of the protein/ligand binding interface. (3) Conformational entropy often show large fluctuations in MD trajectories, and a large number of snapshots are necessary to achieve stable predictions. Next, we evaluated the accuracy of the binding free energies calculated by three Generalized Born (GB) models. We found that the GB model developed by Onufriev and Case was the most successful model in ranking the binding affinities of the studied inhibitors. Finally, we evaluated the performance of MM/GBSA and MM/PBSA in predicting binding free energies. Our results showed that MM/PBSA performed better in calculating absolute, but not necessarily relative, binding free energies than MM/GBSA. Considering its computational efficiency, MM/GBSA can serve as a powerful tool in drug design, where correct ranking of inhibitors is often emphasized.

Prediction of Ordered Water Molecules in Protein Binding Sites from Molecular Dynamics Simulations: The Impact of Ligand Binding on Hydration Networks.

PubMed

Rudling, Axel; Orro, Adolfo; Carlsson, Jens

2018-02-26

Water plays a major role in ligand binding and is attracting increasing attention in structure-based drug design. Water molecules can make large contributions to binding affinity by bridging protein-ligand interactions or by being displaced upon complex formation, but these phenomena are challenging to model at the molecular level. Herein, networks of ordered water molecules in protein binding sites were analyzed by clustering of molecular dynamics (MD) simulation trajectories. Locations of ordered waters (hydration sites) were first identified from simulations of high resolution crystal structures of 13 protein-ligand complexes. The MD-derived hydration sites reproduced 73% of the binding site water molecules observed in the crystal structures. If the simulations were repeated without the cocrystallized ligands, a majority (58%) of the crystal waters in the binding sites were still predicted. In addition, comparison of the hydration sites obtained from simulations carried out in the absence of ligands to those identified for the complexes revealed that the networks of ordered water molecules were preserved to a large extent, suggesting that the locations of waters in a protein-ligand interface are mainly dictated by the protein. Analysis of >1000 crystal structures showed that hydration sites bridged protein-ligand interactions in complexes with different ligands, and those with high MD-derived occupancies were more likely to correspond to experimentally observed ordered water molecules. The results demonstrate that ordered water molecules relevant for modeling of protein-ligand complexes can be identified from MD simulations. Our findings could contribute to development of improved methods for structure-based virtual screening and lead optimization.

Domain Motion Enhanced (DoME) Model for Efficient Conformational Sampling of Multidomain Proteins.

PubMed

Kobayashi, Chigusa; Matsunaga, Yasuhiro; Koike, Ryotaro; Ota, Motonori; Sugita, Yuji

2015-11-19

Large conformational changes of multidomain proteins are difficult to simulate using all-atom molecular dynamics (MD) due to the slow time scale. We show that a simple modification of the structure-based coarse-grained (CG) model enables a stable and efficient MD simulation of those proteins. "Motion Tree", a tree diagram that describes conformational changes between two structures in a protein, provides information on rigid structural units (domains) and the magnitudes of domain motions. In our new CG model, which we call the DoME (domain motion enhanced) model, interdomain interactions are defined as being inversely proportional to the magnitude of the domain motions in the diagram, whereas intradomain interactions are kept constant. We applied the DoME model in combination with the Go model to simulations of adenylate kinase (AdK). The results of the DoME-Go simulation are consistent with an all-atom MD simulation for 10 μs as well as known experimental data. Unlike the conventional Go model, the DoME-Go model yields stable simulation trajectories against temperature changes and conformational transitions are easily sampled despite domain rigidity. Evidently, identification of domains and their interfaces is useful approach for CG modeling of multidomain proteins.

Accurate evaporation rates of pure and doped water clusters in vacuum: A statistico-dynamical approach

NASA Astrophysics Data System (ADS)

Calvo, F.; Douady, J.; Spiegelman, F.

2010-01-01

Unimolecular evaporation of selected pure (H2O)n and heterogeneous (H2O)n-1X+ water clusters containing a single hydronium or ammonium impurity is investigated in the framework of phase space theory (PST) in its orbiting transition state version. Using the many-body polarizable Kozack-Jordan potential and its extensions for X+=H3O+ and NH4+, the thermal evaporation of clusters containing 21 and 50 molecules is simulated at several total energies. Numerous molecular dynamics (MD) trajectories at high internal energies provide estimates of the decay rate constant, as well as the kinetic energy and angular momentum released upon dissociation. Additional Monte Carlo simulations are carried out to determine the anharmonic densities of vibrational states, which combined with suitable forms for the rotational densities of states provide expressions for the energy-resolved differential rates. Successful comparison between the MD results and the independent predictions of PST for the distributions of kinetic energy and angular momentum released shows that the latter statistical approach is quantitative. Using MD data as a reference, the absolute evaporation rates are calculated from PST over broad energy and temperature ranges. Based on these results, the presence of an ionic impurity is generally found to decrease the rate, however the effect is much more significant in the 21-molecule clusters. Our calculations also suggest that due to backbendings in the microcanonical densities of states the variations of the evaporation rates may not be strictly increasing with energy or temperature.

Observation of Complete Pressure-Jump Protein Refolding in Molecular Dynamics Simulation and Experiment

PubMed Central

2015-01-01

Density is an easily adjusted variable in molecular dynamics (MD) simulations. Thus, pressure-jump (P-jump)-induced protein refolding, if it could be made fast enough, would be ideally suited for comparison with MD. Although pressure denaturation perturbs secondary structure less than temperature denaturation, protein refolding after a fast P-jump is not necessarily faster than that after a temperature jump. Recent P-jump refolding experiments on the helix bundle λ-repressor have shown evidence of a <3 μs burst phase, but also of a ∼1.5 ms “slow” phase of refolding, attributed to non-native helical structure frustrating microsecond refolding. Here we show that a λ-repressor mutant is nonetheless capable of refolding in a single explicit solvent MD trajectory in about 19 μs, indicating that the burst phase observed in experiments on the same mutant could produce native protein. The simulation reveals that after about 18.5 μs of conformational sampling, the productive structural rearrangement to the native state does not occur in a single swift step but is spread out over a brief series of helix and loop rearrangements that take about 0.9 μs. Our results support the molecular time scale inferred for λ-repressor from near-downhill folding experiments, where transition-state population can be seen experimentally, and also agrees with the transition-state transit time observed in slower folding proteins by single-molecule spectroscopy. PMID:24437525

Nonadiabatic ab initio molecular dynamics with PME-ONIOM scheme of photoisomerization reaction between 1,3-cyclohexadiene and 1,3,5-cis-hexatriene in solution phase

NASA Astrophysics Data System (ADS)

Ohta, Ayumi; Kobayashi, Osamu; Danielache, Sebastian O.; Nanbu, Shinkoh

2017-03-01

The ultra-fast photoisomerization reactions between 1,3-cyclohexadiene (CHD) and 1,3,5-cis-hexatriene (HT) in both hexane and ethanol solvents were revealed by nonadiabatic ab initio molecular dynamics (AI-MD) with a particle-mesh Ewald summation method and our Own N-layered Integrated molecular Orbital and molecular Mechanics model (PME-ONIOM) scheme. Zhu-Nakamura version trajectory surface hopping method (ZN-TSH) was employed to treat the ultra-fast nonadiabatic decaying process. The results for hexane and ethanol simulations reasonably agree with experimental data. The high nonpolar-nonpolar affinity between CHD and the solvent was observed in hexane solvent, which definitely affected the excited state lifetimes, the product branching ratio of CHD:HT, and solute (CHD) dynamics. In ethanol solvent, however, the CHD solute was isomerized in the solvent cage caused by the first solvation shell. The photochemical dynamics in ethanol solvent results in the similar property to the process appeared in vacuo (isolated CHD dynamics).

Probing Carbohydrate Product Expulsion from a Processive Cellulase with Multiple Absolute Binding Free Energy Methods*

PubMed Central

Bu, Lintao; Beckham, Gregg T.; Shirts, Michael R.; Nimlos, Mark R.; Adney, William S.; Himmel, Michael E.; Crowley, Michael F.

2011-01-01

Understanding the enzymatic mechanism that cellulases employ to degrade cellulose is critical to efforts to efficiently utilize plant biomass as a sustainable energy resource. A key component of cellulase action on cellulose is product inhibition from monosaccharide and disaccharides in the product site of cellulase tunnel. The absolute binding free energy of cellobiose and glucose to the product site of the catalytic tunnel of the Family 7 cellobiohydrolase (Cel7A) of Trichoderma reesei (Hypocrea jecorina) was calculated using two different approaches: steered molecular dynamics (SMD) simulations and alchemical free energy perturbation molecular dynamics (FEP/MD) simulations. For the SMD approach, three methods based on Jarzynski's equality were used to construct the potential of mean force from multiple pulling trajectories. The calculated binding free energies, −14.4 kcal/mol using SMD and −11.2 kcal/mol using FEP/MD, are in good qualitative agreement. Analysis of the SMD pulling trajectories suggests that several protein residues (Arg-251, Asp-259, Asp-262, Trp-376, and Tyr-381) play key roles in cellobiose and glucose binding to the catalytic tunnel. Five mutations (R251A, D259A, D262A, W376A, and Y381A) were made computationally to measure the changes in free energy during the product expulsion process. The absolute binding free energies of cellobiose to the catalytic tunnel of these five mutants are −13.1, −6.0, −11.5, −7.5, and −8.8 kcal/mol, respectively. The results demonstrated that all of the mutants tested can lower the binding free energy of cellobiose, which provides potential applications in engineering the enzyme to accelerate the product expulsion process and improve the efficiency of biomass conversion. PMID:21454590

FATSLiM: a fast and robust software to analyze MD simulations of membranes.

PubMed

Buchoux, Sébastien

2017-01-01

When studying biological membranes, Molecular Dynamics (MD) simulations reveal to be quite complementary to experimental techniques. Because the simulated systems keep increasing both in size and complexity, the analysis of MD trajectories need to be computationally efficient while being robust enough to perform analysis on membranes that may be curved or deformed due to their size and/or protein-lipid interactions. This work presents a new software named FATSLiM ('Fast Analysis Toolbox for Simulations of Lipid Membranes') that can extract physical properties from MD simulations of membranes (with or without interacting proteins). Because it relies on the calculation of local normals, FATSLiM does not depend of the bilayer morphology and thus can handle with the same accuracy vesicles for instance. Thanks to an efficiency-driven development, it is also fast and consumes a rather low amount of memory. FATSLiM (http://fatslim.github.io) is a stand-alone software written in Python. Source code is released under the GNU GPLv3 and is freely available at https://github.com/FATSLiM/fatslim A complete online documentation including instructions for platform-independent installation is available at http://pythonhosted.org/fatslim CONTACT: sebastien.buchoux@u-picardie.frSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Modeling of molecular nitrogen collisions and dissociation processes for direct simulation Monte Carlo.

PubMed

Parsons, Neal; Levin, Deborah A; van Duin, Adri C T; Zhu, Tong

2014-12-21

The Direct Simulation Monte Carlo (DSMC) method typically used for simulating hypersonic Earth re-entry flows requires accurate total collision cross sections and reaction probabilities. However, total cross sections are often determined from extrapolations of relatively low-temperature viscosity data, so their reliability is unknown for the high temperatures observed in hypersonic flows. Existing DSMC reaction models accurately reproduce experimental equilibrium reaction rates, but the applicability of these rates to the strong thermal nonequilibrium observed in hypersonic shocks is unknown. For hypersonic flows, these modeling issues are particularly relevant for nitrogen, the dominant species of air. To rectify this deficiency, the Molecular Dynamics/Quasi-Classical Trajectories (MD/QCT) method is used to accurately compute collision and reaction cross sections for the N2(Σg+1)-N2(Σg+1) collision pair for conditions expected in hypersonic shocks using a new potential energy surface developed using a ReaxFF fit to recent advanced ab initio calculations. The MD/QCT-computed reaction probabilities were found to exhibit better physical behavior and predict less dissociation than the baseline total collision energy reaction model for strong nonequilibrium conditions expected in a shock. The MD/QCT reaction model compared well with computed equilibrium reaction rates and shock-tube data. In addition, the MD/QCT-computed total cross sections were found to agree well with established variable hard sphere total cross sections.

Perspectives in biological physics: the nDDB project for a neutron Dynamics Data Bank for biological macromolecules.

PubMed

Rusevich, Leonid; García Sakai, Victoria; Franzetti, Bruno; Johnson, Mark; Natali, Francesca; Pellegrini, Eric; Peters, Judith; Pieper, Jörg; Weik, Martin; Zaccai, Giuseppe

2013-07-01

Neutron spectroscopy provides experimental data on time-dependent trajectories, which can be directly compared to molecular dynamics simulations. Its importance in helping us to understand biological macromolecules at a molecular level is demonstrated by the results of a literature survey over the last two to three decades. Around 300 articles in refereed journals relate to neutron scattering studies of biological macromolecular dynamics, and the results of the survey are presented here. The scope of the publications ranges from the general physics of protein and solvent dynamics, to the biologically relevant dynamics-function relationships in live cells. As a result of the survey we are currently setting up a neutron Dynamics Data Bank (nDDB) with the aim to make the neutron data on biological systems widely available. This will benefit, in particular, the MD simulation community to validate and improve their force fields. The aim of the database is to expose and give easy access to a body of experimental data to the scientific community. The database will be populated with as much of the existing data as possible. In the future it will give value, as part of a bigger whole, to high throughput data, as well as more detailed studies. A range and volume of experimental data will be of interest in determining how quantitatively MD simulations can reproduce trends across a range of systems and to what extent such trends may depend on sample preparation and data reduction and analysis methods. In this context, we strongly encourage researchers in the field to deposit their data in the nDDB.

Efficient Characterization of Protein Cavities within Molecular Simulation Trajectories: trj_cavity.

PubMed

Paramo, Teresa; East, Alexandra; Garzón, Diana; Ulmschneider, Martin B; Bond, Peter J

2014-05-13

Protein cavities and tunnels are critical in determining phenomena such as ligand binding, molecular transport, and enzyme catalysis. Molecular dynamics (MD) simulations enable the exploration of the flexibility and conformational plasticity of protein cavities, extending the information available from static experimental structures relevant to, for example, drug design. Here, we present a new tool (trj_cavity) implemented within the GROMACS ( www.gromacs.org ) framework for the rapid identification and characterization of cavities detected within MD trajectories. trj_cavity is optimized for usability and computational efficiency and is applicable to the time-dependent analysis of any cavity topology, and optional specialized descriptors can be used to characterize, for example, protein channels. Its novel grid-based algorithm performs an efficient neighbor search whose calculation time is linear with system size, and a comparison of performance with other widely used cavity analysis programs reveals an orders-of-magnitude improvement in the computational cost. To demonstrate its potential for revealing novel mechanistic insights, trj_cavity has been used to analyze long-time scale simulation trajectories for three diverse protein cavity systems. This has helped to reveal, respectively, the lipid binding mechanism in the deep hydrophobic cavity of a soluble mite-allergen protein, Der p 2; a means for shuttling carbohydrates between the surface-exposed substrate-binding and catalytic pockets of a multidomain, membrane-proximal pullulanase, PulA; and the structural basis for selectivity in the transmembrane pore of a voltage-gated sodium channel (NavMs), embedded within a lipid bilayer environment. trj_cavity is available for download under an open-source license ( http://sourceforge.net/projects/trjcavity ). A simplified, GROMACS-independent version may also be compiled.

Multiscale molecular dynamics simulations of rotary motor proteins.

PubMed

Ekimoto, Toru; Ikeguchi, Mitsunori

2018-04-01

Protein functions require specific structures frequently coupled with conformational changes. The scale of the structural dynamics of proteins spans from the atomic to the molecular level. Theoretically, all-atom molecular dynamics (MD) simulation is a powerful tool to investigate protein dynamics because the MD simulation is capable of capturing conformational changes obeying the intrinsically structural features. However, to study long-timescale dynamics, efficient sampling techniques and coarse-grained (CG) approaches coupled with all-atom MD simulations, termed multiscale MD simulations, are required to overcome the timescale limitation in all-atom MD simulations. Here, we review two examples of rotary motor proteins examined using free energy landscape (FEL) analysis and CG-MD simulations. In the FEL analysis, FEL is calculated as a function of reaction coordinates, and the long-timescale dynamics corresponding to conformational changes is described as transitions on the FEL surface. Another approach is the utilization of the CG model, in which the CG parameters are tuned using the fluctuation matching methodology with all-atom MD simulations. The long-timespan dynamics is then elucidated straightforwardly by using CG-MD simulations.

Backbone hydration determines the folding signature of amino acid residues.

PubMed

Bignucolo, Olivier; Leung, Hoi Tik Alvin; Grzesiek, Stephan; Bernèche, Simon

2015-04-08

The relation between the sequence of a protein and its three-dimensional structure remains largely unknown. A lasting dream is to elucidate the side-chain-dependent driving forces that govern the folding process. Different structural data suggest that aromatic amino acids play a particular role in the stabilization of protein structures. To better understand the underlying mechanism, we studied peptides of the sequence EGAAXAASS (X = Gly, Ile, Tyr, Trp) through comparison of molecular dynamics (MD) trajectories and NMR residual dipolar coupling (RDC) measurements. The RDC data for aromatic substitutions provide evidence for a kink in the peptide backbone. Analysis of the MD simulations shows that the formation of internal hydrogen bonds underlying a helical turn is key to reproduce the experimental RDC values. The simulations further reveal that the driving force leading to such helical-turn conformations arises from the lack of hydration of the peptide chain on either side of the bulky aromatic side chain, which can potentially act as a nucleation point initiating the folding process.

Fragmentation network of doubly charged methionine: Interpretation using graph theory

NASA Astrophysics Data System (ADS)

Ha, D. T.; Yamazaki, K.; Wang, Y.; Alcamí, M.; Maeda, S.; Kono, H.; Martín, F.; Kukk, E.

2016-09-01

The fragmentation of doubly charged gas-phase methionine (HO2CCH(NH2)CH2CH2SCH3) is systematically studied using the self-consistent charge density functional tight-binding molecular dynamics (MD) simulation method. We applied graph theory to analyze the large number of the calculated MD trajectories, which appears to be a highly effective and convenient means of extracting versatile information from the large data. The present theoretical results strongly concur with the earlier studied experimental ones. Essentially, the dication dissociates into acidic group CO2H and basic group C4NSH10. The former may carry a single or no charge and stays intact in most cases, whereas the latter may hold either a single or a double charge and tends to dissociate into smaller fragments. The decay of the basic group is observed to follow the Arrhenius law. The dissociation pathways to CO2H and C4NSH10 and subsequent fragmentations are also supported by ab initio calculations.

A fast parallel clustering algorithm for molecular simulation trajectories.

PubMed

Zhao, Yutong; Sheong, Fu Kit; Sun, Jian; Sander, Pedro; Huang, Xuhui

2013-01-15

We implemented a GPU-powered parallel k-centers algorithm to perform clustering on the conformations of molecular dynamics (MD) simulations. The algorithm is up to two orders of magnitude faster than the CPU implementation. We tested our algorithm on four protein MD simulation datasets ranging from the small Alanine Dipeptide to a 370-residue Maltose Binding Protein (MBP). It is capable of grouping 250,000 conformations of the MBP into 4000 clusters within 40 seconds. To achieve this, we effectively parallelized the code on the GPU and utilize the triangle inequality of metric spaces. Furthermore, the algorithm's running time is linear with respect to the number of cluster centers. In addition, we found the triangle inequality to be less effective in higher dimensions and provide a mathematical rationale. Finally, using Alanine Dipeptide as an example, we show a strong correlation between cluster populations resulting from the k-centers algorithm and the underlying density. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

Structural dynamic analysis of apo and ATP-bound IRAK4 kinase

NASA Astrophysics Data System (ADS)

Gosu, Vijayakumar; Choi, Sangdun

2014-07-01

Interleukin-1 receptor-associated kinases (IRAKs) are Ser/Thr protein kinases that play an important role as signaling mediators in the signal transduction facilitated by the Toll-like receptor (TLR) and interleukin-1 receptor families. Among IRAK family members, IRAK4 is one of the drug targets for diseases related to the TLR and IL-1R signaling pathways. Experimental evidence suggests that the IRAK4 kinase domain is phosphorylated in its activation loop at T342, T345, and S346 in the fully activated state. However, the molecular interactions of subdomains within the active and inactive IRAK4 kinase domain are poorly understood. Hence, we employed a long-range molecular dynamics (MD) simulation to compare apo IRAK4 kinase domains (phosphorylated and unphosphorylated) and ATP-bound phosphorylated IRAK4 kinase domains. The MD results strongly suggested that lobe uncoupling occurs in apo unphosphorylated IRAK4 kinase via the disruption of the R334/T345 and R310/T345 interaction. In addition, apo unphosphorylated trajectory result in high mobility, particularly in the N lobe, activation segment, helix αG, and its adjoining loops. The Asp-Phe-Gly (DFG) and His-Arg-Asp (HRD) conserved kinase motif analysis showed the importance of these motifs in IRAK4 kinase activation. This study provides important information on the structural dynamics of IRAK4 kinase, which will aid in inhibitor development.

Brownian Dynamics Simulations of Ion Transport through the VDAC

PubMed Central

Lee, Kyu Il; Rui, Huan; Pastor, Richard W.; Im, Wonpil

2011-01-01

It is important to gain a physical understanding of ion transport through the voltage-dependent anion channel (VDAC) because this channel provides primary permeation pathways for metabolites and electrolytes between the cytosol and mitochondria. We performed grand canonical Monte Carlo/Brownian dynamics (GCMC/BD) simulations to explore the ion transport properties of human VDAC isoform 1 (hVDAC1; PDB:2K4T) embedded in an implicit membrane. When the MD-derived, space-dependent diffusion constant was used in the GCMC/BD simulations, the current-voltage characteristics and ion number profiles inside the pore showed excellent agreement with those calculated from all-atom molecular-dynamics (MD) simulations, thereby validating the GCMC/BD approach. Of the 20 NMR models of hVDAC1 currently available, the third one (NMR03) best reproduces both experimental single-channel conductance and ion selectivity (i.e., the reversal potential). In addition, detailed analyses of the ion trajectories, one-dimensional multi-ion potential of mean force, and protein charge distribution reveal that electrostatic interactions play an important role in the channel structure and ion transport relationship. Finally, the GCMC/BD simulations of various mutants based on NMR03 show good agreement with experimental ion selectivity. The difference in ion selectivity between the wild-type and the mutants is the result of altered potential of mean force profiles that are dominated by the electrostatic interactions. PMID:21281575

A novel approach of dynamic cross correlation analysis on molecular dynamics simulations and its application to Ets1 dimer-DNA complex.

PubMed

Kasahara, Kota; Fukuda, Ikuo; Nakamura, Haruki

2014-01-01

The dynamic cross correlation (DCC) analysis is a popular method for analyzing the trajectories of molecular dynamics (MD) simulations. However, it is difficult to detect correlative motions that appear transiently in only a part of the trajectory, such as atomic contacts between the side-chains of amino acids, which may rapidly flip. In order to capture these multi-modal behaviors of atoms, which often play essential roles, particularly at the interfaces of macromolecules, we have developed the "multi-modal DCC (mDCC)" analysis. The mDCC is an extension of the DCC and it takes advantage of a Bayesian-based pattern recognition technique. We performed MD simulations for molecular systems modeled from the (Ets1)2-DNA complex and analyzed their results with the mDCC method. Ets1 is an essential transcription factor for a variety of physiological processes, such as immunity and cancer development. Although many structural and biochemical studies have so far been performed, its DNA binding properties are still not well characterized. In particular, it is not straightforward to understand the molecular mechanisms how the cooperative binding of two Ets1 molecules facilitates their recognition of Stromelysin-1 gene regulatory elements. A correlation network was constructed among the essential atomic contacts, and the two major pathways by which the two Ets1 molecules communicate were identified. One is a pathway via direct protein-protein interactions and the other is that via the bound DNA intervening two recognition helices. These two pathways intersected at the particular cytosine bases (C110/C11), interacting with the H1, H2, and H3 helices. Furthermore, the mDCC analysis showed that both pathways included the transient interactions at their intermolecular interfaces of Tyr396-C11 and Ala327-Asn380 in multi-modal motions of the amino acid side chains and the nucleotide backbone. Thus, the current mDCC approach is a powerful tool to reveal these complicated behaviors and scrutinize intermolecular communications in a molecular system.

Two-phase thermodynamic model for efficient and accurate absolute entropy of water from molecular dynamics simulations.

PubMed

Lin, Shiang-Tai; Maiti, Prabal K; Goddard, William A

2010-06-24

Presented here is the two-phase thermodynamic (2PT) model for the calculation of energy and entropy of molecular fluids from the trajectory of molecular dynamics (MD) simulations. In this method, the density of state (DoS) functions (including the normal modes of translation, rotation, and intramolecular vibration motions) are determined from the Fourier transform of the corresponding velocity autocorrelation functions. A fluidicity parameter (f), extracted from the thermodynamic state of the system derived from the same MD, is used to partition the translation and rotation modes into a diffusive, gas-like component (with 3Nf degrees of freedom) and a nondiffusive, solid-like component. The thermodynamic properties, including the absolute value of entropy, are then obtained by applying quantum statistics to the solid component and applying hard sphere/rigid rotor thermodynamics to the gas component. The 2PT method produces exact thermodynamic properties of the system in two limiting states: the nondiffusive solid state (where the fluidicity is zero) and the ideal gas state (where the fluidicity becomes unity). We examine the 2PT entropy for various water models (F3C, SPC, SPC/E, TIP3P, and TIP4P-Ew) at ambient conditions and find good agreement with literature results obtained based on other simulation techniques. We also validate the entropy of water in the liquid and vapor phases along the vapor-liquid equilibrium curve from the triple point to the critical point. We show that this method produces converged liquid phase entropy in tens of picoseconds, making it an efficient means for extracting thermodynamic properties from MD simulations.

Linear Response Path Following: A Molecular Dynamics Method To Simulate Global Conformational Changes of Protein upon Ligand Binding.

PubMed

Tamura, Koichi; Hayashi, Shigehiko

2015-07-14

Molecular functions of proteins are often fulfilled by global conformational changes that couple with local events such as the binding of ligand molecules. High molecular complexity of proteins has, however, been an obstacle to obtain an atomistic view of the global conformational transitions, imposing a limitation on the mechanistic understanding of the functional processes. In this study, we developed a new method of molecular dynamics (MD) simulation called the linear response path following (LRPF) to simulate a protein's global conformational changes upon ligand binding. The method introduces a biasing force based on a linear response theory, which determines a local reaction coordinate in the configuration space that represents linear coupling between local events of ligand binding and global conformational changes and thus provides one with fully atomistic models undergoing large conformational changes without knowledge of a target structure. The overall transition process involving nonlinear conformational changes is simulated through iterative cycles consisting of a biased MD simulation with an updated linear response force and a following unbiased MD simulation for relaxation. We applied the method to the simulation of global conformational changes of the yeast calmodulin N-terminal domain and successfully searched out the end conformation. The atomistically detailed trajectories revealed a sequence of molecular events that properly lead to the global conformational changes and identified key steps of local-global coupling that induce the conformational transitions. The LRPF method provides one with a powerful means to model conformational changes of proteins such as motors and transporters where local-global coupling plays a pivotal role in their functional processes.

Will molecular dynamics simulations of proteins ever reach equilibrium?

PubMed

Genheden, Samuel; Ryde, Ulf

2012-06-28

We show that conformational entropies calculated for five proteins and protein-ligand complexes with dihedral-distribution histogramming, the von Mises approach, or quasi-harmonic analysis do not converge to any useful precision even if molecular dynamics (MD) simulations of 380-500 ns length are employed (the uncertainty is 12-89 kJ mol(-1)). To explain this, we suggest a simple protein model involving dihedrals with effective barriers forming a uniform distribution and show that for such a model, the entropy increases logarithmically with time until all significantly populated dihedral states have been sampled, in agreement with the simulations (during the simulations, 52-70% of the available dihedral phase space has been visited). This is also confirmed by the analysis of the trajectories of a 1 ms simulation of bovine pancreatic trypsin inhibitor (31 kJ mol(-1) difference in the entropy between the first and second part of the simulation). Strictly speaking, this means that it is practically impossible to equilibrate MD simulations of proteins. We discuss the implications of such a lack of strict equilibration of protein MD simulations and show that ligand-binding free energies estimated with the MM/GBSA method (molecular mechanics with generalised Born and surface-area solvation) vary by 3-15 kJ mol(-1) during a 500 ns simulation (the higher estimate is caused by rare conformational changes), although they involve a questionable but well-converged normal-mode entropy estimate, whereas free energies estimated by free-energy perturbation vary by less than 0.6 kJ mol(-1) for the same simulation.

Structural basis of transport function in major facilitator superfamily protein from Trichoderma harzianum.

PubMed

Chaudhary, Nitika; Sandhu, Padmani; Ahmed, Mushtaq; Akhter, Yusuf

2017-02-01

Trichothecenes are the sesquiterpenes secreted by Trichoderma spp. residing in the rhizosphere. These compounds have been reported to act as plant growth promoters and bio-control agents. The structural knowledge for the transporter proteins of their efflux remained limited. In this study, three-dimensional structure of Thmfs1 protein, a trichothecene transporter from Trichoderma harzianum, was homology modelled and further Molecular Dynamics (MD) simulations were used to decipher its mechanism. Fourteen transmembrane helices of Thmfs1 protein are observed contributing to an inward-open conformation. The transport channel and ligand binding sites in Thmfs1 are identified based on heuristic, iterative algorithm and structural alignment with homologous proteins. MD simulations were performed to reveal the differential structural behaviour occurring in the ligand free and ligand bound forms. We found that two discrete trichothecene binding sites are located on either side of the central transport tunnel running from the cytoplasmic side to the extracellular side across the Thmfs1 protein. Detailed analysis of the MD trajectories showed an alternative access mechanism between N and C-terminal domains contributing to its function. These results also demonstrate that the transport of trichodermin occurs via hopping mechanism in which the substrate molecule jumps from one binding site to another lining the transport tunnel. Copyright © 2016 Elsevier B.V. All rights reserved.

QM/MD studies on graphene growth from small islands on the Ni(111) surface

NASA Astrophysics Data System (ADS)

Jiao, Menggai; Song, Wei; Qian, Hu-Jun; Wang, Ying; Wu, Zhijian; Irle, Stephan; Morokuma, Keiji

2016-01-01

Quantum chemical molecular dynamics simulations of graphene growth from small island precursors in different carbon nucleation densities on the Ni(111) surface at high temperatures have been conducted. The results indicate that small islands are not static, i.e. lateral diffusion and vertical fluctuation are frequently observed. In the case of low carbon nucleation density, carbon atoms or small carbon patches diffuse and attach to the edge of the nuclei to expand the size of the growing carbon network. The growth of graphene precursors is accompanied by the corresponding changes in the bonding of nickel atoms with the precipitation of subsurface carbon atoms. This is because the carbon-carbon interaction is stronger than the nickel-carbon interaction. In the case of high carbon nucleation densities, the dominant ripening mechanism depends on different growth stages. In the initial stage, the coalescence of carbon islands takes place via the Smoluchowski ripening mechanism. In the later stage the Smoluchowski ripening process is damped owing to the higher diffusion barrier of larger clusters and the restriction of movement by self-assembled nickel step edges. The cross-linking mechanism eventually takes over by the coalescence of extended polyyne chains between graphene islands. In either case, the Ostwald ripening process is not found in our molecular dynamics simulations due to the stability of carbon-carbon bonds within the islands. These investigations should be instructive to the control of graphene growth in experiments.Quantum chemical molecular dynamics simulations of graphene growth from small island precursors in different carbon nucleation densities on the Ni(111) surface at high temperatures have been conducted. The results indicate that small islands are not static, i.e. lateral diffusion and vertical fluctuation are frequently observed. In the case of low carbon nucleation density, carbon atoms or small carbon patches diffuse and attach to the edge of the nuclei to expand the size of the growing carbon network. The growth of graphene precursors is accompanied by the corresponding changes in the bonding of nickel atoms with the precipitation of subsurface carbon atoms. This is because the carbon-carbon interaction is stronger than the nickel-carbon interaction. In the case of high carbon nucleation densities, the dominant ripening mechanism depends on different growth stages. In the initial stage, the coalescence of carbon islands takes place via the Smoluchowski ripening mechanism. In the later stage the Smoluchowski ripening process is damped owing to the higher diffusion barrier of larger clusters and the restriction of movement by self-assembled nickel step edges. The cross-linking mechanism eventually takes over by the coalescence of extended polyyne chains between graphene islands. In either case, the Ostwald ripening process is not found in our molecular dynamics simulations due to the stability of carbon-carbon bonds within the islands. These investigations should be instructive to the control of graphene growth in experiments. Electronic supplementary information (ESI) available: There are two movies showing the simulation process and they are provided in separate files. Movie S1 is the evolution of QM/MD simulations of the growth of graphene from one C13 on the Ni(111) surface for trajectory D@C13. Movie S2 is the evolution of QM/MD simulations of the growth of graphene from two C13 species on the Ni(111) surface for trajectory C@2C13. Fig. S1 shows the optimized geometries of C13-G and C13-H on the Ni(111) surface. Fig. S2 is the final structures of trajectories A-J@C13 following 400 ps QM/MD simulation for the Ni(111) + C13 system. Fig. S3 is the final structures of trajectories A-J@2C13 following 350 ps QM/MD simulation for the Ni(111) + 2C13 system. Fig. S4 shows average polygonal carbon ring populations formed during graphene growth from the Ni(111) + C13 and Ni(111) + 2C13 systems. Fig. S5 shows the averaged δ value of the C13 clusters and the nickel catalyst in the Ni(111) + C13 and Ni(111) + 2C13 systems. Fig. S6 depicts the total Mermin free energy as a function of simulation time in the Ni(111) + 2C13 system. See DOI: 10.1039/c5nr07680c

Structural Insights into σ₁ Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations.

PubMed

Kurciński, Mateusz; Jarończyk, Małgorzata; Lipiński, Piotr F J; Dobrowolski, Jan Cz; Sadlej, Joanna

2018-02-18

Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ₁ receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ₁ receptor has made elucidating the structure-activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ₁ receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor-ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue-ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands' affinities toward the σ₁ receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand-receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol.

The effects of the L29F mutation on the ligand migration kinetics in crystallized myoglobin as revealed by molecular dynamics simulations.

PubMed

Anselmi, Massimiliano; Di Nola, Alfredo; Amadei, Andrea

2011-03-01

By using multiple molecular dynamics (MD) trajectories, a quantitative description of carbon monoxide (CO) migration within crystal of L29F myoglobin mutant (L29F-Mb) was obtained. The aim was to provide a detailed model for ligand diffusion in the protein to be compared to the available L29F-Mb experimental-computational data and to the corresponding model kinetics we previously obtained for photolyzed CO within crystallized wild-type myoglobin (wt-Mb). Results suggest a clear migration pathway from distal pocket to the proximal site, similar to the one observed in wt-Mb, with a relaxation kinetics differing from the wt-Mb one essentially for the escape rate which is much higher in the mutant. Moreover MD data indicated a clear correlation between CO location within the protein and the conformation adopted by Phe29, well matching the available experimental data as obtained by time-resolved X-ray density maps. Such data, further validating the model used in the simulations, point out the subtle mutual effect between ligand diffusion and protein functional motions possibly explaining the observed dramatic variation of CO exit rate in L29F-Mb. Copyright © 2010 Wiley-Liss, Inc.

Identification of a new binding site in E. coli FabH using Molecular dynamics simulations: validation by computational alanine mutagenesis and docking studies.

PubMed

Ramamoorthy, Divya; Turos, Edward; Guida, Wayne C

2013-05-24

FabH (Fatty acid biosynthesis, enzyme H, also referred to as β-ketoacyl-ACP-synthase III) is a key condensing enzyme in the type II fatty acid synthesis (FAS) system. The FAS pathway in bacteria is essential for growth and survival and vastly differs from the human FAS pathway. Enzymes involved in this pathway have arisen as promising biomolecular targets for discovery of new antibacterial drugs. However, currently there are no clinical drugs that selectively target FabH, and known inhibitors of FabH all act within the active site. FabH exerts its catalytic function as a dimer, which could potentially be exploited in developing new strategies for inhibitor design. The aim of this study was to elucidate structural details of the dimer interface region by means of computational modeling, including molecular dynamics (MD) simulations, in order to derive information for the structure-based design of new FabH inhibitors. The dimer interface region was analyzed by MD simulations, trajectory snapshots were collected for further analyses, and docking studies were performed with potential small molecule disruptors. Alanine mutation and docking studies strongly suggest that the dimer interface could be a potential target for anti-infection drug discovery.

The Impact of a Ligand Binding on Strand Migration in the SAM-I Riboswitch

PubMed Central

Huang, Wei; Kim, Joohyun; Jha, Shantenu; Aboul-ela, Fareed

2013-01-01

Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule (<500 MW) binding to a limited surface can trigger a large scale conformational rearrangement in a 40 kDa RNA by perturbing the Free Energy Landscape. Such a mechanism can explain minimal requirements for SAM binding and transcription termination for SAM-I riboswitches previously reported experimentally. PMID:23704854

Adaptive sampling strategies with high-throughput molecular dynamics

NASA Astrophysics Data System (ADS)

Clementi, Cecilia

Despite recent significant hardware and software developments, the complete thermodynamic and kinetic characterization of large macromolecular complexes by molecular simulations still presents significant challenges. The high dimensionality of these systems and the complexity of the associated potential energy surfaces (creating multiple metastable regions connected by high free energy barriers) does not usually allow to adequately sample the relevant regions of their configurational space by means of a single, long Molecular Dynamics (MD) trajectory. Several different approaches have been proposed to tackle this sampling problem. We focus on the development of ensemble simulation strategies, where data from a large number of weakly coupled simulations are integrated to explore the configurational landscape of a complex system more efficiently. Ensemble methods are of increasing interest as the hardware roadmap is now mostly based on increasing core counts, rather than clock speeds. The main challenge in the development of an ensemble approach for efficient sampling is in the design of strategies to adaptively distribute the trajectories over the relevant regions of the systems' configurational space, without using any a priori information on the system global properties. We will discuss the definition of smart adaptive sampling approaches that can redirect computational resources towards unexplored yet relevant regions. Our approaches are based on new developments in dimensionality reduction for high dimensional dynamical systems, and optimal redistribution of resources. NSF CHE-1152344, NSF CHE-1265929, Welch Foundation C-1570.

PyContact: Rapid, Customizable, and Visual Analysis of Noncovalent Interactions in MD Simulations.

PubMed

Scheurer, Maximilian; Rodenkirch, Peter; Siggel, Marc; Bernardi, Rafael C; Schulten, Klaus; Tajkhorshid, Emad; Rudack, Till

2018-02-06

Molecular dynamics (MD) simulations have become ubiquitous in all areas of life sciences. The size and model complexity of MD simulations are rapidly growing along with increasing computing power and improved algorithms. This growth has led to the production of a large amount of simulation data that need to be filtered for relevant information to address specific biomedical and biochemical questions. One of the most relevant molecular properties that can be investigated by all-atom MD simulations is the time-dependent evolution of the complex noncovalent interaction networks governing such fundamental aspects as molecular recognition, binding strength, and mechanical and structural stability. Extracting, evaluating, and visualizing noncovalent interactions is a key task in the daily work of structural biologists. We have developed PyContact, an easy-to-use, highly flexible, and intuitive graphical user interface-based application, designed to provide a toolkit to investigate biomolecular interactions in MD trajectories. PyContact is designed to facilitate this task by enabling identification of relevant noncovalent interactions in a comprehensible manner. The implementation of PyContact as a standalone application enables rapid analysis and data visualization without any additional programming requirements, and also preserves full in-program customization and extension capabilities for advanced users. The statistical analysis representation is interactively combined with full mapping of the results on the molecular system through the synergistic connection between PyContact and VMD. We showcase the capabilities and scientific significance of PyContact by analyzing and visualizing in great detail the noncovalent interactions underlying the ion permeation pathway of the human P2X 3 receptor. As a second application, we examine the protein-protein interaction network of the mechanically ultrastable cohesin-dockering complex. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Multiscale simulations of PS-SiO2 nanocomposites: from melt to glassy state.

PubMed

Mathioudakis, I G; Vogiatzis, G G; Tzoumanekas, C; Theodorou, D N

2016-09-28

The interaction energetics, molecular packing, entanglement network properties, segmental dynamics, and elastic constants of atactic polystyrene-amorphous silica nanocomposites in the molten and the glassy state are studied via molecular simulations using two interconnected levels of representation: (a) a coarse-grained one, wherein each polystyrene repeat unit is mapped onto a single "superatom" and the silica nanoparticle is viewed as a solid sphere. Equilibration at all length scales at this level is achieved via connectivity-altering Monte Carlo simulations. (b) A united-atom (UA) level, wherein the polymer chains are represented in terms of a united-atom forcefield and the silica nanoparticle is represented in terms of a simplified, fully atomistic model. Initial configurations for UA molecular dynamics (MD) simulations are obtained by reverse mapping well-equilibrated coarse-grained configurations. By analysing microcanonical UA MD trajectories, the polymer density profile is studied and the polymer is found to exhibit layering in the vicinity of the nanoparticle surface. An estimate of the enthalpy of mixing between polymer and nanoparticles, derived from the UA simulations, compares favourably against available experimental values. The dynamical behaviour of polystyrene (in neat and filled melt systems) is characterized in terms of bond orientation and dihedral angle time autocorrelation functions. At low concentration in the molten polymer matrix, silica nanoparticles are found to cause a slight deceleration of the segmental dynamics close to their surface compared to the bulk polymer. Well-equilibrated coarse-grained long-chain configurations are reduced to entanglement networks via topological analysis with the CReTA algorithm, yielding a slightly lower density of entanglements in the filled than in the neat systems. UA melt configurations are glassified by MD cooling. The elastic moduli of the resulting glassy nanocomposites are computed through an analysis of strain fluctuations in the undeformed state and through explicit mechanical deformation by MD, showing a stiffening of the polymer in the presence of nanoparticles. UA simulation results for the elastic constants are compared to continuum micromechanical calculations invoked in homogenization models of the overall mechanical behaviour of heterogeneous materials. They can be interpreted in terms of the presence of an "interphase" of approximate thickness 2 nm around the nanoparticles, with elastic constants intermediate between those of the filler and the matrix.

Protein Folding Simulations Combining Self-Guided Langevin Dynamics and Temperature-Based Replica Exchange

DTIC Science & Technology

2010-01-01

formulations of molecular dynamics (MD) and Langevin dynamics (LD) simulations for the prediction of thermodynamic folding observables of the Trp-cage...ad hoc force term in the SGLD model. Introduction Molecular dynamics (MD) simulations of small proteins provide insight into the mechanisms and... molecular dynamics (MD) and Langevin dynamics (LD) simulations for the prediction of thermodynamic folding observables of the Trp-cage mini-protein. All

Molecular dynamic simulation of Trastuzumab F(ab’)2 structure in corporation with HER2 as a theranostic agent of breast cancer

NASA Astrophysics Data System (ADS)

Hermanto, S.; Yusuf, M.; Mutalib, A.; Hudiyono, S.

2017-05-01

Trastuzumab as intact IgG are well researched for theranostic agent in HER2 overexpressed breast cancer. However, due to the relatively large of molecules it is slowly moved and weak penetration of the target cells. Fragmentation of trastzumab has been developed by pepsin cleavages to get the F(ab’)2 fragments. To observe the stability and accessibility of F(ab’)2 structure in corporation with HER2 (human epidermal growth factor receptor-2), the structure of antibody modeling had been developed with 1IGT as a template. Molecular dynamics (MD) of the F(ab’)2 structure simulation has been done in the aqueous phase with AMBER trajectories for 20 ns. Computational visualization by VMD (Visual Molecular Dynamics) were applied to identify binding site interaction details between trastuzumab F(ab’)2 and HER2 receptor. The results of MD simulations indicated that the fragmentation of trastuzumab F(ab’)2 did not change the structure and conformation of F(ab’)2 as a whole, especially in the CDR (Complementarity Determining Region) area. SASA (solvent accessibility surface area) analysis on lysine residues showed that formation of conjugate DOTA-F(ab’)2 predicted occur on outside of the CDR regions so its not interfered with binding affinity for the HER2 receptor. The molecular dynamic simulation of DOTA-F(ab’)2 with HER2 receptor in aqueous system generated ΔGbinding more highly (15.5066 kkal/mol) than positive control HER2-Fab (-45.1446 kkal/mol).

Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling

NASA Astrophysics Data System (ADS)

Pérez-Castillo, Yunierkis; Froeyen, Matheus; Cabrera-Pérez, Miguel Ángel; Nowé, Ann

2011-04-01

Bacterial β-ketoacyl-acyl carrier protein synthase III (FabH) has become an attractive target for the development of new antibacterial agents which can overcome the increased resistance of these pathogens to antibiotics in clinical use. Despite several efforts have been dedicated to find inhibitors for this enzyme, it is not a straightforward task, mainly due its high flexibility which makes difficult the structure-based design of FabH inhibitors. Here, we present for the first time a Molecular Dynamics (MD) study of the E. colil FabH enzyme to explore its conformational space. We compare the flexibility of this enzyme for the unliganded protein and an enzyme-inhibitor complex and find a correspondence between our modeling results and the experimental evidence previously reported for this enzyme. Furthermore, through a 100 ns MD simulation of the unliganded enzyme we extract useful information related to the concerted motions that take place along the principal components of displacement. We also establish a relation between the presence of water molecules in the oxyanion hole with the conformational stability of structural important loops. Representative conformations of the binding pocket along the whole trajectory of the unliganded protein are selected through cluster analysis and we find that they contain a conformational diversity which is not provided by the X-ray structures of ecFabH. As a proof of this last hypothesis, we use a set of 10 FabH inhibitors and show that they cannot be correctly modeled in any available X-ray structure, while by using our set of conformations extracted from the MD simulations, this task can be accomplish. Finally, we show the ability of short MD simulations for the refinement of the docking binding poses and for MM-PBSA calculations to predict stable protein-inhibitor complexes in this enzyme.

Structure, Stiffness and Substates of the Dickerson-Drew Dodecamer

PubMed Central

Dršata, Tomáš; Pérez, Alberto; Orozco, Modesto; Morozov, Alexandre V.; Šponer, Jiřĺ; Lankaš, Filip

2013-01-01

The Dickerson–Drew dodecamer (DD) d-[CGCGAATTCGCG]2 is a prototypic B-DNA molecule whose sequence-specific structure and dynamics have been investigated by many experimental and computational studies. Here, we present an analysis of DD properties based on extensive atomistic molecular dynamics (MD) simulations using different ionic conditions and water models. The 0.6–2.4-µs-long MD trajectories are compared to modern crystallographic and NMR data. In the simulations, the duplex ends can adopt an alternative base-pairing, which influences the oligomer structure. A clear relationship between the BI/BII backbone substates and the basepair step conformation has been identified, extending previous findings and exposing an interesting structural polymorphism in the helix. For a given end pairing, distributions of the basepair step coordinates can be decomposed into Gaussian-like components associated with the BI/BII backbone states. The nonlocal stiffness matrices for a rigid-base mechanical model of DD are reported for the first time, suggesting salient stiffness features of the central A-tract. The Riemann distance and Kullback–Leibler divergence are used for stiffness matrix comparison. The basic structural parameters converge very well within 300 ns, convergence of the BI/BII populations and stiffness matrices is less sharp. Our work presents new findings about the DD structural dynamics, mechanical properties, and the coupling between basepair and backbone configurations, including their statistical reliability. The results may also be useful for optimizing future force fields for DNA. PMID:23976886

Energy landscape of LeuT from molecular simulations

NASA Astrophysics Data System (ADS)

Gur, Mert; Zomot, Elia; Cheng, Mary Hongying; Bahar, Ivet

2015-12-01

The bacterial sodium-coupled leucine transporter (LeuT) has been broadly used as a structural model for understanding the structure-dynamics-function of mammalian neurotransmitter transporters as well as other solute carriers that share the same fold (LeuT fold), as the first member of the family crystallographically resolved in multiple states: outward-facing open, outward-facing occluded, and inward-facing open. Yet, a complete picture of the energy landscape of (sub)states visited along the LeuT transport cycle has been elusive. In an attempt to visualize the conformational spectrum of LeuT, we performed extensive simulations of LeuT dimer dynamics in the presence of substrate (Ala or Leu) and co-transported Na+ ions, in explicit membrane and water. We used both conventional molecular dynamics (MD) simulations (with Anton supercomputing machine) and a recently introduced method, collective MD, that takes advantage of collective modes of motions predicted by the anisotropic network model. Free energy landscapes constructed based on ˜40 μs trajectories reveal multiple substates occluded to the extracellular (EC) and/or intracellular (IC) media, varying in the levels of exposure of LeuT to EC or IC vestibules. The IC-facing transmembrane (TM) helical segment TM1a shows an opening, albeit to a smaller extent and in a slightly different direction than that observed in the inward-facing open crystal structure. The study provides insights into the spectrum of conformational substates and paths accessible to LeuT and highlights the differences between Ala- and Leu-bound substates.

Energy landscape of LeuT from molecular simulations.

PubMed

Gur, Mert; Zomot, Elia; Cheng, Mary Hongying; Bahar, Ivet

2015-12-28

The bacterial sodium-coupled leucine transporter (LeuT) has been broadly used as a structural model for understanding the structure-dynamics-function of mammalian neurotransmitter transporters as well as other solute carriers that share the same fold (LeuT fold), as the first member of the family crystallographically resolved in multiple states: outward-facing open, outward-facing occluded, and inward-facing open. Yet, a complete picture of the energy landscape of (sub)states visited along the LeuT transport cycle has been elusive. In an attempt to visualize the conformational spectrum of LeuT, we performed extensive simulations of LeuT dimer dynamics in the presence of substrate (Ala or Leu) and co-transported Na(+) ions, in explicit membrane and water. We used both conventional molecular dynamics (MD) simulations (with Anton supercomputing machine) and a recently introduced method, collective MD, that takes advantage of collective modes of motions predicted by the anisotropic network model. Free energy landscapes constructed based on ∼40 μs trajectories reveal multiple substates occluded to the extracellular (EC) and/or intracellular (IC) media, varying in the levels of exposure of LeuT to EC or IC vestibules. The IC-facing transmembrane (TM) helical segment TM1a shows an opening, albeit to a smaller extent and in a slightly different direction than that observed in the inward-facing open crystal structure. The study provides insights into the spectrum of conformational substates and paths accessible to LeuT and highlights the differences between Ala- and Leu-bound substates.

Energy landscape of LeuT from molecular simulations

PubMed Central

Gur, Mert; Zomot, Elia; Cheng, Mary Hongying; Bahar, Ivet

2015-01-01

The bacterial sodium-coupled leucine transporter (LeuT) has been broadly used as a structural model for understanding the structure-dynamics-function of mammalian neurotransmitter transporters as well as other solute carriers that share the same fold (LeuT fold), as the first member of the family crystallographically resolved in multiple states: outward-facing open, outward-facing occluded, and inward-facing open. Yet, a complete picture of the energy landscape of (sub)states visited along the LeuT transport cycle has been elusive. In an attempt to visualize the conformational spectrum of LeuT, we performed extensive simulations of LeuT dimer dynamics in the presence of substrate (Ala or Leu) and co-transported Na+ ions, in explicit membrane and water. We used both conventional molecular dynamics (MD) simulations (with Anton supercomputing machine) and a recently introduced method, collective MD, that takes advantage of collective modes of motions predicted by the anisotropic network model. Free energy landscapes constructed based on ∼40 μs trajectories reveal multiple substates occluded to the extracellular (EC) and/or intracellular (IC) media, varying in the levels of exposure of LeuT to EC or IC vestibules. The IC-facing transmembrane (TM) helical segment TM1a shows an opening, albeit to a smaller extent and in a slightly different direction than that observed in the inward-facing open crystal structure. The study provides insights into the spectrum of conformational substates and paths accessible to LeuT and highlights the differences between Ala- and Leu-bound substates. PMID:26723619

Comprehensive Peptide Ion Structure Studies Using Ion Mobility Techniques: Part 1. An Advanced Protocol for Molecular Dynamics Simulations and Collision Cross-Section Calculation.

PubMed

Ghassabi Kondalaji, Samaneh; Khakinejad, Mahdiar; Tafreshian, Amirmahdi; J Valentine, Stephen

2017-05-01

Collision cross-section (CCS) measurements with a linear drift tube have been utilized to study the gas-phase conformers of a model peptide (acetyl-PAAAAKAAAAKAAAAKAAAAK). Extensive molecular dynamics (MD) simulations have been conducted to derive an advanced protocol for the generation of a comprehensive pool of in-silico structures; both higher energy and more thermodynamically stable structures are included to provide an unbiased sampling of conformational space. MD simulations at 300 K are applied to the in-silico structures to more accurately describe the gas-phase transport properties of the ion conformers including their dynamics. Different methods used previously for trajectory method (TM) CCS calculation employing the Mobcal software [1] are evaluated. A new method for accurate CCS calculation is proposed based on clustering and data mining techniques. CCS values are calculated for all in-silico structures, and those with matching CCS values are chosen as candidate structures. With this approach, more than 300 candidate structures with significant structural variation are produced; although no final gas-phase structure is proposed here, in a second installment of this work, gas-phase hydrogen deuterium exchange data will be utilized as a second criterion to select among these structures as well as to propose relative populations for these ion conformers. Here the need to increase conformer diversity and accurate CCS calculation is demonstrated and the advanced methods are discussed. Graphical Abstract ᅟ.

Comprehensive Peptide Ion Structure Studies Using Ion Mobility Techniques: Part 1. An Advanced Protocol for Molecular Dynamics Simulations and Collision Cross-Section Calculation

NASA Astrophysics Data System (ADS)

Ghassabi Kondalaji, Samaneh; Khakinejad, Mahdiar; Tafreshian, Amirmahdi; J. Valentine, Stephen

2017-05-01

Collision cross-section (CCS) measurements with a linear drift tube have been utilized to study the gas-phase conformers of a model peptide (acetyl-PAAAAKAAAAKAAAAKAAAAK). Extensive molecular dynamics (MD) simulations have been conducted to derive an advanced protocol for the generation of a comprehensive pool of in-silico structures; both higher energy and more thermodynamically stable structures are included to provide an unbiased sampling of conformational space. MD simulations at 300 K are applied to the in-silico structures to more accurately describe the gas-phase transport properties of the ion conformers including their dynamics. Different methods used previously for trajectory method (TM) CCS calculation employing the Mobcal software [1] are evaluated. A new method for accurate CCS calculation is proposed based on clustering and data mining techniques. CCS values are calculated for all in-silico structures, and those with matching CCS values are chosen as candidate structures. With this approach, more than 300 candidate structures with significant structural variation are produced; although no final gas-phase structure is proposed here, in a second installment of this work, gas-phase hydrogen deuterium exchange data will be utilized as a second criterion to select among these structures as well as to propose relative populations for these ion conformers. Here the need to increase conformer diversity and accurate CCS calculation is demonstrated and the advanced methods are discussed.

Novel rattling of K atoms in aluminium-doped defect pyrochlore tungstate

NASA Astrophysics Data System (ADS)

Shoko, Elvis; Kearley, Gordon J.; Peterson, Vanessa K.; Mutka, Hannu; Koza, Michael M.; Yamaura, Jun-ichi; Hiroi, Zenji; Thorogood, Gordon J.

2014-07-01

Rattling dynamics have been identified as fundamental to superconductivity in defect pyrochlore osmates and aluminium vanadium intermetallics, as well as low thermal conductivity in clathrates and filled skutterudites. Combining inelastic neutron scattering (INS) measurements and ab initio molecular dynamics (MD) simulations, we use a new approach to investigate rattling in the Al-doped defect pyrochlore tungstates: AAl0.33W1.67O6 (A = K, Rb, Cs). We find that although all the alkali metals rattle, the rattling of the K atoms is unique, not only among the tungstates but also among the analogous defect osmates, KOs2O6 and RbOs2O6. Detailed analysis of the MD trajectories reveals that two unique features set the K dynamics apart from the rest, namely, (1) quasi one-dimensional local diffusion within a cage, and (2) vibration at a range of frequencies. The local diffusion is driven by strongly anharmonic local potentials around the K atoms exhibiting a double-well structure in the direction of maximum displacement, which is also the direction of local diffusion. On the other hand, vibration at a range of frequencies is a consequence of the strong anisotropy in the local potentials around the K atoms as revealed by directional magnitude spectra. We present evidence to show that it is the smaller size rather than the smaller mass of the K rattler which leads to the unusual dynamics. Finally, we suggest that the occurrence of local diffusion and vibration at a range of frequencies in the dynamics of a single rattler, as found here for the K atoms, may open new possibilities for phonon engineering in thermoelectric materials.

Vibrational spectra from atomic fluctuations in dynamics simulations. II. Solvent-induced frequency fluctuations at femtosecond time resolution

NASA Astrophysics Data System (ADS)

Schmitz, Matthias; Tavan, Paul

2004-12-01

The midinfrared (MIR) spectra of molecules in polar solvents exhibit inhomogeneously broadened bands whose spectral positions are shifted as compared to the gas phase. The shifts are caused by interactions with structured solvation shells and the broadenings by fluctuations of these interactions. The MIR spectra can be calculated from hybrid molecular dynamics (MD) simulations, which treat the solute molecule by density functional theory and the solvent by molecular mechanics by the so-called instantaneous normal mode analysis (INMA) or by Fourier transforming the time correlation function (FTTCF) of the molecular dipole moment. In Paper I of this work [M. Schmitz and P. Tavan, J. Chem. Phys. 121, 12233 (2004)] we explored an alternative method based on generalized virial (GV) frequencies noting, however, that GV systematically underestimates frequencies. As shown by us these artifacts are caused by solvent-induced fluctuations of the (i) equilibrium geometry, (ii) force constants, and (iii) normal mode directions as well as by (iv) diagonal and (v) off-diagonal anharmonicities. Here we now show, by analyzing the time scales of fluctuations and sample MD trajectories of formaldehyde in the gas phase and in water, that all these sources of computational artifacts can be made visible by a Fourier analysis of the normal coordinates. Correspondingly, the error sources (i) and (iii)-(v) can be removed by bandpass filtering, as long as the spectral signatures of the respective effects are well separated from the fundamental band. Furthermore, the artifacts arising from effect (ii) can be strongly diminished by a time-resolved version of the GV approach (TF-GV). The TF-GV method then yields for each mode j a trajectory of the vibrational frequency ωj(t|τ) at a time resolution τ>τj, which is only limited by the corresponding oscillation time τj=2π/ωj and, thus, is in the femtosecond range. A correlation analysis of these trajectories clearly separates the librational motions from the conformational dynamics of the solvation shells and yields the inhomogeneously broadened MIR spectra, if the theory of motional narrowing is properly included. The MIR spectrum of formaldehyde in solution obtained by TF-GV agrees very well with the FTTCF result, if one applies the so-called "harmonic approximation" quantum correction factor and a temperature scaling to the FTTCF intensities. Also for INMA an excellent agreement is achieved if one disregards a slight INMA overestimate of linewidths.

Set-free Markov state model building

NASA Astrophysics Data System (ADS)

Weber, Marcus; Fackeldey, Konstantin; Schütte, Christof

2017-03-01

Molecular dynamics (MD) simulations face challenging problems since the time scales of interest often are much longer than what is possible to simulate; and even if sufficiently long simulations are possible the complex nature of the resulting simulation data makes interpretation difficult. Markov State Models (MSMs) help to overcome these problems by making experimentally relevant time scales accessible via coarse grained representations that also allow for convenient interpretation. However, standard set-based MSMs exhibit some caveats limiting their approximation quality and statistical significance. One of the main caveats results from the fact that typical MD trajectories repeatedly re-cross the boundary between the sets used to build the MSM which causes statistical bias in estimating the transition probabilities between these sets. In this article, we present a set-free approach to MSM building utilizing smooth overlapping ansatz functions instead of sets and an adaptive refinement approach. This kind of meshless discretization helps to overcome the recrossing problem and yields an adaptive refinement procedure that allows us to improve the quality of the model while exploring state space and inserting new ansatz functions into the MSM.

Heat conductivity in graphene and related materials: A time-domain modal analysis

NASA Astrophysics Data System (ADS)

Gill-Comeau, Maxime; Lewis, Laurent J.

2015-11-01

We use molecular dynamics (MD) simulations to study heat conductivity in single-layer graphene and graphite. We analyze the MD trajectories through a time-domain modal analysis and show that this is essential for obtaining a reliable representation of the heat flow in graphene and graphite as it permits the proper treatment of collective vibrational excitations, in contrast to a frequency-domain formulation. Our temperature-dependent results are in very good agreement with experiment and, for temperatures in the range 300-1200 K, we find that the ZA branch allows more heat flow than all other branches combined while the contributions of the TA, LA, and ZO branches are comparable at all temperatures. Conductivity mappings reveal strong collective excitations associated with low-frequency ZA modes. We demonstrate that these collective effects are a consequence of the quadratic nature of the ZA branch as they also show up in graphite but are reduced in strained graphene, where the dispersion becomes linear, and are absent in diamond, where acoustic branches are linear. In general, neglecting collective excitations yields errors similar to those from the single-mode relaxation-time approximation.

Extracting ligands from receptors by reversed targeted molecular dynamics.

PubMed

Wolf, Romain M

2015-11-01

Short targeted MD trajectories are used to expel ligands from binding sites. The expulsion is governed by a linear increase of the target RMSD value, growing from zero to an arbitrary chosen final RMSD that forces the ligand to a selected distance outside of the receptor. The RMSD lag (i.e., the difference between the imposed and the actual RMSD) can be used to follow barriers encountered by the ligand during its way out of the receptor. The force constant used for the targeted MD can transform the RMSD lag into a strain energy. Integration of the (time-dependent) strain energy over time yields a value with the dimensions of "action" (i.e, energy multiplied by time) and can serve as a measure for the overall effort required to extract the ligand from its binding site. Possibilities to compare (numerically and graphically) the randomly detected exit pathways are discussed. As an example, the method is tested on the exit of bisphenol A from the human estrogen-related receptor [Formula: see text] and of GW0072 from the peroxysome proliferator activated receptor.

Long timestep dynamics of peptides by the dynamics driver approach.

PubMed

Derreumaux, P; Schlick, T

1995-04-01

Previous experience with the Langevin/implicit-Euler scheme for dynamics ("LI") on model systems (butane, water) has shown that LI is numerically stable for timesteps in the 5-20 fs range but quenches high-frequency modes. To explore applications to polypeptides, we apply LI to model systems (several dipeptides, a tetrapeptide, and a 13-residue oligoalanine) and also develop a new dynamics driver approach ("DA"). The DA scheme, based on LI, addresses the important issue of proper sampling, which is unlikely to be solved by small-timestep integration methods or implicit methods with intrinsic damping at room temperature, such as LI. Equilibrium averages, time-dependent molecular properties, and sampling trends at room temperature are reported for both LI and DA dynamics simulations, which are then compared to those generated by a standard explicit discretization of the Langevin equation with a 1 fs timestep. We find that LI's quenching effects are severe on both the fast and slow (due to vibrational coupling) frequency modes of all-atom polypeptides and lead to more restricted dynamics at moderate timesteps (40 fs). The DA approach empirically counteracts these damping effects by adding random atomic perturbations to the coordinates at each step (before the minimization of a dynamics function). By restricting the energetic fluctuations and controlling the kinetic energy, we are able with a 60 fs timestep to generate continuous trajectories that sample more of the relevant conformational space and also reproduce reasonably Boltzmann statistics. Although the timescale for transition may be accelerated by the DA approach, the transitional information obtained for the alanine dipeptide and the tetrapeptide is consistent with that obtained by several other theoretical approaches that focus specifically on the determination of pathways. While the trajectory for oligoalanine by the explicit scheme over the nanosecond timeframe remains in the vicinity of the full alpha R-helix starting structure, and a high-temperature (600 degrees K) MD trajectory departs slowly from the alpha helical structure, the DA-generated trajectory for the same CPU time exhibits unfolding and refolding and reveals a range of conformations with an intermediate helix content. Significantly, this range of states is more consistent with spectroscopic experiments on small peptides, as well as the cooperative two-state model for helix-coil transition. The good, near-Boltzmann statistics reported for the smaller systems above, in combination with the interesting oligoalanine results, suggest that DA is a promising tool for efficiently exploring conformational spaces of biomolecules and exploring folding/unfolding processes of polypeptides.

A GPU-Accelerated Parameter Interpolation Thermodynamic Integration Free Energy Method.

PubMed

Giese, Timothy J; York, Darrin M

2018-03-13

There has been a resurgence of interest in free energy methods motivated by the performance enhancements offered by molecular dynamics (MD) software written for specialized hardware, such as graphics processing units (GPUs). In this work, we exploit the properties of a parameter-interpolated thermodynamic integration (PI-TI) method to connect states by their molecular mechanical (MM) parameter values. This pathway is shown to be better behaved for Mg 2+ → Ca 2+ transformations than traditional linear alchemical pathways (with and without soft-core potentials). The PI-TI method has the practical advantage that no modification of the MD code is required to propagate the dynamics, and unlike with linear alchemical mixing, only one electrostatic evaluation is needed (e.g., single call to particle-mesh Ewald) leading to better performance. In the case of AMBER, this enables all the performance benefits of GPU-acceleration to be realized, in addition to unlocking the full spectrum of features available within the MD software, such as Hamiltonian replica exchange (HREM). The TI derivative evaluation can be accomplished efficiently in a post-processing step by reanalyzing the statistically independent trajectory frames in parallel for high throughput. We also show how one can evaluate the particle mesh Ewald contribution to the TI derivative evaluation without needing to perform two reciprocal space calculations. We apply the PI-TI method with HREM on GPUs in AMBER to predict p K a values in double stranded RNA molecules and make comparison with experiments. Convergence to under 0.25 units for these systems required 100 ns or more of sampling per window and coupling of windows with HREM. We find that MM charges derived from ab initio QM/MM fragment calculations improve the agreement between calculation and experimental results.

Motions and entropies in proteins as seen in NMR relaxation experiments and molecular dynamics simulations.

PubMed

Allnér, Olof; Foloppe, Nicolas; Nilsson, Lennart

2015-01-22

Molecular dynamics simulations of E. coli glutaredoxin1 in water have been performed to relate the dynamical parameters and entropy obtained in NMR relaxation experiments, with results extracted from simulated trajectory data. NMR relaxation is the most widely used experimental method to obtain data on dynamics of proteins, but it is limited to relatively short timescales and to motions of backbone amides or in some cases (13)C-H vectors. By relating the experimental data to the all-atom picture obtained in molecular dynamics simulations, valuable insights on the interpretation of the experiment can be gained. We have estimated the internal dynamics and their timescales by calculating the generalized order parameters (O) for different time windows. We then calculate the quasiharmonic entropy (S) and compare it to the entropy calculated from the NMR-derived generalized order parameter of the amide vectors. Special emphasis is put on characterizing dynamics that are not expressed through the motions of the amide group. The NMR and MD methods suffer from complementary limitations, with NMR being restricted to local vectors and dynamics on a timescale determined by the rotational diffusion of the solute, while in simulations, it may be difficult to obtain sufficient sampling to ensure convergence of the results. We also evaluate the amount of sampling obtained with molecular dynamics simulations and how it is affected by the length of individual simulations, by clustering of the sampled conformations. We find that two structural turns act as hinges, allowing the α helix between them to undergo large, long timescale motions that cannot be detected in the time window of the NMR dipolar relaxation experiments. We also show that the entropy obtained from the amide vector does not account for correlated motions of adjacent residues. Finally, we show that the sampling in a total of 100 ns molecular dynamics simulation can be increased by around 50%, by dividing the trajectory into 10 replicas with different starting velocities.

A novel energy conversion based method for velocity correction in molecular dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Hanhui; Collaborative Innovation Center of Advanced Aero-Engine, Hangzhou 310027; Liu, Ningning

2017-05-01

Molecular dynamics (MD) simulation has become an important tool for studying micro- or nano-scale dynamics and the statistical properties of fluids and solids. In MD simulations, there are mainly two approaches: equilibrium and non-equilibrium molecular dynamics (EMD and NEMD). In this paper, a new energy conversion based correction (ECBC) method for MD is developed. Unlike the traditional systematic correction based on macroscopic parameters, the ECBC method is developed strictly based on the physical interaction processes between the pair of molecules or atoms. The developed ECBC method can apply to EMD and NEMD directly. While using MD with this method, themore » difference between the EMD and NEMD is eliminated, and no macroscopic parameters such as external imposed potentials or coefficients are needed. With this method, many limits of using MD are lifted. The application scope of MD is greatly extended.« less

Study of intermolecular contacts in the proline-rich homeodomain (PRH)-DNA complex using molecular dynamics simulations.

PubMed

Jalili, Seifollah; Karami, Leila

2012-03-01

The proline-rich homeodomain (PRH)-DNA complex consists of a protein with 60 residues and a 13-base-pair DNA. The PRH protein is a transcription factor that plays a key role in the regulation of gene expression. PRH is a significant member of the Q50 class of homeodomain proteins. The homeodomain section of PRH is essential for binding to DNA and mediates sequence-specific DNA binding. Three 20-ns molecular dynamics (MD) simulations (free protein, free DNA and protein-DNA complex) in explicit solvent water were performed to elucidate the intermolecular contacts in the PRH-DNA complex and the role of dynamics of water molecules forming water-mediated contacts. The simulation provides a detailed explanation of the trajectory of hydration water molecules. The simulations show that some water molecules in the protein-DNA interface exchange with bulk waters. The simulation identifies that most of the contacts consisted of direct interactions between the protein and DNA including specific and non-specific contacts, but several water-mediated polar contacts were also observed. The specific interaction between Gln50 and C18 and water-mediated hydrogen bond between Gln50 and T7 were found to be present during almost the entire time of the simulation. These results show good consistency with experimental and previous computational studies. Structural properties such as root-mean-square deviations (RMSD), root-mean-square fluctuations (RMSF) and secondary structure were also analyzed as a function of time. Analyses of the trajectories showed that the dynamic fluctuations of both the protein and the DNA were lowered by the complex formation.

Heme Distortions in Sperm-Whale Carbonmonoxy Myoglobin: Correlations between Rotational Strengths and Heme Distortions in MD-Generated Structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

KIEFL,CHRISTOPH; SCREERAMA,NARASIMHA; LU,YI

2000-07-13

The authors have investigated the effects of heme rotational isomerism in sperm-whale carbonmonoxy myoglobin using computational techniques. Several molecular dynamics simulations have been performed for the two rotational isomers A and B, which are related by a 180{degree} rotation around the {alpha}-{gamma} axis of the heme, of sperm-whale carbonmonoxy myoglobin in water. Both neutron diffraction and NMR structures were used as starting structures. In the absence of an experimental structure, the structure of isomer B was generated by rotating the heme in the structure of isomer A. Distortions of the heme from planarity were characterized by normal coordinate structural decompositionmore » and by the angle of twist of the pyrrole rings from the heme plane. The heme distortions of the neutron diffraction structure were conserved in the MD trajectories, but in the NMR-based trajectories, where the heme distortions are less well defined, they differ from the original heme deformations. The protein matrix induced similar distortions on the heroes in orientations A and B. The results suggest that the binding site prefers a particular macrocycle conformation, and a 180{degree} rotation of the heme does not significantly alter the protein's preference for this conformation. The intrinsic rotational strengths of the two Soret transitions, separated according to their polarization in the heme plane, show strong correlations with the ruf-deformation and the average twist angle of the pyrrole rings. The total rotational strength, which includes contributions from the chromophores in the protein, shows a weaker correlation with heme distortions.« less

RECENT ADVANCES IN MACROMOLECULAR HYDRODYNAMIC MODELING

PubMed Central

Aragon, Sergio R.

2010-01-01

The modern implementation of the boundary element method (S.R. Aragon, J. Comput. Chem. 25(2004)1191–12055) has ushered unprecedented accuracy and precision for the solution of the Stokes equations of hydrodynamics with stick boundary conditions. This article begins by reviewing computations with the program BEST of smooth surface objects such as ellipsoids, the dumbbell, and cylinders that demonstrate that the numerical solution of the integral equation formulation of hydrodynamics yields very high precision and accuracy. When BEST is used for macromolecular computations, the limiting factor becomes the definition of the molecular hydrodynamic surface and the implied effective solvation of the molecular surface. Studies on 49 different proteins, ranging in molecular weight from 9 to over 400 kDa, have shown that a model using a 1.1 A thick hydration layer describes all protein transport properties very well for the overwhelming majority of them. In addition, this data implies that the crystal structure is an excellent representation of the average solution structure for most of them. In order to investigate the origin of a handful of significant discrepancies in some multimeric proteins (over −20% observed in the intrinsic viscosity), the technique of Molecular Dynamics simulation (MD) has been incorporated into the research program. A preliminary study of dimeric α-chymotrypsin using approximate implicit water MD is presented. In addition I describe the successful validation of modern protein force fields, ff03 and ff99SB, for the accurate computation of solution structure in explicit water simulation by comparison of trajectory ensemble average computed transport properties with experimental measurements. This work includes small proteins such as lysozyme, ribonuclease and ubiquitin using trajectories around 10 ns duration. We have also studied a 150 kDa flexible monoclonal IgG antibody, trastuzumab, with multiple independent trajectories encompassing over 320 ns of simulation. The close agreement within experimental error of the computed and measured properties allows us to conclude that MD does produce structures typical of those in solution, and that flexible molecules can be properly described using the method of ensemble averaging over a trajectory. We review similar work on the study of a transfer RNA molecule and DNA oligomers that demonstrate that within 3% a simple uniform hydration model 1.1 A thick provides agreement with experiment for these nucleic acids. In the case of linear oligomers, the precision can be improved close to 1% by a non-uniform hydration model that hydrates mainly in the DNA grooves, in agreement with high resolution x-ray diffraction. We conclude with a vista on planned improvements for the BEST program to decrease its memory requirements and increase its speed without sacrificing accuracy. PMID:21073955

Towards fast, rigorous and efficient conformational sampling of biomolecules: Advances in accelerated molecular dynamics.

PubMed

Doshi, Urmi; Hamelberg, Donald

2015-05-01

Accelerated molecular dynamics (aMD) has been proven to be a powerful biasing method for enhanced sampling of biomolecular conformations on general-purpose computational platforms. Biologically important long timescale events that are beyond the reach of standard molecular dynamics can be accessed without losing the detailed atomistic description of the system in aMD. Over other biasing methods, aMD offers the advantages of tuning the level of acceleration to access the desired timescale without any advance knowledge of the reaction coordinate. Recent advances in the implementation of aMD and its applications to small peptides and biological macromolecules are reviewed here along with a brief account of all the aMD variants introduced in the last decade. In comparison to the original implementation of aMD, the recent variant in which all the rotatable dihedral angles are accelerated (RaMD) exhibits faster convergence rates and significant improvement in statistical accuracy of retrieved thermodynamic properties. RaMD in conjunction with accelerating diffusive degrees of freedom, i.e. dual boosting, has been rigorously tested for the most difficult conformational sampling problem, protein folding. It has been shown that RaMD with dual boosting is capable of efficiently sampling multiple folding and unfolding events in small fast folding proteins. RaMD with the dual boost approach opens exciting possibilities for sampling multiple timescales in biomolecules. While equilibrium properties can be recovered satisfactorily from aMD-based methods, directly obtaining dynamics and kinetic rates for larger systems presents a future challenge. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014 Elsevier B.V. All rights reserved.

Evidence for ProTα-TLR4/MD-2 binding: molecular dynamics and gravimetric assay studies.

PubMed

Omotuyi, Olaposi; Matsunaga, Hayato; Ueda, Hiroshi

2015-01-01

During preconditioning, lipopolysaccharide (LPS) selectively activates TLR4/MD-2/Toll/IL-1 receptor-domain-containing adaptor inducing IFN-β (TRIF) pathway instead of pro-inflammatory myeloid differentiation protein-88 (MyD88)/MyD88-adaptor-like protein (MAL) pathway. Extracellular prothymosin alpha (ProTα) is also known to selectively activate the TLR4/MD2/TRIF-IRF3 pathway in certain diseased conditions. In the current study, biophysical evidence for ProTα/TLR4/MD-2 complex formation and its interaction dynamics have been studied. Gravimetric assay was used to investigate ProTα/TLR4/MD-2 complex formation while molecular dynamics (MD) simulation was used to study its interaction dynamics. Through electrostatic interaction, full-length ProTα (F-ProTα) C-terminal peptide (aa 91 - 111) superficially interacts with similar TLR4/MD-2 (KD = 273.36 nm vs 16.07 μg/ml [LPS]) conformation with LPS at an overlapping three-dimensional space while F-ProTα is hinged to the TLR4 scaffold by one-amino acid shift-Mosoian domain (aa-51 - 90). Comparatively, F-ProTα better stabilizes MD-2 metastable states transition and mediates higher TLR4/MD-2 interaction than LPS. ProTα via its C-terminal peptide (aa 91 - 111) exhibits in vitro biophysical contact with TLR4/MD-2 complex conformation recognized by LPS at overlapping LPS-binding positions.

Multidimensional Recurrence Quantification Analysis (MdRQA) for the Analysis of Multidimensional Time-Series: A Software Implementation in MATLAB and Its Application to Group-Level Data in Joint Action

PubMed Central

Wallot, Sebastian; Roepstorff, Andreas; Mønster, Dan

2016-01-01

We introduce Multidimensional Recurrence Quantification Analysis (MdRQA) as a tool to analyze multidimensional time-series data. We show how MdRQA can be used to capture the dynamics of high-dimensional signals, and how MdRQA can be used to assess coupling between two or more variables. In particular, we describe applications of the method in research on joint and collective action, as it provides a coherent analysis framework to systematically investigate dynamics at different group levels—from individual dynamics, to dyadic dynamics, up to global group-level of arbitrary size. The Appendix in Supplementary Material contains a software implementation in MATLAB to calculate MdRQA measures. PMID:27920748

Multidimensional Recurrence Quantification Analysis (MdRQA) for the Analysis of Multidimensional Time-Series: A Software Implementation in MATLAB and Its Application to Group-Level Data in Joint Action.

PubMed

Wallot, Sebastian; Roepstorff, Andreas; Mønster, Dan

2016-01-01

We introduce Multidimensional Recurrence Quantification Analysis (MdRQA) as a tool to analyze multidimensional time-series data. We show how MdRQA can be used to capture the dynamics of high-dimensional signals, and how MdRQA can be used to assess coupling between two or more variables. In particular, we describe applications of the method in research on joint and collective action, as it provides a coherent analysis framework to systematically investigate dynamics at different group levels-from individual dynamics, to dyadic dynamics, up to global group-level of arbitrary size. The Appendix in Supplementary Material contains a software implementation in MATLAB to calculate MdRQA measures.

Towards data warehousing and mining of protein unfolding simulation data.

PubMed

Berrar, Daniel; Stahl, Frederic; Silva, Candida; Rodrigues, J Rui; Brito, Rui M M; Dubitzky, Werner

2005-10-01

The prediction of protein structure and the precise understanding of protein folding and unfolding processes remains one of the greatest challenges in structural biology and bioinformatics. Computer simulations based on molecular dynamics (MD) are at the forefront of the effort to gain a deeper understanding of these complex processes. Currently, these MD simulations are usually on the order of tens of nanoseconds, generate a large amount of conformational data and are computationally expensive. More and more groups run such simulations and generate a myriad of data, which raises new challenges in managing and analyzing these data. Because the vast range of proteins researchers want to study and simulate, the computational effort needed to generate data, the large data volumes involved, and the different types of analyses scientists need to perform, it is desirable to provide a public repository allowing researchers to pool and share protein unfolding data. To adequately organize, manage, and analyze the data generated by unfolding simulation studies, we designed a data warehouse system that is embedded in a grid environment to facilitate the seamless sharing of available computer resources and thus enable many groups to share complex molecular dynamics simulations on a more regular basis. To gain insight into the conformational fluctuations and stability of the monomeric forms of the amyloidogenic protein transthyretin (TTR), molecular dynamics unfolding simulations of the monomer of human TTR have been conducted. Trajectory data and meta-data of the wild-type (WT) protein and the highly amyloidogenic variant L55P-TTR represent the test case for the data warehouse. Web and grid services, especially pre-defined data mining services that can run on or 'near' the data repository of the data warehouse, are likely to play a pivotal role in the analysis of molecular dynamics unfolding data.

Gaussian Accelerated Molecular Dynamics in NAMD

PubMed Central

2016-01-01

Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for “unconstrained” enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules. PMID:28034310

Gaussian Accelerated Molecular Dynamics in NAMD.

PubMed

Pang, Yui Tik; Miao, Yinglong; Wang, Yi; McCammon, J Andrew

2017-01-10

Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for "unconstrained" enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M 3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M 3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules.

Insilico modeling and molecular dynamic simulation of claudin-1 point mutations in HCV infection.

PubMed

Vipperla, Bhavaniprasad; Dass, J Febin Prabhu; Jayanthi, S

2014-01-01

Claudin-1 (CLDN1) in association with envelope glycoprotein (CD81) mediates the fusion of HCV into the cytosol. Recent studies have indicated that point mutations in CLDN1 are important for the entry of hepatitis C virus (HCV). To validate these findings, we employed a computational platform to investigate the structural effect of two point mutations (I32M and E48K). Initially, three-dimensional co-ordinates for CLDN1 receptor sequence were generated. Then, three mutant models were built using the point mutation including a double mutant (I32M/E48K) model from the native model structure. Finally, all the four model structures including the native and three mutant models were subjected to molecular dynamics (MD) simulation for a period of 25 ns to appreciate their dynamic behavior. The MD trajectory files were analyzed using cluster and principal component method. The analysis suggested that either of the single mutation has negligible effect on the overall structure of CLDN1 compared to the double mutant form. However, the double mutant model of CLDN1 shows significant negative impact through the impairment of H-bonds and the simultaneous increase in solvent accessible surface area. Our simulation results are visibly consistent with the experimental report suggesting that the CLDN1 receptor distortion is prominent due to the double mutation with large surface accessibility. This increase in accessible surface area due to the coexistence of double mutation may be presumed as one of the key factor that results in permissive action of HCV attachment and infection.

A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

PubMed Central

Fattebert, Jean-Luc; Emigh, Aiyana

2015-01-01

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures. PMID:25874456

A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone andmore » sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.« less

A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

DOE PAGES

Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.; ...

2015-04-13

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone andmore » sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.« less

NbIT - A New Information Theory-Based Analysis of Allosteric Mechanisms Reveals Residues that Underlie Function in the Leucine Transporter LeuT

PubMed Central

LeVine, Michael V.; Weinstein, Harel

2014-01-01

Complex networks of interacting residues and microdomains in the structures of biomolecular systems underlie the reliable propagation of information from an input signal, such as the concentration of a ligand, to sites that generate the appropriate output signal, such as enzymatic activity. This information transduction often carries the signal across relatively large distances at the molecular scale in a form of allostery that is essential for the physiological functions performed by biomolecules. While allosteric behaviors have been documented from experiments and computation, the mechanism of this form of allostery proved difficult to identify at the molecular level. Here, we introduce a novel analysis framework, called N-body Information Theory (NbIT) analysis, which is based on information theory and uses measures of configurational entropy in a biomolecular system to identify microdomains and individual residues that act as (i)-channels for long-distance information sharing between functional sites, and (ii)-coordinators that organize dynamics within functional sites. Application of the new method to molecular dynamics (MD) trajectories of the occluded state of the bacterial leucine transporter LeuT identifies a channel of allosteric coupling between the functionally important intracellular gate and the substrate binding sites known to modulate it. NbIT analysis is shown also to differentiate residues involved primarily in stabilizing the functional sites, from those that contribute to allosteric couplings between sites. NbIT analysis of MD data thus reveals rigorous mechanistic elements of allostery underlying the dynamics of biomolecular systems. PMID:24785005

Energetics and kinetics of primary charge separation in bacterial photosynthesis.

PubMed

LeBard, David N; Kapko, Vitaliy; Matyushov, Dmitry V

2008-08-21

We report the results of molecular dynamics (MD) simulations and formal modeling of the free-energy surfaces and reaction rates of primary charge separation in the reaction center of Rhodobacter sphaeroides. Two simulation protocols were used to produce MD trajectories. Standard force-field potentials were employed in the first protocol. In the second protocol, the special pair was made polarizable to reproduce a high polarizability of its photoexcited state observed by Stark spectroscopy. The charge distribution between covalent and charge-transfer states of the special pair was dynamically adjusted during the simulation run. We found from both protocols that the breadth of electrostatic fluctuations of the protein/water environment far exceeds previous estimates, resulting in about 1.6 eV reorganization energy of electron transfer in the first protocol and 2.5 eV in the second protocol. Most of these electrostatic fluctuations become dynamically frozen on the time scale of primary charge separation, resulting in much smaller solvation contributions to the activation barrier. While water dominates solvation thermodynamics on long observation times, protein emerges as the major thermal bath coupled to electron transfer on the picosecond time of the reaction. Marcus parabolas were obtained for the free-energy surfaces of electron transfer by using the first protocol, while a highly asymmetric surface was obtained in the second protocol. A nonergodic formulation of the diffusion-reaction electron-transfer kinetics has allowed us to reproduce the experimental results for both the temperature dependence of the rate and the nonexponential decay of the population of the photoexcited special pair.

Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 1. Generalized Born

PubMed Central

2012-01-01

We present an implementation of generalized Born implicit solvent all-atom classical molecular dynamics (MD) within the AMBER program package that runs entirely on CUDA enabled NVIDIA graphics processing units (GPUs). We discuss the algorithms that are used to exploit the processing power of the GPUs and show the performance that can be achieved in comparison to simulations on conventional CPU clusters. The implementation supports three different precision models in which the contributions to the forces are calculated in single precision floating point arithmetic but accumulated in double precision (SPDP), or everything is computed in single precision (SPSP) or double precision (DPDP). In addition to performance, we have focused on understanding the implications of the different precision models on the outcome of implicit solvent MD simulations. We show results for a range of tests including the accuracy of single point force evaluations and energy conservation as well as structural properties pertainining to protein dynamics. The numerical noise due to rounding errors within the SPSP precision model is sufficiently large to lead to an accumulation of errors which can result in unphysical trajectories for long time scale simulations. We recommend the use of the mixed-precision SPDP model since the numerical results obtained are comparable with those of the full double precision DPDP model and the reference double precision CPU implementation but at significantly reduced computational cost. Our implementation provides performance for GB simulations on a single desktop that is on par with, and in some cases exceeds, that of traditional supercomputers. PMID:22582031

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uberuaga, Blas Pedro; Voter, Arthur F; Perez, Danny

A long-standing limitation in the use of molecular dynamics (MD) simulation is that it can only be applied directly to processes that take place on very short timescales: nanoseconds if empirical potentials are employed, or picoseconds if we rely on electronic structure methods. Many processes of interest in chemistry, biochemistry, and materials science require study over microseconds and beyond, due either to the natural timescale for the evolution or to the duration of the experiment of interest. Ignoring the case of liquids xxx, the dynamics on these time scales is typically characterized by infrequent-event transitions, from state to state, usuallymore » involving an energy barrier. There is a long and venerable tradition in chemistry of using transition state theory (TST) [10, 19, 23] to directly compute rate constants for these kinds of activated processes. If needed dynamical corrections to the TST rate, and even quantum corrections, can be computed to achieve an accuracy suitable for the problem at hand. These rate constants then allow them to understand the system behavior on longer time scales than we can directly reach with MD. For complex systems with many reaction paths, the TST rates can be fed into a stochastic simulation procedure such as kinetic Monte Carlo xxx, and a direct simulation of the advance of the system through its possible states can be obtained in a probabilistically exact way. A problem that has become more evident in recent years, however, is that for many systems of interest there is a complexity that makes it difficult, if not impossible, to determine all the relevant reaction paths to which TST should be applied. This is a serious issue, as omitted transition pathways can have uncontrollable consequences on the simulated long-time kinetics. Over the last decade or so, we have been developing a new class of methods for treating the long-time dynamics in these complex, infrequent-event systems. Rather than trying to guess in advance what reaction pathways may be important, we return instead to a molecular dynamics treatment, in which the trajectory itself finds an appropriate way to escape from each state of the system. Since a direct integration of the trajectory would be limited to nanoseconds, while we are seeking to follow the system for much longer times, we modify the dynamics in some way to cause the first escape to happen much more quickly, thereby accelerating the dynamics. The key is to design the modified dynamics in a way that does as little damage as possible to the probability for escaping along a given pathway - i.e., we try to preserve the relative rate constants for the different possible escape paths out of the state. We can then use this modified dynamics to follow the system from state to state, reaching much longer times than we could reach with direct MD. The dynamics within any one state may no longer be meaningful, but the state-to-state dynamics, in the best case, as we discuss in the paper, can be exact. We have developed three methods in this accelerated molecular dynamics (AMD) class, in each case appealing to TST, either implicitly or explicitly, to design the modified dynamics. Each of these methods has its own advantages, and we and others have applied these methods to a wide range of problems. The purpose of this article is to give the reader a brief introduction to how these methods work, and discuss some of the recent developments that have been made to improve their power and applicability. Note that this brief review does not claim to be exhaustive: various other methods aiming at similar goals have been proposed in the literature. For the sake of brevity, our focus will exclusively be on the methods developed by the group.« less

MD Simulations of P-Type ATPases in a Lipid Bilayer System.

PubMed

Autzen, Henriette Elisabeth; Musgaard, Maria

2016-01-01

Molecular dynamics (MD) simulation is a computational method which provides insight on protein dynamics with high resolution in both space and time, in contrast to many experimental techniques. MD simulations can be used as a stand-alone method to study P-type ATPases as well as a complementary method aiding experimental studies. In particular, MD simulations have proved valuable in generating and confirming hypotheses relating to the structure and function of P-type ATPases. In the following, we describe a detailed practical procedure on how to set up and run a MD simulation of a P-type ATPase embedded in a lipid bilayer using software free of use for academics. We emphasize general considerations and problems typically encountered when setting up simulations. While full coverage of all possible procedures is beyond the scope of this chapter, we have chosen to illustrate the MD procedure with the Nanoscale Molecular Dynamics (NAMD) and the Visual Molecular Dynamics (VMD) software suites.

Gaussian Accelerated Molecular Dynamics: Theory, Implementation, and Applications

PubMed Central

Miao, Yinglong; McCammon, J. Andrew

2018-01-01

A novel Gaussian Accelerated Molecular Dynamics (GaMD) method has been developed for simultaneous unconstrained enhanced sampling and free energy calculation of biomolecules. Without the need to set predefined reaction coordinates, GaMD enables unconstrained enhanced sampling of the biomolecules. Furthermore, by constructing a boost potential that follows a Gaussian distribution, accurate reweighting of GaMD simulations is achieved via cumulant expansion to the second order. The free energy profiles obtained from GaMD simulations allow us to identify distinct low energy states of the biomolecules and characterize biomolecular structural dynamics quantitatively. In this chapter, we present the theory of GaMD, its implementation in the widely used molecular dynamics software packages (AMBER and NAMD), and applications to the alanine dipeptide biomolecular model system, protein folding, biomolecular large-scale conformational transitions and biomolecular recognition. PMID:29720925

The first nationwide survey of MD-PhDs in the social sciences and humanities: training patterns and career choices.

PubMed

Holmes, Seth M; Karlin, Jennifer; Stonington, Scott D; Gottheil, Diane L

2017-03-21

While several articles on MD-PhD trainees in the basic sciences have been published in the past several years, very little research exists on physician-investigators in the social sciences and humanities. However, the numbers of MD-PhDs training in these fields and the number of programs offering training in these fields are increasing, particularly within the US. In addition, accountability for the public funding for MD-PhD programs requires knowledge about this growing population of trainees and their career trajectories. The aim of this paper is to describe the first cohorts of MD-PhDs in the social sciences and humanities, to characterize their training and career paths, and to better understand their experiences of training and subsequent research and practice. This paper utilizes a multi-pronged recruitment method and novel survey instrument to examine an understudied population of MD-PhD trainees in the social sciences and humanities, many of whom completed both degrees without formal programmatic support. The survey instrument was designed to collect demographic, training and career trajectory data, as well as experiences of and perspectives on training and career. It describes their routes to professional development, characterizes obstacles to and predictors of success, and explores career trends. The average length of time to complete both degrees was 9 years. The vast majority (90%) completed a clinical residency, almost all (98%) were engaged in research, the vast majority (88%) were employed in academic institutions, and several others (9%) held leadership positions in national and international health organizations. Very few (4%) went into private practice. The survey responses supply recommendations for supporting current trainees as well as areas for future research. In general, MD-PhDs in the social sciences and humanities have careers that fit the goals of agencies providing public funding for training physician-investigators: they are involved in mutually-informative medical research, clinical practice, and teaching - working to improve our responses to the social, cultural, and political determinants of health and health care. These findings provide strong evidence for continued and improved funding and programmatic support for MD-PhD trainees in the social sciences and humanities.

Nontrivial behavior of water in the vicinity and inside lipid bilayers as probed by molecular dynamics simulations.

PubMed

Krylov, Nikolay A; Pentkovsky, Vladimir M; Efremov, Roman G

2013-10-22

The atomic-scale diffusion of water in the presence of several lipid bilayers mimicking biomembranes is characterized via unconstrained molecular dynamics (MD) simulations. Although the overall water dynamics corresponds well to literature data, namely, the efficient braking near polar head groups of lipids, a number of interesting and biologically relevant details observed in this work have not been sufficiently discussed so far; for instance, the fact that waters "sense" the membrane unexpectedly early, before water density begins to decrease. In this "transitional zone" the velocity distributions of water and their H-bonding patterns deviate from those in the bulk solution. The boundaries of this zone are well preserved even despite the local (<1 nm size) perturbation of the lipid bilayer, thus indicating a decoupling of the surface and bulk dynamics of water. This is in excellent agreement with recent experimental data. Near the membrane surface, water movement becomes anisotropic, that is, solvent molecules preferentially move outward the bilayer. Deep in the membrane interior, the velocities can even exceed those in the bulk solvent and undergo large-scale fluctuations. The analysis of MD trajectories of individual waters in the middle part of the acyl chain region of lipids reveals a number of interesting rare phenomena, such as the fast (ca. 50 ps) breakthrough across the membrane or long-time (up to 750 ps) "roaming" between lipid leaflets. The analysis of these events was accomplished to delineate the mechanisms of spontaneous water permeation inside the hydrophobic membrane core. It was shown that such nontrivial dynamics of water in an "alien" environment is driven by the dynamic heterogeneities of the local bilayer structure and the formation of transient atomic-scale "defects" in it. The picture observed in lipid bilayers is drastically different from that in a primitive membrane mimic, a hydrated cyclohexane slab. The possible biological impact of such phenomena in equilibrated lipid bilayers is discussed.

Atomistic non-adiabatic dynamics of the LH2 complex with a GPU-accelerated ab initio exciton model.

PubMed

Sisto, Aaron; Stross, Clem; van der Kamp, Marc W; O'Connor, Michael; McIntosh-Smith, Simon; Johnson, Graham T; Hohenstein, Edward G; Manby, Fred R; Glowacki, David R; Martinez, Todd J

2017-06-14

We recently outlined an efficient multi-tiered parallel ab initio excitonic framework that utilizes time dependent density functional theory (TDDFT) to calculate ground and excited state energies and gradients of large supramolecular complexes in atomistic detail - enabling us to undertake non-adiabatic simulations which explicitly account for the coupled anharmonic vibrational motion of all the constituent atoms in a supramolecular system. Here we apply that framework to the 27 coupled bacterio-chlorophyll-a chromophores which make up the LH2 complex, using it to compute an on-the-fly nonadiabatic surface-hopping (SH) trajectory of electronically excited LH2. Part one of this article is focussed on calibrating our ab initio exciton Hamiltonian using two key parameters: a shift δ, which corrects for the error in TDDFT vertical excitation energies; and an effective dielectric constant ε, which describes the average screening of the transition-dipole coupling between chromophores. Using snapshots obtained from equilibrium molecular dynamics simulations (MD) of LH2, we tune the values of both δ and ε through fitting to the thermally broadened experimental absorption spectrum, giving a linear absorption spectrum that agrees reasonably well with experiment. In part two of this article, we construct a time-resolved picture of the coupled vibrational and excitation energy transfer (EET) dynamics in the sub-picosecond regime following photo-excitation. Assuming Franck-Condon excitation of a narrow eigenstate band centred at 800 nm, we use surface hopping to follow a single nonadiabatic dynamics trajectory within the full eigenstate manifold. Consistent with experimental data, this trajectory gives timescales for B800→B850 population transfer (τ B800→B850 ) between 650-1050 fs, and B800 population decay (τ 800→ ) between 10-50 fs. The dynamical picture that emerges is one of rapidly fluctuating LH2 eigenstates that are delocalized over multiple chromophores and undergo frequent crossing on a femtosecond timescale as a result of the atomic vibrations of the constituent chromophores. The eigenstate fluctuations arise from disorder that is driven by vibrational dynamics with multiple characteristic timescales. The scalability of our ab initio excitonic computational framework across massively parallel architectures opens up the possibility of addressing a wide range of questions, including how specific dynamical motions impact both the pathways and efficiency of electronic energy-transfer within large supramolecular systems.

Coupling all-atom molecular dynamics simulations of ions in water with Brownian dynamics.

PubMed

Erban, Radek

2016-02-01

Molecular dynamics (MD) simulations of ions (K + , Na + , Ca 2+ and Cl - ) in aqueous solutions are investigated. Water is described using the SPC/E model. A stochastic coarse-grained description for ion behaviour is presented and parametrized using MD simulations. It is given as a system of coupled stochastic and ordinary differential equations, describing the ion position, velocity and acceleration. The stochastic coarse-grained model provides an intermediate description between all-atom MD simulations and Brownian dynamics (BD) models. It is used to develop a multiscale method which uses all-atom MD simulations in parts of the computational domain and (less detailed) BD simulations in the remainder of the domain.

Personalized Prediction of Glaucoma Progression Under Different Target Intraocular Pressure Levels Using Filtered Forecasting Methods.

PubMed

Kazemian, Pooyan; Lavieri, Mariel S; Van Oyen, Mark P; Andrews, Chris; Stein, Joshua D

2018-04-01

To generate personalized forecasts of how patients with open-angle glaucoma (OAG) experience disease progression at different intraocular pressure (IOP) levels to aid clinicians with setting personalized target IOPs. Secondary analyses using longitudinal data from 2 randomized controlled trials. Participants with moderate or advanced OAG from the Collaborative Initial Glaucoma Treatment Study (CIGTS) or the Advanced Glaucoma Intervention Study (AGIS). By using perimetric and tonometric data from trial participants, we developed and validated Kalman Filter (KF) models for fast-, slow-, and nonprogressing patients with OAG. The KF can generate personalized and dynamically updated forecasts of OAG progression under different target IOP levels. For each participant, we determined how mean deviation (MD) would change if the patient maintains his/her IOP at 1 of 7 levels (6, 9, 12, 15, 18, 21, or 24 mmHg) over the next 5 years. We also model and predict changes to MD over the same time horizon if IOP is increased or decreased by 3, 6, and 9 mmHg from the level attained in the trials. Personalized estimates of the change in MD under different target IOP levels. A total of 571 participants (mean age, 64.2 years; standard deviation, 10.9) were followed for a mean of 6.5 years (standard deviation, 2.8). Our models predicted that, on average, fast progressors would lose 2.1, 6.7, and 11.2 decibels (dB) MD under target IOPs of 6, 15, and 24 mmHg, respectively, over 5 years. In contrast, on average, slow progressors would lose 0.8, 2.1, and 4.1 dB MD under the same target IOPs and time frame. When using our tool to quantify the OAG progression dynamics for all 571 patients, we found no statistically significant differences over 5 years between progression for black versus white, male versus female, and CIGTS versus AGIS participants under different target IOPs (P > 0.05 for all). To our knowledge, this is the first clinical decision-making tool that generates personalized forecasts of the trajectory of OAG progression at different target IOP levels. This approach can help clinicians determine appropriate, personalized target IOPs for patients with OAG. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

A study of QM/Langevin-MD simulation for oxygen-evolving center of photosystem II

DOE Office of Scientific and Technical Information (OSTI.GOV)

Uchida, Waka; Kimura, Yoshiro; Wakabayashi, Masamitsu

2013-12-10

We have performed three QM/Langevin-MD simulations for oxygen-evolving complex (OEC) and surrounding residues, which are different configurations of the oxidation numbers on Mn atoms in the Mn{sub 4}O{sub 5}Ca cluster. By analyzing these trajectories, we have observed sensitivity of the change to the configuration of Mn oxidation state on O atoms of carboxyl on three amino acids, Glu354, Ala344, and Glu333. The distances from Mn to O atoms in residues contacting with the Mn{sub 4}O{sub 5}Ca cluster were analyzed for the three trajectories. We found the good correlation of the distances among the simulations. However, the distances with Glu354, Ala344,more » and Glu333 have not shown the correlation. These residues can be sensitive index of the changes of Mn oxidation numbers.« less

An Angular Overlap Model for Cu(II) Ion in the AMOEBA Polarizable Force Field

PubMed Central

Xiang, Jin Yu; Ponder, Jay W.

2014-01-01

An extensible polarizable force field for transition metal ion was developed based on AMOEBA and the angular overlap model (AOM) with consistent treatment of electrostatics for all atoms. Parameters were obtained by fitting molecular mechanics (MM) energies to various ab initio gas-phase calculations. The results of parameterization were presented for copper (II) ion ligated to water and model fragments of amino acid residues involved in the copper binding sites of type 1 copper proteins. Molecular dynamics (MD) simulations were performed on aqueous copper (II) ion at various temperatures, as well as plastocyanin (1AG6) and azurin (1DYZ). Results demonstrated that the AMOEBA-AOM significantly improves the accuracy of classical MM in a number of test cases when compared to ab initio calculations. The Jahn-Teller distortion for hexa-aqua copper (II) complex was handled automatically without specifically designating axial and in-plane ligands. Analyses of MD trajectories resulted in a 6-coordination first solvation shell for aqueous copper (II) ion and a 1.8ns average residence time of water molecules. The ensemble average geometries of 1AG6 and 1DYZ copper binding sites were in general agreement with X-ray and previous computational studies. PMID:25045338

Thermodynamic interpretation of reactive processes in Ni-Al nanolayers from atomistic simulations

NASA Astrophysics Data System (ADS)

Sandoval, Luis; Campbell, Geoffrey H.; Marian, Jaime

2014-03-01

Metals that can form intermetallic compounds by exothermic reactions constitute a class of reactive materials with multiple applications. Ni-Al laminates of thin alternating layers are being considered as model nanometric metallic multilayers for studying various reaction processes. However, the reaction kinetics at short timescales after mixing are not entirely understood. In this work, we calculate the free energies of Ni-Al alloys as a function of composition and temperature for different solid phases using thermodynamic integration based on state-of-the-art interatomic potentials. We use this information to interpret molecular dynamics (MD) simulations of bilayer systems at 800 K and zero pressure, both in isothermal and isenthalpic conditions. We find that a disordered phase always forms upon mixing as a precursor to a more stable nano crystalline B2 phase. We construe the reactions observed in terms of thermodynamic trajectories governed by the state variables computed. Simulated times of up to 30 ns were achieved, which provides a window to phenomena not previously observed in MD simulations. Our results provide insight into the early experimental reaction timescales and suggest that the path (segregated reactants) → (disordered phase) → (B2 structure) is always realized irrespective of the imposed boundary conditions.

Structure and electrical properties of DNA nanotubes embedded in lipid bilayer membranes

PubMed Central

Maiti, Prabal K

2018-01-01

Abstract Engineering the synthetic nanopores through lipid bilayer membrane to access the interior of a cell is a long persisting challenge in biotechnology. Here, we demonstrate the stability and dynamics of a tile-based 6-helix DNA nanotube (DNT) embedded in POPC lipid bilayer using the analysis of 0.2 μs long equilibrium MD simulation trajectories. We observe that the head groups of the lipid molecules close to the lumen cooperatively tilt towards the hydrophilic sugar-phosphate backbone of DNA and form a toroidal structure around the patch of DNT protruding in the membrane. Further, we explore the effect of ionic concentrations to the in-solution structure and stability of the lipid-DNT complex. Transmembrane ionic current measurements for the constant electric field MD simulation provide the I-V characteristics of the water filled DNT lumen in lipid membrane. With increasing salt concentrations, the measured values of transmembrane ionic conductance of the porous DNT lumen vary from 4.3 to 20.6 nS. Simulations of the DNTs with ssDNA and dsDNA overhangs at the mouth of the pore show gating effect with remarkable difference in the transmembrane ionic conductivities for open and close state nanopores. PMID:29136243

Quantifying chain reptation in entangled polymer melts: Topological and dynamical mapping of atomistic simulation results onto the tube model

NASA Astrophysics Data System (ADS)

Stephanou, Pavlos S.; Baig, Chunggi; Tsolou, Georgia; Mavrantzas, Vlasis G.; Kröger, Martin

2010-03-01

The topological state of entangled polymers has been analyzed recently in terms of primitive paths which allowed obtaining reliable predictions of the static (statistical) properties of the underlying entanglement network for a number of polymer melts. Through a systematic methodology that first maps atomistic molecular dynamics (MD) trajectories onto time trajectories of primitive chains and then documents primitive chain motion in terms of a curvilinear diffusion in a tubelike region around the coarse-grained chain contour, we are extending these static approaches here even further by computing the most fundamental function of the reptation theory, namely, the probability ψ(s,t) that a segment s of the primitive chain remains inside the initial tube after time t, accounting directly for contour length fluctuations and constraint release. The effective diameter of the tube is independently evaluated by observing tube constraints either on atomistic displacements or on the displacement of primitive chain segments orthogonal to the initial primitive path. Having computed the tube diameter, the tube itself around each primitive path is constructed by visiting each entanglement strand along the primitive path one after the other and approximating it by the space of a small cylinder having the same axis as the entanglement strand itself and a diameter equal to the estimated effective tube diameter. Reptation of the primitive chain longitudinally inside the effective constraining tube as well as local transverse fluctuations of the chain driven mainly from constraint release and regeneration mechanisms are evident in the simulation results; the latter causes parts of the chains to venture outside their average tube surface for certain periods of time. The computed ψ(s,t) curves account directly for both of these phenomena, as well as for contour length fluctuations, since all of them are automatically captured in the atomistic simulations. Linear viscoelastic properties such as the zero shear rate viscosity and the spectra of storage and loss moduli obtained on the basis of the obtained ψ(s,t) curves for three different polymer melts (polyethylene, cis-1,4-polybutadiene, and trans-1,4-polybutadiene) are consistent with experimental rheological data and in qualitative agreement with the double reptation and dual constraint models. The new methodology is general and can be routinely applied to analyze primitive path dynamics and chain reptation in atomistic trajectories (accumulated through long MD simulations) of other model polymers or polymeric systems (e.g., bidisperse, branched, grafted, etc.); it is thus believed to be particularly useful in the future in evaluating proposed tube models and developing more accurate theories for entangled systems.

Coupled protein-ligand dynamics in truncated hemoglobin N from atomistic simulations and transition networks.

PubMed

Cazade, Pierre-André; Berezovska, Ganna; Meuwly, Markus

2015-05-01

The nature of ligand motion in proteins is difficult to characterize directly using experiment. Specifically, it is unclear to what degree these motions are coupled. All-atom simulations are used to sample ligand motion in truncated Hemoglobin N. A transition network analysis including ligand- and protein-degrees of freedom is used to analyze the microscopic dynamics. Clustering of two different subsets of MD trajectories highlights the importance of a diverse and exhaustive description to define the macrostates for a ligand-migration network. Monte Carlo simulations on the transition matrices from one particular clustering are able to faithfully capture the atomistic simulations. Contrary to clustering by ligand positions only, including a protein degree of freedom yields considerably improved coarse grained dynamics. Analysis with and without imposing detailed balance agree closely which suggests that the underlying atomistic simulations are converged with respect to sampling transitions between neighboring sites. Protein and ligand dynamics are not independent from each other and ligand migration through globular proteins is not passive diffusion. Transition network analysis is a powerful tool to analyze and characterize the microscopic dynamics in complex systems. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014 Elsevier B.V. All rights reserved.

Drug search for leishmaniasis: a virtual screening approach by grid computing

NASA Astrophysics Data System (ADS)

Ochoa, Rodrigo; Watowich, Stanley J.; Flórez, Andrés; Mesa, Carol V.; Robledo, Sara M.; Muskus, Carlos

2016-07-01

The trypanosomatid protozoa Leishmania is endemic in 100 countries, with infections causing 2 million new cases of leishmaniasis annually. Disease symptoms can include severe skin and mucosal ulcers, fever, anemia, splenomegaly, and death. Unfortunately, therapeutics approved to treat leishmaniasis are associated with potentially severe side effects, including death. Furthermore, drug-resistant Leishmania parasites have developed in most endemic countries. To address an urgent need for new, safe and inexpensive anti-leishmanial drugs, we utilized the IBM World Community Grid to complete computer-based drug discovery screens (Drug Search for Leishmaniasis) using unique leishmanial proteins and a database of 600,000 drug-like small molecules. Protein structures from different Leishmania species were selected for molecular dynamics (MD) simulations, and a series of conformational "snapshots" were chosen from each MD trajectory to simulate the protein's flexibility. A Relaxed Complex Scheme methodology was used to screen 2000 MD conformations against the small molecule database, producing >1 billion protein-ligand structures. For each protein target, a binding spectrum was calculated to identify compounds predicted to bind with highest average affinity to all protein conformations. Significantly, four different Leishmania protein targets were predicted to strongly bind small molecules, with the strongest binding interactions predicted to occur for dihydroorotate dehydrogenase (LmDHODH; PDB:3MJY). A number of predicted tight-binding LmDHODH inhibitors were tested in vitro and potent selective inhibitors of Leishmania panamensis were identified. These promising small molecules are suitable for further development using iterative structure-based optimization and in vitro/in vivo validation assays.

Drug search for leishmaniasis: a virtual screening approach by grid computing.

PubMed

Ochoa, Rodrigo; Watowich, Stanley J; Flórez, Andrés; Mesa, Carol V; Robledo, Sara M; Muskus, Carlos

2016-07-01

The trypanosomatid protozoa Leishmania is endemic in ~100 countries, with infections causing ~2 million new cases of leishmaniasis annually. Disease symptoms can include severe skin and mucosal ulcers, fever, anemia, splenomegaly, and death. Unfortunately, therapeutics approved to treat leishmaniasis are associated with potentially severe side effects, including death. Furthermore, drug-resistant Leishmania parasites have developed in most endemic countries. To address an urgent need for new, safe and inexpensive anti-leishmanial drugs, we utilized the IBM World Community Grid to complete computer-based drug discovery screens (Drug Search for Leishmaniasis) using unique leishmanial proteins and a database of 600,000 drug-like small molecules. Protein structures from different Leishmania species were selected for molecular dynamics (MD) simulations, and a series of conformational "snapshots" were chosen from each MD trajectory to simulate the protein's flexibility. A Relaxed Complex Scheme methodology was used to screen ~2000 MD conformations against the small molecule database, producing >1 billion protein-ligand structures. For each protein target, a binding spectrum was calculated to identify compounds predicted to bind with highest average affinity to all protein conformations. Significantly, four different Leishmania protein targets were predicted to strongly bind small molecules, with the strongest binding interactions predicted to occur for dihydroorotate dehydrogenase (LmDHODH; PDB:3MJY). A number of predicted tight-binding LmDHODH inhibitors were tested in vitro and potent selective inhibitors of Leishmania panamensis were identified. These promising small molecules are suitable for further development using iterative structure-based optimization and in vitro/in vivo validation assays.

Solvent induced conformational fluctuation of alanine dipeptide studied by using vibrational probes

NASA Astrophysics Data System (ADS)

Cai, Kaicong; Du, Fenfen; Liu, Jia; Su, Tingting

2015-02-01

The solvation effect on the three dimensional structure and the vibrational feature of alanine dipeptide (ALAD) was evaluated by applying the implicit solvents from polarizable continuum solvent model (PCM) through ab initio calculations, by using molecular dynamic (MD) simulations with explicit solvents, and by combining these two approaches. The implicit solvent induced potential energy fluctuations of ALAD in CHCl3, DMSO and H2O are revealed by means of ab initio calculations, and a global view of conformational and solvation environmental dependence of amide I frequencies is achieved. The results from MD simulations with explicit solvents show that ALAD trends to form PPII, αL, αR, and C5 in water, PPII and C5 in DMSO, and C5 in CHCl3, ordered by population, and the demonstration of the solvated structure, the solute-solvent interaction and hydrogen bonding is therefore enhanced. Representative ALAD-solvent clusters were sampled from MD trajectories and undergone ab initio calculations. The explicit solvents reveal the hydrogen bonding between ALAD and solvents, and the correlation between amide I frequencies and the Cdbnd O bond length is built. The implicit solvents applied to the ALAD-solvent clusters further compensate the solvation effect from the bulk, and thus enlarge the degree of structural distortion and the amide I frequency red shift. The combination of explicit solvent in the first hydration shell and implicit solvent in the bulk is helpful for our understanding about the conformational fluctuation of solvated polypeptides through vibrational probes.

Binding free energy and counterion release for adsorption of the antimicrobial peptide lactoferricin B on a POPG membrane.

PubMed

Tolokh, Igor S; Vivcharuk, Victor; Tomberli, Bruno; Gray, C G

2009-09-01

Molecular dynamics (MD) simulations are used to study the interaction of an anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with a POPG bilayer is employed as a model system for studying the details of membrane adsorption selectivity of cationic antimicrobial peptides. Seventy eight 4 ns MD production run trajectories of the equilibrated system, with six restrained orientations of LFCinB at 13 different separations from the POPG membrane, are generated to determine the free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the profile for this relatively large system, a variant of constrained MD and thermodynamic integration is used. A simplified method for relating the free energy profile to the LFCinB-POPG membrane binding constant is employed to predict a free energy of adsorption of -5.4+/-1.3 kcal/mol and a corresponding maximum adsorption binding force of about 58 pN. We analyze the results using Poisson-Boltzmann theory. We find the peptide-membrane attraction to be dominated by the entropy increase due to the release of counterions and polarized water from the region between the charged membrane and peptide, as the two approach each other. We contrast these results with those found earlier for adsorption of LFCinB on the mammalianlike palmitoyl-oleoyl-phosphatidylcholine membrane.

Simulation studies of substrate recognition by the exocellulase CelF from Clostridium cellulolyticum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Mo; Himmel, Michael E.; Wilson, David B.

Molecular dynamics (MD) simulations were used to study substrate recognition by the family 48 exocellulase CelF from Clostridium cellulolyticum. It was hypothesized that residues around the entrance of the active site tunnel of this enzyme might serve to recognize and bind the substrate through an affinity for the cellulose monomer repeat unit, ..beta..-d-glucopyranose. Simulations were conducted of the catalytic domain of this enzyme surrounded by a concentrated solution of ..beta..-d-glucopyranose, and the full three-dimensional probability distribution for finding sugar molecules adjacent to the enzyme was calculated from the trajectory. A significant probability of finding the sugar stacked against the planarmore » faces of Trp 310 and Trp 312 at the entrance of the active site tunnel was observed.« less

Molecular dynamics simulation of trp-repressor/operator complex: analysis of hydrogen bond patterns of protein DNA interaction

NASA Astrophysics Data System (ADS)

Suenaga, A.; Yatsu, C.; Komeiji, Y.; Uebayasi, M.; Meguro, T.; Yamato, I.

2000-08-01

Molecular dynamics simulation of Escherichia colitrp-repressor/operator complex was performed to elucidate protein-DNA interactions in solution for 800 ps on special-purpose computer MD-GRAPE. The Ewald summation method was employed to treat the electrostatic interaction without cutoff. DNA kept stable conformation in comparison with the result of the conventional cutoff method. Thus, the trajectories obtained were used to analyze the protein-DNA interaction and to understand the role of dynamics of water molecules forming sequence specific recognition interface. The dynamical cross-correlation map showed a significant positive correlation between the helix-turn-helix DNA-binding motifs and the major grooves of operator DNA. The extensive contact surface was stable during the simulation. Most of the contacts consisted of direct interactions between phosphates of DNA and the protein, but several water-mediated polar contacts were also observed. These water-mediated interactions, which were also seen in the crystal structure (Z. Otwinowski, et al., Nature, 335 (1998) 321) emerged spontaneously from the randomized initial configuration of the solvent. This result suggests the importance of the water-mediated interaction in specific recognition of DNA by the trp-repressor, consistent with X-ray structural information.

Consistent View of Protein Fluctuations from All-Atom Molecular Dynamics and Coarse-Grained Dynamics with Knowledge-Based Force-Field.

PubMed

Jamroz, Michal; Orozco, Modesto; Kolinski, Andrzej; Kmiecik, Sebastian

2013-01-08

It is widely recognized that atomistic Molecular Dynamics (MD), a classical simulation method, captures the essential physics of protein dynamics. That idea is supported by a theoretical study showing that various MD force-fields provide a consensus picture of protein fluctuations in aqueous solution [Rueda, M. et al. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 796-801]. However, atomistic MD cannot be applied to most biologically relevant processes due to its limitation to relatively short time scales. Much longer time scales can be accessed by properly designed coarse-grained models. We demonstrate that the aforementioned consensus view of protein dynamics from short (nanosecond) time scale MD simulations is fairly consistent with the dynamics of the coarse-grained protein model - the CABS model. The CABS model employs stochastic dynamics (a Monte Carlo method) and a knowledge-based force-field, which is not biased toward the native structure of a simulated protein. Since CABS-based dynamics allows for the simulation of entire folding (or multiple folding events) in a single run, integration of the CABS approach with all-atom MD promises a convenient (and computationally feasible) means for the long-time multiscale molecular modeling of protein systems with atomistic resolution.

Free Energy Calculations using a Swarm-Enhanced Sampling Molecular Dynamics Approach.

PubMed

Burusco, Kepa K; Bruce, Neil J; Alibay, Irfan; Bryce, Richard A

2015-10-26

Free energy simulations are an established computational tool in modelling chemical change in the condensed phase. However, sampling of kinetically distinct substates remains a challenge to these approaches. As a route to addressing this, we link the methods of thermodynamic integration (TI) and swarm-enhanced sampling molecular dynamics (sesMD), where simulation replicas interact cooperatively to aid transitions over energy barriers. We illustrate the approach by using alchemical alkane transformations in solution, comparing them with the multiple independent trajectory TI (IT-TI) method. Free energy changes for transitions computed by using IT-TI grew increasingly inaccurate as the intramolecular barrier was heightened. By contrast, swarm-enhanced sampling TI (sesTI) calculations showed clear improvements in sampling efficiency, leading to more accurate computed free energy differences, even in the case of the highest barrier height. The sesTI approach, therefore, has potential in addressing chemical change in systems where conformations exist in slow exchange. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Equilibration and analysis of first-principles molecular dynamics simulations of water

NASA Astrophysics Data System (ADS)

Dawson, William; Gygi, François

2018-03-01

First-principles molecular dynamics (FPMD) simulations based on density functional theory are becoming increasingly popular for the description of liquids. In view of the high computational cost of these simulations, the choice of an appropriate equilibration protocol is critical. We assess two methods of estimation of equilibration times using a large dataset of first-principles molecular dynamics simulations of water. The Gelman-Rubin potential scale reduction factor [A. Gelman and D. B. Rubin, Stat. Sci. 7, 457 (1992)] and the marginal standard error rule heuristic proposed by White [Simulation 69, 323 (1997)] are evaluated on a set of 32 independent 64-molecule simulations of 58 ps each, amounting to a combined cumulative time of 1.85 ns. The availability of multiple independent simulations also allows for an estimation of the variance of averaged quantities, both within MD runs and between runs. We analyze atomic trajectories, focusing on correlations of the Kohn-Sham energy, pair correlation functions, number of hydrogen bonds, and diffusion coefficient. The observed variability across samples provides a measure of the uncertainty associated with these quantities, thus facilitating meaningful comparisons of different approximations used in the simulations. We find that the computed diffusion coefficient and average number of hydrogen bonds are affected by a significant uncertainty in spite of the large size of the dataset used. A comparison with classical simulations using the TIP4P/2005 model confirms that the variability of the diffusivity is also observed after long equilibration times. Complete atomic trajectories and simulation output files are available online for further analysis.

Equilibration and analysis of first-principles molecular dynamics simulations of water.

PubMed

Dawson, William; Gygi, François

2018-03-28

First-principles molecular dynamics (FPMD) simulations based on density functional theory are becoming increasingly popular for the description of liquids. In view of the high computational cost of these simulations, the choice of an appropriate equilibration protocol is critical. We assess two methods of estimation of equilibration times using a large dataset of first-principles molecular dynamics simulations of water. The Gelman-Rubin potential scale reduction factor [A. Gelman and D. B. Rubin, Stat. Sci. 7, 457 (1992)] and the marginal standard error rule heuristic proposed by White [Simulation 69, 323 (1997)] are evaluated on a set of 32 independent 64-molecule simulations of 58 ps each, amounting to a combined cumulative time of 1.85 ns. The availability of multiple independent simulations also allows for an estimation of the variance of averaged quantities, both within MD runs and between runs. We analyze atomic trajectories, focusing on correlations of the Kohn-Sham energy, pair correlation functions, number of hydrogen bonds, and diffusion coefficient. The observed variability across samples provides a measure of the uncertainty associated with these quantities, thus facilitating meaningful comparisons of different approximations used in the simulations. We find that the computed diffusion coefficient and average number of hydrogen bonds are affected by a significant uncertainty in spite of the large size of the dataset used. A comparison with classical simulations using the TIP4P/2005 model confirms that the variability of the diffusivity is also observed after long equilibration times. Complete atomic trajectories and simulation output files are available online for further analysis.

Using collective variables to drive molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Fiorin, Giacomo; Klein, Michael L.; Hénin, Jérôme

2013-12-01

A software framework is introduced that facilitates the application of biasing algorithms to collective variables of the type commonly employed to drive massively parallel molecular dynamics (MD) simulations. The modular framework that is presented enables one to combine existing collective variables into new ones, and combine any chosen collective variable with available biasing methods. The latter include the classic time-dependent biases referred to as steered MD and targeted MD, the temperature-accelerated MD algorithm, as well as the adaptive free-energy biases called metadynamics and adaptive biasing force. The present modular software is extensible, and portable between commonly used MD simulation engines.

Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC)

PubMed Central

Galindo-Murillo, Rodrigo; Roe, Daniel R.; Cheatham, Thomas E.

2014-01-01

Background The structure and dynamics of DNA are critically related to its function. Molecular dynamics (MD) simulations augment experiment by providing detailed information about the atomic motions. However, to date the simulations have not been long enough for convergence of the dynamics and structural properties of DNA. Methods MD simulations performed with AMBER using the ff99SB force field with the parmbsc0 modifications, including ensembles of independent simulations, were compared to long timescale MD performed with the specialized Anton MD engine on the B-DNA structure d(GCACGAACGAACGAACGC). To assess convergence, the decay of the average RMSD values over longer and longer time intervals was evaluated in addition to assessing convergence of the dynamics via the Kullback-Leibler divergence of principal component projection histograms. Results These MD simulations —including one of the longest simulations of DNA published to date at ~44 μs—surprisingly suggest that the structure and dynamics of the DNA helix, neglecting the terminal base pairs, are essentially fully converged on the ~1–5 μs timescale. Conclusions We can now reproducibly converge the structure and dynamics of B-DNA helices, omitting the terminal base pairs, on the μs time scale with both the AMBER and CHARMM C36 nucleic acid force fields. Results from independent ensembles of simulations starting from different initial conditions, when aggregated, match the results from long timescale simulations on the specialized Anton MD engine. General Significance With access to large-scale GPU resources or the specialized MD engine “Anton” it is possibly for a variety of molecular systems to reproducibly and reliably converge the conformational ensemble of sampled structures. PMID:25219455

Conformational and dynamics changes induced by bile acids binding to chicken liver bile acid binding protein.

PubMed

Eberini, Ivano; Guerini Rocco, Alessandro; Ientile, Anna Rita; Baptista, António M; Gianazza, Elisabetta; Tomaselli, Simona; Molinari, Henriette; Ragona, Laura

2008-06-01

The correlation between protein motions and function is a central problem in protein science. Several studies have demonstrated that ligand binding and protein dynamics are strongly correlated in intracellular lipid binding proteins (iLBPs), in which the high degree of flexibility, principally occurring at the level of helix-II, CD, and EF loops (the so-called portal area), is significantly reduced upon ligand binding. We have recently investigated by NMR the dynamic properties of a member of the iLBP family, chicken liver bile acid binding protein (cL-BABP), in its apo and holo form, as a complex with two bile salts molecules. Binding was found to be regulated by a dynamic process and a conformational rearrangement was associated with this event. We report here the results of molecular dynamics (MD) simulations performed on apo and holo cL-BABP with the aim of further characterizing the protein regions involved in motion propagation and of evaluating the main molecular interactions stabilizing bound ligands. Upon binding, the root mean square fluctuation values substantially decrease for CD and EF loops while increase for the helix-loop-helix region, thus indicating that the portal area is the region mostly affected by complex formation. These results nicely correlate with backbone dynamics data derived from NMR experiments. Essential dynamics analysis of the MD trajectories indicates that the major concerted motions involve the three contiguous structural elements of the portal area, which however are dynamically coupled in different ways whether in the presence or in the absence of the ligands. Motions of the EF loop and of the helical region are part of the essential space of both apo and holo-BABP and sample a much wider conformational space in the apo form. Together with NMR results, these data support the view that, in the apo protein, the flexible EF loop visits many conformational states including those typical of the holo state and that the ligand acts stabilizing one of these pre-existing conformations. The present results, in agreement with data reported for other iLBPs, sharpen our knowledge on the binding mechanism for this protein family. (c) 2008 Wiley-Liss, Inc.

Accelerated molecular dynamics simulations of protein folding.

PubMed

Miao, Yinglong; Feixas, Ferran; Eun, Changsun; McCammon, J Andrew

2015-07-30

Folding of four fast-folding proteins, including chignolin, Trp-cage, villin headpiece and WW domain, was simulated via accelerated molecular dynamics (aMD). In comparison with hundred-of-microsecond timescale conventional molecular dynamics (cMD) simulations performed on the Anton supercomputer, aMD captured complete folding of the four proteins in significantly shorter simulation time. The folded protein conformations were found within 0.2-2.1 Å of the native NMR or X-ray crystal structures. Free energy profiles calculated through improved reweighting of the aMD simulations using cumulant expansion to the second-order are in good agreement with those obtained from cMD simulations. This allows us to identify distinct conformational states (e.g., unfolded and intermediate) other than the native structure and the protein folding energy barriers. Detailed analysis of protein secondary structures and local key residue interactions provided important insights into the protein folding pathways. Furthermore, the selections of force fields and aMD simulation parameters are discussed in detail. Our work shows usefulness and accuracy of aMD in studying protein folding, providing basic references in using aMD in future protein-folding studies. © 2015 Wiley Periodicals, Inc.

Enhanced conformational sampling of nucleic acids by a new Hamiltonian replica exchange molecular dynamics approach.

PubMed

Curuksu, Jeremy; Zacharias, Martin

2009-03-14

Although molecular dynamics (MD) simulations have been applied frequently to study flexible molecules, the sampling of conformational states separated by barriers is limited due to currently possible simulation time scales. Replica-exchange (Rex)MD simulations that allow for exchanges between simulations performed at different temperatures (T-RexMD) can achieve improved conformational sampling. However, in the case of T-RexMD the computational demand grows rapidly with system size. A Hamiltonian RexMD method that specifically enhances coupled dihedral angle transitions has been developed. The method employs added biasing potentials as replica parameters that destabilize available dihedral substates and was applied to study coupled dihedral transitions in nucleic acid molecules. The biasing potentials can be either fixed at the beginning of the simulation or optimized during an equilibration phase. The method was extensively tested and compared to conventional MD simulations and T-RexMD simulations on an adenine dinucleotide system and on a DNA abasic site. The biasing potential RexMD method showed improved sampling of conformational substates compared to conventional MD simulations similar to T-RexMD simulations but at a fraction of the computational demand. It is well suited to study systematically the fine structure and dynamics of large nucleic acids under realistic conditions including explicit solvent and ions and can be easily extended to other types of molecules.

Parallel cascade selection molecular dynamics (PaCS-MD) to generate conformational transition pathway

NASA Astrophysics Data System (ADS)

Harada, Ryuhei; Kitao, Akio

2013-07-01

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) is proposed as a molecular simulation method to generate conformational transition pathway under the condition that a set of "reactant" and "product" structures is known a priori. In PaCS-MD, the cycle of short multiple independent molecular dynamics simulations and selection of the structures close to the product structure for the next cycle are repeated until the simulated structures move sufficiently close to the product. Folding of 10-residue mini-protein chignolin from the extended to native structures and open-close conformational transition of T4 lysozyme were investigated by PaCS-MD. In both cases, tens of cycles of 100-ps MD were sufficient to reach the product structures, indicating the efficient generation of conformational transition pathway in PaCS-MD with a series of conventional MD without additional external biases. Using the snapshots along the pathway as the initial coordinates, free energy landscapes were calculated by the combination with multiple independent umbrella samplings to statistically elucidate the conformational transition pathways.

A high performance system for molecular dynamics simulation of biomolecules using a special-purpose computer.

PubMed

Komeiji, Y; Yokoyama, H; Uebayasi, M; Taiji, M; Fukushige, T; Sugimoto, D; Takata, R; Shimizu, A; Itsukashi, K

1996-01-01

GRAPE (GRavity PipE) processors are special purpose computers for simulation of classical particles. The performance of MD-GRAPE, one of the GRAPEs developed for molecular dynamics, was investigated. The effective speed of MD-GRAPE was equivalent to approximately 6 Gflops. The precision of MD-GRAPE was good judging from the acceptable fluctuation of the total energy. Then a software named PEACH (Program for Energetic Analysis of bioCHemical molecules) was developed for molecular dynamics of biomolecules in combination with MD-GRAPE. Molecular dynamics simulation was performed for several protein-solvent systems with different sizes. Simulation of the largest system investigated (27,000 atoms) took only 5 sec/step. Thus, the PEACH-GRAPE system is expected to be useful in accurate and reliable simulation of large biomolecules.

Molecular dynamics coupled with a virtual system for effective conformational sampling.

PubMed

Hayami, Tomonori; Kasahara, Kota; Nakamura, Haruki; Higo, Junichi

2018-07-15

An enhanced conformational sampling method is proposed: virtual-system coupled canonical molecular dynamics (VcMD). Although VcMD enhances sampling along a reaction coordinate, this method is free from estimation of a canonical distribution function along the reaction coordinate. This method introduces a virtual system that does not necessarily obey a physical law. To enhance sampling the virtual system couples with a molecular system to be studied. Resultant snapshots produce a canonical ensemble. This method was applied to a system consisting of two short peptides in an explicit solvent. Conventional molecular dynamics simulation, which is ten times longer than VcMD, was performed along with adaptive umbrella sampling. Free-energy landscapes computed from the three simulations mutually converged well. The VcMD provided quicker association/dissociation motions of peptides than the conventional molecular dynamics did. The VcMD method is applicable to various complicated systems because of its methodological simplicity. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Applicability of effective fragment potential version 2 - Molecular dynamics (EFP2-MD) simulations for predicting excess properties of mixed solvents

NASA Astrophysics Data System (ADS)

Kuroki, Nahoko; Mori, Hirotoshi

2018-02-01

Effective fragment potential version 2 - molecular dynamics (EFP2-MD) simulations, where the EFP2 is a polarizable force field based on ab initio electronic structure calculations were applied to water-methanol binary mixture. Comparing EFP2s defined with (aug-)cc-pVXZ (X = D,T) basis sets, it was found that large sets are necessary to generate sufficiently accurate EFP2 for predicting mixture properties. It was shown that EFP2-MD could predict the excess molar volume. Since the computational cost of EFP2-MD are far less than ab initio MD, the results presented herein demonstrate that EFP2-MD is promising for predicting physicochemical properties of novel mixed solvents.

Molecular Dynamics Simulations and XAFS (MD-XAFS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schenter, Gregory K.; Fulton, John L.

2017-01-20

MD-XAFS (Molecular Dynamics X-ray Adsorption Fine Structure) makes the connection between simulation techniques that generate an ensemble of molecular configurations and the direct signal observed from X-ray measurement.

Conformational transition in signal transduction: metastable states and transition pathways in the activation of a signaling protein.

PubMed

Banerjee, Rahul; Yan, Honggao; Cukier, Robert I

2015-06-04

Signal transduction is of vital importance to the growth and adaptation of living organisms. The key to understand mechanisms of biological signal transduction is elucidation of the conformational dynamics of its signaling proteins, as the activation of a signaling protein is fundamentally a process of conformational transition from an inactive to an active state. A predominant form of signal transduction for bacterial sensing of environmental changes in the wild or inside their hosts is a variety of two-component systems, in which the conformational transition of a response regulator (RR) from an inactive to an active state initiates responses to the environmental changes. Here, RR activation has been investigated using RR468 as a model system by extensive unbiased all-atom molecular dynamics (MD) simulations in explicit solvent, starting from snapshots along a targeted MD trajectory that covers the conformational transition. Markov state modeling, transition path theory, and geometric analyses of the wealth of the MD data have provided a comprehensive description of the RR activation. It involves a network of metastable states, with one metastable state essentially the same as the inactive state and another very similar to the active state that are connected via a small set of intermediates. Five major pathways account for >75% of the fluxes of the conformational transition from the inactive to the active-like state. The thermodynamic stability of the states and the activation barriers between states are found, to identify rate-limiting steps. The conformal transition is initiated predominantly by movements of the β3α3 loop, followed by movements of the β4α4-loop and neighboring α4 helix region, and capped by additional movements of the β3α3 loop. A number of transient hydrophobic and hydrogen bond interactions are revealed, and they may be important for the conformational transition.

Insights from molecular dynamics simulations for computational protein design.

PubMed

Childers, Matthew Carter; Daggett, Valerie

2017-02-01

A grand challenge in the field of structural biology is to design and engineer proteins that exhibit targeted functions. Although much success on this front has been achieved, design success rates remain low, an ever-present reminder of our limited understanding of the relationship between amino acid sequences and the structures they adopt. In addition to experimental techniques and rational design strategies, computational methods have been employed to aid in the design and engineering of proteins. Molecular dynamics (MD) is one such method that simulates the motions of proteins according to classical dynamics. Here, we review how insights into protein dynamics derived from MD simulations have influenced the design of proteins. One of the greatest strengths of MD is its capacity to reveal information beyond what is available in the static structures deposited in the Protein Data Bank. In this regard simulations can be used to directly guide protein design by providing atomistic details of the dynamic molecular interactions contributing to protein stability and function. MD simulations can also be used as a virtual screening tool to rank, select, identify, and assess potential designs. MD is uniquely poised to inform protein design efforts where the application requires realistic models of protein dynamics and atomic level descriptions of the relationship between dynamics and function. Here, we review cases where MD simulations was used to modulate protein stability and protein function by providing information regarding the conformation(s), conformational transitions, interactions, and dynamics that govern stability and function. In addition, we discuss cases where conformations from protein folding/unfolding simulations have been exploited for protein design, yielding novel outcomes that could not be obtained from static structures.

Insights from molecular dynamics simulations for computational protein design

PubMed Central

Childers, Matthew Carter; Daggett, Valerie

2017-01-01

A grand challenge in the field of structural biology is to design and engineer proteins that exhibit targeted functions. Although much success on this front has been achieved, design success rates remain low, an ever-present reminder of our limited understanding of the relationship between amino acid sequences and the structures they adopt. In addition to experimental techniques and rational design strategies, computational methods have been employed to aid in the design and engineering of proteins. Molecular dynamics (MD) is one such method that simulates the motions of proteins according to classical dynamics. Here, we review how insights into protein dynamics derived from MD simulations have influenced the design of proteins. One of the greatest strengths of MD is its capacity to reveal information beyond what is available in the static structures deposited in the Protein Data Bank. In this regard simulations can be used to directly guide protein design by providing atomistic details of the dynamic molecular interactions contributing to protein stability and function. MD simulations can also be used as a virtual screening tool to rank, select, identify, and assess potential designs. MD is uniquely poised to inform protein design efforts where the application requires realistic models of protein dynamics and atomic level descriptions of the relationship between dynamics and function. Here, we review cases where MD simulations was used to modulate protein stability and protein function by providing information regarding the conformation(s), conformational transitions, interactions, and dynamics that govern stability and function. In addition, we discuss cases where conformations from protein folding/unfolding simulations have been exploited for protein design, yielding novel outcomes that could not be obtained from static structures. PMID:28239489

Edge effects control helical wrapping of carbon nanotubes by polysaccharides

NASA Astrophysics Data System (ADS)

Liu, Yingzhe; Chipot, Christophe; Shao, Xueguang; Cai, Wensheng

2012-03-01

Carbon nanotubes (CNTs) wrapped by polysaccharide chains via noncovalent interactions have been shown to be soluble and dispersed in aqueous environments, and have several potential chemical and biomedical applications. The wrapping mechanism, in particular the role played by the end of the CNT, remains, however, unknown. In this work, a hybrid complex formed by an amylose (AMYL) chain and a single-walled carbon nanotube (SWNT) has been examined by means of atomistic molecular dynamics (MD) simulations to assess its propensity toward self-assembly, alongside its structural characteristics in water. To explore edge effects, the middle and end regions of the SWNT have been chosen as two initial wrapping sites, to which two relative orientations have been assigned, i.e. parallel and orthogonal. The present results prove that AMYL can wrap spontaneously around the tubular surface, starting from the end of the SWNT and driven by both favorable van der Waals attraction and hydrophobic interactions, and resulting in a perfectly compact, helical conformation stabilized by an interlaced hydrogen-bond network. Principal component analysis carried out over the MD trajectories reveals that stepwise burial of hydrophobic faces of pyranose rings controlled by hydrophobic interactions is a key step in the formation of the helix. Conversely, if wrapping proceeds from the middle of the SWNT, self-organization into a helical structure is not observed due to strong van der Waals attractions preventing the hydrophobic faces of the AMYL chain generating enough contacts with the tubular surface.Carbon nanotubes (CNTs) wrapped by polysaccharide chains via noncovalent interactions have been shown to be soluble and dispersed in aqueous environments, and have several potential chemical and biomedical applications. The wrapping mechanism, in particular the role played by the end of the CNT, remains, however, unknown. In this work, a hybrid complex formed by an amylose (AMYL) chain and a single-walled carbon nanotube (SWNT) has been examined by means of atomistic molecular dynamics (MD) simulations to assess its propensity toward self-assembly, alongside its structural characteristics in water. To explore edge effects, the middle and end regions of the SWNT have been chosen as two initial wrapping sites, to which two relative orientations have been assigned, i.e. parallel and orthogonal. The present results prove that AMYL can wrap spontaneously around the tubular surface, starting from the end of the SWNT and driven by both favorable van der Waals attraction and hydrophobic interactions, and resulting in a perfectly compact, helical conformation stabilized by an interlaced hydrogen-bond network. Principal component analysis carried out over the MD trajectories reveals that stepwise burial of hydrophobic faces of pyranose rings controlled by hydrophobic interactions is a key step in the formation of the helix. Conversely, if wrapping proceeds from the middle of the SWNT, self-organization into a helical structure is not observed due to strong van der Waals attractions preventing the hydrophobic faces of the AMYL chain generating enough contacts with the tubular surface. Electronic supplementary information (ESI) available: Table S1 shows the details of the systems for molecular dynamics simulations. Figure S1 shows time evolution of the distance RMSD over the heavy atoms of the AMYL chain with respect to the initial structure. The hydrogen-bond network including inter-residue and inter-turn hydrogen bonds monitored in the course of self-assembly is delineated in Figure S2. Figure S3 shows the equilibrium conformation of the initial right-handed AMYL chain wrapping the nanotube. See DOI: 10.1039/c2nr11979j

Role of electrostatic interactions in binding of peptides and intrinsically disordered proteins to their folded targets. 1. NMR and MD characterization of the complex between the c-Crk N-SH3 domain and the peptide Sos.

PubMed

Xue, Yi; Yuwen, Tairan; Zhu, Fangqiang; Skrynnikov, Nikolai R

2014-10-21

Intrinsically disordered proteins (IDPs) often rely on electrostatic interactions to bind their structured targets. To obtain insight into the mechanism of formation of the electrostatic encounter complex, we investigated the binding of the peptide Sos (PPPVPPRRRR), which serves as a minimal model for an IDP, to the c-Crk N-terminal SH3 domain. Initially, we measured ¹⁵N relaxation rates at two magnetic field strengths and determined the binding shifts for the complex of Sos with wild-type SH3. We have also recorded a 3 μs molecular dynamics (MD) trajectory of this complex using the Amber ff99SB*-ILDN force field. The comparison of the experimental and simulated data shows that MD simulation consistently overestimates the strength of salt bridge interactions at the binding interface. The series of simulations using other advanced force fields also failed to produce any satisfactory results. To address this issue, we have devised an empirical correction to the Amber ff99SB*-ILDN force field whereby the Lennard-Jones equilibrium distance for the nitrogen-oxygen pair across the Arg-to-Asp and Arg-to-Glu salt bridges has been increased by 3%. Implementing this correction resulted in a good agreement between the simulations and the experiment. Adjusting the strength of salt bridge interactions removed a certain amount of strain contained in the original MD model, thus improving the binding of the hydrophobic N-terminal portion of the peptide. The arginine-rich C-terminal portion of the peptide, freed from the effect of the overstabilized salt bridges, was found to interconvert more rapidly between its multiple conformational states. The modified MD protocol has also been successfully used to simulate the entire binding process. In doing so, the peptide was initially placed high above the protein surface. It then arrived at the correct bound pose within ∼2 Å of the crystallographic coordinates. This simulation allowed us to analyze the details of the dynamic binding intermediate, i.e., the electrostatic encounter complex. However, an experimental characterization of this transient, weakly populated state remains out of reach. To overcome this problem, we designed the double mutant of c-Crk N-SH3 in which mutations Y186L and W169F abrogate tight Sos binding and shift the equilibrium toward the intermediate state resembling the electrostatic encounter complex. The results of the combined NMR and MD study of this engineered system will be reported in the next part of this paper.

Tutorial: Determination of thermal boundary resistance by molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Liang, Zhi; Hu, Ming

2018-05-01

Due to the high surface-to-volume ratio of nanostructured components in microelectronics and other advanced devices, the thermal resistance at material interfaces can strongly affect the overall thermal behavior in these devices. Therefore, the thermal boundary resistance, R, must be taken into account in the thermal analysis of nanoscale structures and devices. This article is a tutorial on the determination of R and the analysis of interfacial thermal transport via molecular dynamics (MD) simulations. In addition to reviewing the commonly used equilibrium and non-equilibrium MD models for the determination of R, we also discuss several MD simulation methods which can be used to understand interfacial thermal transport behavior. To illustrate how these MD models work for various interfaces, we will show several examples of MD simulation results on thermal transport across solid-solid, solid-liquid, and solid-gas interfaces. The advantages and drawbacks of a few other MD models such as approach-to-equilibrium MD and first-principles MD are also discussed.

Molecular basis of HHQ biosynthesis: molecular dynamics simulations, enzyme kinetic and surface plasmon resonance studies

PubMed Central

2013-01-01

Background PQS (PseudomonasQuinolone Signal) and its precursor HHQ are signal molecules of the P. aeruginosa quorum sensing system. They explicate their role in mammalian pathogenicity by binding to the receptor PqsR that induces virulence factor production and biofilm formation. The enzyme PqsD catalyses the biosynthesis of HHQ. Results Enzyme kinetic analysis and surface plasmon resonance (SPR) biosensor experiments were used to determine mechanism and substrate order of the biosynthesis. Comparative analysis led to the identification of domains involved in functionality of PqsD. A kinetic cycle was set up and molecular dynamics (MD) simulations were used to study the molecular bases of the kinetics of PqsD. Trajectory analysis, pocket volume measurements, binding energy estimations and decompositions ensured insights into the binding mode of the substrates anthraniloyl-CoA and β-ketodecanoic acid. Conclusions Enzyme kinetics and SPR experiments hint at a ping-pong mechanism for PqsD with ACoA as first substrate. Trajectory analysis of different PqsD complexes evidenced ligand-dependent induced-fit motions affecting the modified ACoA funnel access to the exposure of a secondary channel. A tunnel-network is formed in which Ser317 plays an important role by binding to both substrates. Mutagenesis experiments resulting in the inactive S317F mutant confirmed the importance of this residue. Two binding modes for β-ketodecanoic acid were identified with distinct catalytic mechanism preferences. PMID:23916145

Proton transfer to charged platinum electrodes. A molecular dynamics trajectory study.

PubMed

Wilhelm, Florian; Schmickler, Wolfgang; Spohr, Eckhard

2010-05-05

A recently developed empirical valence bond (EVB) model for proton transfer on Pt(111) electrodes (Wilhelm et al 2008 J. Phys. Chem. C 112 10814) has been applied in molecular dynamics (MD) simulations of a water film in contact with a charged Pt surface. A total of seven negative surface charge densities σ between -7.5 and -18.9 µC cm(-2) were investigated. For each value of σ, between 30 and 84 initial conditions of a solvated proton within a water slab were sampled, and the trajectories were integrated until discharge of a proton occurred on the charged surfaces. We have calculated the mean rates for discharge and for adsorption of solvated protons within the adsorbed water layer in contact with the metal electrode as a function of surface charge density. For the less negative values of σ we observe a Tafel-like exponential increase of discharge rate with decreasing σ. At the more negative values this exponential increase levels off and the discharge process is apparently transport limited. Mechanistically, the Tafel regime corresponds to a stepwise proton transfer: first, a proton is transferred from the bulk into the contact water layer, which is followed by transfer of a proton to the charged surface and concomitant discharge. At the more negative surface charge densities the proton transfer into the contact water layer and the transfer of another proton to the surface and its discharge occur almost simultaneously.

Resolvent analysis of exact coherent solutions

NASA Astrophysics Data System (ADS)

Rosenberg, Kevin; McKeon, Beverley

2017-11-01

Exact coherent solutions have been hypothesized to constitute the state-space skeleton of turbulent trajectories and thus are of interest as a means to better understand the underlying dynamics of turbulent flows. An asymptotic description of how these types of solutions self-sustain was provided by Hall & Sherwin. Here we offer a fully-nonlinear perspective on the self-sustainment of these solutions in terms of triadic scale interactions and use the resolvent framework of McKeon & Sharma to interpret these results from an input/output point of view. We analyze traveling wave solutions and periodic orbits in channel flow, and demonstrate how resolvent analysis can be used to obtain low-dimensional representations of these flows. We gratefully acknowledge funding from the AFOSR (FA9550-16-1-0361) and J.S. Park, M.D. Graham, and J.F. Gibson for providing data for the ECS solutions.

Evaporation of tiny water aggregation on solid surfaces with different wetting properties.

PubMed

Wang, Shen; Tu, Yusong; Wan, Rongzheng; Fang, Haiping

2012-11-29

The evaporation of a tiny amount of water on the solid surface with different wettabilities has been studied by molecular dynamics simulations. From nonequilibrium MD simulations, we found that, as the surface changed from hydrophobic to hydrophilic, the evaporation speed did not show a monotonic decrease as intuitively expected, but increased first, and then decreased after it reached a maximum value. The analysis of the simulation trajectory and calculation of the surface water interaction illustrate that the competition between the number of water molecules on the water-gas surface from where the water molecules can evaporate and the potential barrier to prevent those water molecules from evaporating results in the unexpected behavior of the evaporation. This finding is helpful in understanding the evaporation on biological surfaces, designing artificial surfaces of ultrafast water evaporating, or preserving water in soil.

Effects of two-temperature model on cascade evolution in Ni and NiFe

DOE PAGES

Samolyuk, German D.; Xue, Haizhou; Bei, Hongbin; ...

2016-07-05

We perform molecular dynamics simulations of Ni ion cascades in Ni and equiatomic NiFe under the following conditions: (a) classical molecular dynamics (MD) simulations without consideration of electronic energy loss, (b) classical MD simulations with the electronic stopping included, and (c) using the coupled two-temperature MD (2T-MD) model that incorporates both the electronic stopping and the electron-phonon interactions. Our results indicate that the electronic effects are more profound in the higher-energy cascades, and that the 2T-MD model results in a smaller amount of surviving damage and smaller defect clusters, while less damage is produced in NiFe than in Ni.

Atomistic non-adiabatic dynamics of the LH2 complex with a GPU-accelerated ab initio exciton model

DOE PAGES

Sisto, Aaron; Stross, Clem; van der Kamp, Marc W.; ...

2017-03-28

We recently outlined an efficient multi-tiered parallel ab initio excitonic framework that utilizes time dependent density functional theory (TDDFT) to calculate ground and excited state energies and gradients of large supramolecular complexes in atomistic detail – enabling us to undertake non-adiabatic simulations which explicitly account for the coupled anharmonic vibrational motion of all the constituent atoms in a supramolecular system. Here we apply that framework to the 27 coupled bacterio-chlorophyll-a chromophores which make up the LH2 complex, using it to compute an on-the-fly nonadiabatic surface-hopping (SH) trajectory of electronically excited LH2. Part one of this article is focussed on calibratingmore » our ab initio exciton Hamiltonian using two key parameters: a shift δ, which corrects for the error in TDDFT vertical excitation energies; and an effective dielectric constant ε, which describes the average screening of the transition-dipole coupling between chromophores. Using snapshots obtained from equilibrium molecular dynamics simulations (MD) of LH2, we tune the values of both δ and ε through fitting to the thermally broadened experimental absorption spectrum, giving a linear absorption spectrum that agrees reasonably well with experiment. In part two of this article, we construct a time-resolved picture of the coupled vibrational and excitation energy transfer (EET) dynamics in the sub-picosecond regime following photo-excitation. Assuming Franck–Condon excitation of a narrow eigenstate band centred at 800 nm, we use surface hopping to follow a single nonadiabatic dynamics trajectory within the full eigenstate manifold. Consistent with experimental data, this trajectory gives timescales for B800→B850 population transfer (τ B800→B850) between 650–1050 fs, and B800 population decay (τ 800→) between 10–50 fs. The dynamical picture that emerges is one of rapidly fluctuating LH2 eigenstates that are delocalized over multiple chromophores and undergo frequent crossing on a femtosecond timescale as a result of the atomic vibrations of the constituent chromophores. The eigenstate fluctuations arise from disorder that is driven by vibrational dynamics with multiple characteristic timescales. The scalability of our ab initio excitonic computational framework across massively parallel architectures opens up the possibility of addressing a wide range of questions, including how specific dynamical motions impact both the pathways and efficiency of electronic energy-transfer within large supramolecular systems.« less

Charge-dependent conformations and dynamics of pamam dendrimers revealed by neutron scattering and molecular dynamics

NASA Astrophysics Data System (ADS)

Wu, Bin

Neutron scattering and fully atomistic molecular dynamics (MD) are employed to investigate the structural and dynamical properties of polyamidoamine (PAMAM) dendrimers with ethylenediamine (EDA) core under various charge conditions. Regarding to the conformational characteristics, we focus on scrutinizing density profile evolution of PAMAM dendrimers as the molecular charge of dendrimer increases from neutral state to highly charged condition. It should be noted that within the context of small angle neutron scattering (SANS), the dendrimers are composed of hydrocarbon component (dry part) and the penetrating water molecules. Though there have been SANS experiments that studied the charge-dependent structural change of PAMAM dendrimers, their results were limited to the collective behavior of the aforementioned two parts. This study is devoted to deepen the understanding towards the structural responsiveness of intra-molecular polymeric and hydration parts separately through advanced contrast variation SANS data analysis scheme available recently and unravel the governing principles through coupling with MD simulations. Two kinds of acids, namely hydrochloric and sulfuric acids, are utilized to tune the pH condition and hence the molecular charge. As far as the dynamical properties, we target at understanding the underlying mechanism that leads to segmental dynamic enhancement observed from quasielstic neutron scattering (QENS) experiment previously. PAMAM dendrimers have a wealth of potential applications, such as drug delivery agency, energy harvesting medium, and light emitting diodes. More importantly, it is regarded as an ideal system to test many theoretical predictions since dendrimers conjugate both colloid-like globular shape and polymer-like flexible chains. This Ph.D. research addresses two main challenges in studying PAMAM dendrimers. Even though neutron scattering is an ideal tool to study this PAMAM dendrimer solution due to its matching temporal and spatial instrumental scales, understanding experimental results involves extensive and difficult data analysis based on liquid theory and condensed matter physics. Therefore, a model that successfully describes the inter- and intra-dendrimer correlations is crucial in obtaining and delivering reliable information. On the other hand, making meaningful comparisons between molecular dynamics and neutron scattering is a fundamental challenge to link simulations and experiments at the nano-scale. This challenge stems from our approach to utilize MD simulation to explain the underlying mechanism of experimental observation. The SANS measurements were conducted on a series of SANS spectrometers including the Extended Q-Range Small-Angle Neutron Scattering Diffractometer (EQ-SANS) and the General-Purpose Small-Angle Neutron Scattering Diffractometer (GP-SANS) at the Oak Ridge National Laboratory (ORNL), and NG7 Small Angle Neutron Scattering Spectrometer at National Institute of Standards (NIST) and Technology in U.S.A., large dynamic range small-angle diffractometer D22 at Institut Laue-Langevin (ILL) in France, and 40m-SANS Spectrometer at Korea Atomic Energy Research Institute (KAERI) in Korea. On the other hand, the Amber molecular dynamics simulation package is utilized to carry out the computational study. In this dissertation, the following observations have been revealed. The previously developed theoretical model for polyelectrolyte dendrimers are adopted to analyze SANS measurements and superb model fitting quality is found. Coupling with advanced contrast variation small angle neutron scattering (CVSANS) data analysis scheme reported recently, the intra-dendrimer hydration and hydrocarbon components distributions are revealed experimentally. The results indeed indicate that the maximum density is located in the molecular center rather than periphery, which is consistent to previous SANS studies and the back-folding picture of PAMAM dendrimers. According to this picture, at neutral condition, the exterior residues folding back into interior would necessarily lead to higher entropy and equivalently lower free energy and thereby is energetically favored. As one decreases the pH condition of PAMAM dendrimers, the constituent residues would carry positive charges. The resultant inter-residue Coulomb repulsion would naturally result in conformational evolution. We found from CVSANS analysis that when dendrimers are charged by different acids, this conformational evolution is not the same. For dendrimers charged by DCl, the mass is seen to relocate from molecular interior to periphery. Nevertheless, those acidified by D 2SO4 exhibit surprisingly minor structural change under variation of molecular charge. To explain the above observation, we performed MD simulations and calculated the excess free energy of Cl- and SO 42- counterions. The binding between sulfate ions and charged amines of PAMAM dendrimers are found to be much stronger than the case for chlorides. This more energetic binding would serve as better screening effect among charged residues. Consequently, electrostatic repulsion triggered outstretching tendency is effectively diminished. In order to make direct comparison between MD simulations and neutron scattering experiments, we proposed and implemented a rigorous method, which incorporates the contribution from those invasive water molecules, to calculate scattering functions of a single PAMAM dendrimer using equilibrium MD trajectories. The bridge between neutron scattering experiments and MD simulation is successfully established. Aside from structural comparisons between MD simulations and experiments, we utilized MD simulation to decipher the previously reported QENS experimental observation that the segmental dynamics of PAMAM dendrimer would enhance with increasing molecular charge. We pursued the mechanism from the perspective of hydrocarbon component of dendrimer and solvent (water) interaction as a form similar to hydrogen bonding. It is found that the population of this bonding would increase and the corresponding relaxation would slow down as molecular charge increases. We perceive that through more and longer interaction between penetrating water molecules and polymeric part of dendrimer, the dynamics of latter could be enhanced.

Protecting High Energy Barriers: A New Equation to Regulate Boost Energy in Accelerated Molecular Dynamics Simulations.

PubMed

Sinko, William; de Oliveira, César Augusto F; Pierce, Levi C T; McCammon, J Andrew

2012-01-10

Molecular dynamics (MD) is one of the most common tools in computational chemistry. Recently, our group has employed accelerated molecular dynamics (aMD) to improve the conformational sampling over conventional molecular dynamics techniques. In the original aMD implementation, sampling is greatly improved by raising energy wells below a predefined energy level. Recently, our group presented an alternative aMD implementation where simulations are accelerated by lowering energy barriers of the potential energy surface. When coupled with thermodynamic integration simulations, this implementation showed very promising results. However, when applied to large systems, such as proteins, the simulation tends to be biased to high energy regions of the potential landscape. The reason for this behavior lies in the boost equation used since the highest energy barriers are dramatically more affected than the lower ones. To address this issue, in this work, we present a new boost equation that prevents oversampling of unfavorable high energy conformational states. The new boost potential provides not only better recovery of statistics throughout the simulation but also enhanced sampling of statistically relevant regions in explicit solvent MD simulations.

MD Simulations of tRNA and Aminoacyl-tRNA Synthetases: Dynamics, Folding, Binding, and Allostery

PubMed Central

Li, Rongzhong; Macnamara, Lindsay M.; Leuchter, Jessica D.; Alexander, Rebecca W.; Cho, Samuel S.

2015-01-01

While tRNA and aminoacyl-tRNA synthetases are classes of biomolecules that have been extensively studied for decades, the finer details of how they carry out their fundamental biological functions in protein synthesis remain a challenge. Recent molecular dynamics (MD) simulations are verifying experimental observations and providing new insight that cannot be addressed from experiments alone. Throughout the review, we briefly discuss important historical events to provide a context for how far the field has progressed over the past few decades. We then review the background of tRNA molecules, aminoacyl-tRNA synthetases, and current state of the art MD simulation techniques for those who may be unfamiliar with any of those fields. Recent MD simulations of tRNA dynamics and folding and of aminoacyl-tRNA synthetase dynamics and mechanistic characterizations are discussed. We highlight the recent successes and discuss how important questions can be addressed using current MD simulations techniques. We also outline several natural next steps for computational studies of AARS:tRNA complexes. PMID:26184179

Effect of early institutionalization and foster care on long-term white matter development: a randomized clinical trial.

PubMed

Bick, Johanna; Zhu, Tong; Stamoulis, Catherine; Fox, Nathan A; Zeanah, Charles; Nelson, Charles A

2015-03-01

Severe neglect in early life is associated with compromises in brain development and associated behavioral functioning. Although early intervention has been shown to support more normative trajectories of brain development, specific improvements in the white matter pathways that underlie emotional and cognitive development are unknown. To examine associations among neglect in early life, early intervention, and the microstructural integrity of white matter pathways in middle childhood. The Bucharest Early Intervention Project is a randomized clinical trial of high-quality foster care as an intervention for institutionally reared children in Bucharest, Romania, from 2000 through the present. During infancy, children were randomly selected to remain in an institution or to be placed in foster care. Those who remained in institutions experienced neglect, including social, emotional, linguistic, and cognitive impoverishment. Developmental trajectories of these children were compared with a group of sociodemographically matched children reared in biological families at baseline and several points throughout development. At approximately 8 years of age, 69 of the original 136 children underwent structural magnetic resonance imaging scans. Four estimates of white matter integrity (fractional anisotropy [FA] and mean [MD], radial [RD], and axial [AD] diffusivity) for 48 white matter tracts throughout the brain were obtained through diffusion tensor imaging. Significant associations emerged between neglect in early life and microstructural integrity of the body of the corpus callosum (FA, β = 0.01 [P = .01]; RD, β = -0.02 [P = .005]; MD, β = -0.01 [P = .02]) and tracts involved in limbic circuitry (fornix crus [AD, β = 0.02 (P = .046)] and cingulum [RD, β = -0.01 (P = .02); MD, β = -0.01 (P = .049)]), frontostriatal circuitry (anterior [AD, β = -0.01 (P = .02)] and superior [AD, β = -0.02 (P = .02); MD, β = -0.01 (P = .03)] corona radiata and external capsule [right FA, β = 0.01 (P = .03); left FA, β = 0.01 (P = .03); RD, β = -0.01 (P = .01); MD, β = -0.01 (P = .03)]), and sensory processing (medial lemniscus [AD, β = -0.02 (P = .045); MD, β = -0.01 (P = .04)] and retrolenticular internal capsule [FA, β = -0.01 (P = .002); RD, β = 0.01 (P = .003); MD, β = 0.01 (P = .04)]). Follow-up analyses revealed that early intervention promoted more normative white matter development among previously neglected children who entered foster care. Results suggest that removal from conditions of neglect in early life and entry into a high-quality family environment can support more normative trajectories of white matter growth. Our findings have implications for public health and policy efforts designed to promote normative brain development among vulnerable children. clinicaltrials.gov Identifier: NCT00747396.

Rotational dynamics in supercooled water from nuclear spin relaxation and molecular simulations.

PubMed

Qvist, Johan; Mattea, Carlos; Sunde, Erik P; Halle, Bertil

2012-05-28

Structural dynamics in liquid water slow down dramatically in the supercooled regime. To shed further light on the origin of this super-Arrhenius temperature dependence, we report high-precision (17)O and (2)H NMR relaxation data for H(2)O and D(2)O, respectively, down to 37 K below the equilibrium freezing point. With the aid of molecular dynamics (MD) simulations, we provide a detailed analysis of the rotational motions probed by the NMR experiments. The NMR-derived rotational correlation time τ(R) is the integral of a time correlation function (TCF) that, after a subpicosecond librational decay, can be described as a sum of two exponentials. Using a coarse-graining algorithm to map the MD trajectory on a continuous-time random walk (CTRW) in angular space, we show that the slowest TCF component can be attributed to large-angle molecular jumps. The mean jump angle is ∼48° at all temperatures and the waiting time distribution is non-exponential, implying dynamical heterogeneity. We have previously used an analogous CTRW model to analyze quasielastic neutron scattering data from supercooled water. Although the translational and rotational waiting times are of similar magnitude, most translational jumps are not synchronized with a rotational jump of the same molecule. The rotational waiting time has a stronger temperature dependence than the translation one, consistent with the strong increase of the experimentally derived product τ(R) D(T) at low temperatures. The present CTRW jump model is related to, but differs in essential ways from the extended jump model proposed by Laage and co-workers. Our analysis traces the super-Arrhenius temperature dependence of τ(R) to the rotational waiting time. We present arguments against interpreting this temperature dependence in terms of mode-coupling theory or in terms of mixture models of water structure.

Development of New Transferable Coarse-Grained Models of Hydrocarbons.

PubMed

An, Yaxin; Bejagam, Karteek K; Deshmukh, Sanket A

2018-06-21

We have utilized an approach that integrates molecular dynamics (MD) simulations with particle swarm optimization (PSO) to accelerate the development of coarse-grained (CG) models of hydrocarbons. Specifically, we have developed new transferable CG beads, which can be used to model the hydrocarbons (C5 to C17) and reproduce their experimental properties with good accuracy. Firstly, the PSO method was used to develop the CG beads of the decane model represented with 2:1 (2-2-2-2-2) mapping scheme. This was followed by the development of the nonane model described with hybrid 2-2-3-2, and 3:1 (3-3-3) mapping schemes. The force-field (FF) parameters for these three CG models were optimized to reproduce four experimentally observed properties including density, enthalpy of vaporization, surface tension, and self-diffusion coefficient at 300 K. The CG MD simulations conducted with these new CG models of decane and nonane, at different timesteps, for various system sizes, and at a range of different temperatures, were able to predict their density, enthalpy of vaporization, surface tension, self-diffusion coefficient, expansibility, and isothermal compressibility with a good accuracy. Moreover, comparison of structural features obtained from the CG MD simulations and the CG beads of mapped all-atom (AA) trajectories of decane and nonane showed very good agreement. To test the chemical transferability of these models, we have constructed the models for hydrocarbons ranging from pentane to heptadecane, by using different combination of the CG beads of decane and nonane. The properties of pentane to heptadecane predicted by these new CG models showed an excellent agreement with the experimental data.

Electronic Circular Dichroism of [16]Helicene With Simplified TD-DFT: Beyond the Single Structure Approach.

PubMed

Bannwarth, Christoph; Seibert, Jakob; Grimme, Stefan

2016-05-01

The electronic circular dichroism (ECD) spectrum of the recently synthesized [16]helicene and a derivative comprising two triisopropylsilyloxy protection groups was computed by means of the very efficient simplified time-dependent density functional theory (sTD-DFT) approach. Different from many previous ECD studies of helicenes, nonequilibrium structure effects were accounted for by computing ECD spectra on "snapshots" obtained from a molecular dynamics (MD) simulation including solvent molecules. The trajectories are based on a molecule specific classical potential as obtained from the recently developed quantum chemically derived force field (QMDFF) scheme. The reduced computational cost in the MD simulation due to the use of the QMDFF (compared to ab-initio MD) as well as the sTD-DFT approach make realistic spectral simulations feasible for these compounds that comprise more than 100 atoms. While the ECD spectra of [16]helicene and its derivative computed vertically on the respective gas phase, equilibrium geometries show noticeable differences, these are "washed" out when nonequilibrium structures are taken into account. The computed spectra with two recommended density functionals (ωB97X and BHLYP) and extended basis sets compare very well with the experimental one. In addition we provide an estimate for the missing absolute intensities of the latter. The approach presented here could also be used in future studies to capture nonequilibrium effects, but also to systematically average ECD spectra over different conformations in more flexible molecules. Chirality 28:365-369, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Binding free energy and counterion release for adsorption of the antimicrobial peptide lactoferricin B on a POPG membrane

NASA Astrophysics Data System (ADS)

Tolokh, Igor S.; Vivcharuk, Victor; Tomberli, Bruno; Gray, C. G.

2009-09-01

Molecular dynamics (MD) simulations are used to study the interaction of an anionic palmitoyl-oleoyl-phosphatidylglycerol (POPG) bilayer with the cationic antimicrobial peptide bovine lactoferricin (LFCinB) in a 100 mM NaCl solution at 310 K. The interaction of LFCinB with a POPG bilayer is employed as a model system for studying the details of membrane adsorption selectivity of cationic antimicrobial peptides. Seventy eight 4 ns MD production run trajectories of the equilibrated system, with six restrained orientations of LFCinB at 13 different separations from the POPG membrane, are generated to determine the free energy profile for the peptide as a function of the distance between LFCinB and the membrane surface. To calculate the profile for this relatively large system, a variant of constrained MD and thermodynamic integration is used. A simplified method for relating the free energy profile to the LFCinB-POPG membrane binding constant is employed to predict a free energy of adsorption of -5.4±1.3kcal/mol and a corresponding maximum adsorption binding force of about 58 pN. We analyze the results using Poisson-Boltzmann theory. We find the peptide-membrane attraction to be dominated by the entropy increase due to the release of counterions and polarized water from the region between the charged membrane and peptide, as the two approach each other. We contrast these results with those found earlier for adsorption of LFCinB on the mammalianlike palmitoyl-oleoyl-phosphatidylcholine membrane.

Replica Exchange Gaussian Accelerated Molecular Dynamics: Improved Enhanced Sampling and Free Energy Calculation.

PubMed

Huang, Yu-Ming M; McCammon, J Andrew; Miao, Yinglong

2018-04-10

Through adding a harmonic boost potential to smooth the system potential energy surface, Gaussian accelerated molecular dynamics (GaMD) provides enhanced sampling and free energy calculation of biomolecules without the need of predefined reaction coordinates. This work continues to improve the acceleration power and energy reweighting of the GaMD by combining the GaMD with replica exchange algorithms. Two versions of replica exchange GaMD (rex-GaMD) are presented: force constant rex-GaMD and threshold energy rex-GaMD. During simulations of force constant rex-GaMD, the boost potential can be exchanged between replicas of different harmonic force constants with fixed threshold energy. However, the algorithm of threshold energy rex-GaMD tends to switch the threshold energy between lower and upper bounds for generating different levels of boost potential. Testing simulations on three model systems, including the alanine dipeptide, chignolin, and HIV protease, demonstrate that through continuous exchanges of the boost potential, the rex-GaMD simulations not only enhance the conformational transitions of the systems but also narrow down the distribution width of the applied boost potential for accurate energetic reweighting to recover biomolecular free energy profiles.

Rapid exploration of configuration space with diffusion-map-directed molecular dynamics.

PubMed

Zheng, Wenwei; Rohrdanz, Mary A; Clementi, Cecilia

2013-10-24

The gap between the time scale of interesting behavior in macromolecular systems and that which our computational resources can afford often limits molecular dynamics (MD) from understanding experimental results and predicting what is inaccessible in experiments. In this paper, we introduce a new sampling scheme, named diffusion-map-directed MD (DM-d-MD), to rapidly explore molecular configuration space. The method uses a diffusion map to guide MD on the fly. DM-d-MD can be combined with other methods to reconstruct the equilibrium free energy, and here, we used umbrella sampling as an example. We present results from two systems: alanine dipeptide and alanine-12. In both systems, we gain tremendous speedup with respect to standard MD both in exploring the configuration space and reconstructing the equilibrium distribution. In particular, we obtain 3 orders of magnitude of speedup over standard MD in the exploration of the configurational space of alanine-12 at 300 K with DM-d-MD. The method is reaction coordinate free and minimally dependent on a priori knowledge of the system. We expect wide applications of DM-d-MD to other macromolecular systems in which equilibrium sampling is not affordable by standard MD.

Rapid Exploration of Configuration Space with Diffusion Map-directed-Molecular Dynamics

PubMed Central

Zheng, Wenwei; Rohrdanz, Mary A.; Clementi, Cecilia

2013-01-01

The gap between the timescale of interesting behavior in macromolecular systems and that which our computational resources can afford oftentimes limits Molecular Dynamics (MD) from understanding experimental results and predicting what is inaccessible in experiments. In this paper, we introduce a new sampling scheme, named Diffusion Map-directed-MD (DM-d-MD), to rapidly explore molecular configuration space. The method uses diffusion map to guide MD on the fly. DM-d-MD can be combined with other methods to reconstruct the equilibrium free energy, and here we used umbrella sampling as an example. We present results from two systems: alanine dipeptide and alanine-12. In both systems we gain tremendous speedup with respect to standard MD both in exploring the configuration space and reconstructing the equilibrium distribution. In particular, we obtain 3 orders of magnitude of speedup over standard MD in the exploration of the configurational space of alanine-12 at 300K with DM-d-MD. The method is reaction coordinate free and minimally dependent on a priori knowledge of the system. We expect wide applications of DM-d-MD to other macromolecular systems in which equilibrium sampling is not affordable by standard MD. PMID:23865517

Fluctuating observation time ensembles in the thermodynamics of trajectories

NASA Astrophysics Data System (ADS)

Budini, Adrián A.; Turner, Robert M.; Garrahan, Juan P.

2014-03-01

The dynamics of stochastic systems, both classical and quantum, can be studied by analysing the statistical properties of dynamical trajectories. The properties of ensembles of such trajectories for long, but fixed, times are described by large-deviation (LD) rate functions. These LD functions play the role of dynamical free energies: they are cumulant generating functions for time-integrated observables, and their analytic structure encodes dynamical phase behaviour. This ‘thermodynamics of trajectories’ approach is to trajectories and dynamics what the equilibrium ensemble method of statistical mechanics is to configurations and statics. Here we show that, just like in the static case, there are a variety of alternative ensembles of trajectories, each defined by their global constraints, with that of trajectories of fixed total time being just one of these. We show how the LD functions that describe an ensemble of trajectories where some time-extensive quantity is constant (and large) but where total observation time fluctuates can be mapped to those of the fixed-time ensemble. We discuss how the correspondence between generalized ensembles can be exploited in path sampling schemes for generating rare dynamical trajectories.

mdFoam+: Advanced molecular dynamics in OpenFOAM

NASA Astrophysics Data System (ADS)

Longshaw, S. M.; Borg, M. K.; Ramisetti, S. B.; Zhang, J.; Lockerby, D. A.; Emerson, D. R.; Reese, J. M.

2018-03-01

This paper introduces mdFoam+, which is an MPI parallelised molecular dynamics (MD) solver implemented entirely within the OpenFOAM software framework. It is open-source and released under the same GNU General Public License (GPL) as OpenFOAM. The source code is released as a publicly open software repository that includes detailed documentation and tutorial cases. Since mdFoam+ is designed entirely within the OpenFOAM C++ object-oriented framework, it inherits a number of key features. The code is designed for extensibility and flexibility, so it is aimed first and foremost as an MD research tool, in which new models and test cases can be developed and tested rapidly. Implementing mdFoam+ in OpenFOAM also enables easier development of hybrid methods that couple MD with continuum-based solvers. Setting up MD cases follows the standard OpenFOAM format, as mdFoam+ also relies upon the OpenFOAM dictionary-based directory structure. This ensures that useful pre- and post-processing capabilities provided by OpenFOAM remain available even though the fully Lagrangian nature of an MD simulation is not typical of most OpenFOAM applications. Results show that mdFoam+ compares well to another well-known MD code (e.g. LAMMPS) in terms of benchmark problems, although it also has additional functionality that does not exist in other open-source MD codes.

Hierarchical structure of the energy landscape of proteins revisited by time series analysis. I. Mimicking protein dynamics in different time scales

NASA Astrophysics Data System (ADS)

Alakent, Burak; Camurdan, Mehmet C.; Doruker, Pemra

2005-10-01

Time series models, which are constructed from the projections of the molecular-dynamics (MD) runs on principal components (modes), are used to mimic the dynamics of two proteins: tendamistat and immunity protein of colicin E7 (ImmE7). Four independent MD runs of tendamistat and three independent runs of ImmE7 protein in vacuum are used to investigate the energy landscapes of these proteins. It is found that mean-square displacements of residues along the modes in different time scales can be mimicked by time series models, which are utilized in dividing protein dynamics into different regimes with respect to the dominating motion type. The first two regimes constitute the dominance of intraminimum motions during the first 5ps and the random walk motion in a hierarchically higher-level energy minimum, which comprise the initial time period of the trajectories up to 20-40ps for tendamistat and 80-120ps for ImmE7. These are also the time ranges within which the linear nonstationary time series are completely satisfactory in explaining protein dynamics. Encountering energy barriers enclosing higher-level energy minima constrains the random walk motion of the proteins, and pseudorelaxation processes at different levels of minima are detected in tendamistat, depending on the sampling window size. Correlation (relaxation) times of 30-40ps and 150-200ps are detected for two energy envelopes of successive levels for tendamistat, which gives an overall idea about the hierarchical structure of the energy landscape. However, it should be stressed that correlation times of the modes are highly variable with respect to conformational subspaces and sampling window sizes, indicating the absence of an actual relaxation. The random-walk step sizes and the time length of the second regime are used to illuminate an important difference between the dynamics of the two proteins, which cannot be clarified by the investigation of relaxation times alone: ImmE7 has lower-energy barriers enclosing the higher-level energy minimum, preventing the protein to relax and letting it move in a random-walk fashion for a longer period of time.

Microscopic modeling of gas-surface scattering: II. Application to argon atom adsorption on a platinum (111) surface

NASA Astrophysics Data System (ADS)

Filinov, A.; Bonitz, M.; Loffhagen, D.

2018-06-01

A new combination of first principle molecular dynamics (MD) simulations with a rate equation model presented in the preceding paper (paper I) is applied to analyze in detail the scattering of argon atoms from a platinum (111) surface. The combined model is based on a classification of all atom trajectories according to their energies into trapped, quasi-trapped and scattering states. The number of particles in each of the three classes obeys coupled rate equations. The coefficients in the rate equations are the transition probabilities between these states which are obtained from MD simulations. While these rates are generally time-dependent, after a characteristic time scale t E of several tens of picoseconds they become stationary allowing for a rather simple analysis. Here, we investigate this time scale by analyzing in detail the temporal evolution of the energy distribution functions of the adsorbate atoms. We separately study the energy loss distribution function of the atoms and the distribution function of in-plane and perpendicular energy components. Further, we compute the sticking probability of argon atoms as a function of incident energy, angle and lattice temperature. Our model is important for plasma-surface modeling as it allows to extend accurate simulations to longer time scales.

Cellulose Crystal Dissolution in Imidazolium-Based Ionic Liquids: A Theoretical Study.

PubMed

Uto, Takuya; Yamamoto, Kazuya; Kadokawa, Jun-Ichi

2018-01-11

The highly crystalline nature of cellulose results in poor processability and solubility, necessitating the search for solvents that can efficiently dissolve this material. Thus, ionic liquids (ILs) have recently been shown to be well suited for this purpose, although the corresponding dissolution mechanism has not been studied in detail. Herein, we adopt a molecular dynamics (MD) approach to study the dissolution of model cellulose crystal structures in imidazolium-based ILs and gain deep mechanistic insights, demonstrating that dissolution involves IL penetration-induced cleavage of hydrogen bonds between cellulose molecular chains. Moreover, we reveal that in ILs with high cellulose dissolving power (powerful solvents, such as 1-allyl-3-methylimidazolium chloride and 1-ethyl-3-methylimidazolium chloride), the above molecular chains are peeled from the crystal phase and subsequently dispersed in the solvent, whereas no significant structural changes are observed in poor-dissolving-power solvents. Finally, we utilize MD trajectory analysis to show that the solubility of microcrystalline cellulose is well correlated with the number of intermolecular hydrogen bonds in cellulose crystals. The obtained results allow us to conclude that both anions and cations of high-dissolving-power ILs contribute to the stepwise breakage of hydrogen bonds between cellulose chains, whereas this breakage does not occur to a sufficient extent in poorly solubilizing ILs.

Modeling crystal growth from solution with molecular dynamics simulations: approaches to transition rate constants.

PubMed

Reilly, Anthony M; Briesen, Heiko

2012-01-21

The feasibility of using the molecular dynamics (MD) simulation technique to study crystal growth from solution quantitatively, as well as to obtain transition rate constants, has been studied. The dynamics of an interface between a solution of Lennard-Jones particles and the (100) face of an fcc lattice comprised of solute particles have been studied using MD simulations, showing that MD is, in principle, capable of following growth behavior over large supersaturation and temperature ranges. Using transition state theory, and a nearest-neighbor approximation growth and dissolution rate constants have been extracted from equilibrium MD simulations at a variety of temperatures. The temperature dependence of the rates agrees well with the expected transition state theory behavior. © 2012 American Institute of Physics

Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation.

PubMed

Miao, Yinglong; Feher, Victoria A; McCammon, J Andrew

2015-08-11

A Gaussian accelerated molecular dynamics (GaMD) approach for simultaneous enhanced sampling and free energy calculation of biomolecules is presented. By constructing a boost potential that follows Gaussian distribution, accurate reweighting of the GaMD simulations is achieved using cumulant expansion to the second order. Here, GaMD is demonstrated on three biomolecular model systems: alanine dipeptide, chignolin folding, and ligand binding to the T4-lysozyme. Without the need to set predefined reaction coordinates, GaMD enables unconstrained enhanced sampling of these biomolecules. Furthermore, the free energy profiles obtained from reweighting of the GaMD simulations allow us to identify distinct low-energy states of the biomolecules and characterize the protein-folding and ligand-binding pathways quantitatively.

Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation

PubMed Central

2016-01-01

A Gaussian accelerated molecular dynamics (GaMD) approach for simultaneous enhanced sampling and free energy calculation of biomolecules is presented. By constructing a boost potential that follows Gaussian distribution, accurate reweighting of the GaMD simulations is achieved using cumulant expansion to the second order. Here, GaMD is demonstrated on three biomolecular model systems: alanine dipeptide, chignolin folding, and ligand binding to the T4-lysozyme. Without the need to set predefined reaction coordinates, GaMD enables unconstrained enhanced sampling of these biomolecules. Furthermore, the free energy profiles obtained from reweighting of the GaMD simulations allow us to identify distinct low-energy states of the biomolecules and characterize the protein-folding and ligand-binding pathways quantitatively. PMID:26300708

Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) for Conformational Space Search of Peptide and Miniprotein

PubMed Central

Hao, Ge-Fei; Xu, Wei-Fang; Yang, Sheng-Gang; Yang, Guang-Fu

2015-01-01

Protein and peptide structure predictions are of paramount importance for understanding their functions, as well as the interactions with other molecules. However, the use of molecular simulation techniques to directly predict the peptide structure from the primary amino acid sequence is always hindered by the rough topology of the conformational space and the limited simulation time scale. We developed here a new strategy, named Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) to identify the native states of a peptide and miniprotein. A cluster of near native structures could be obtained by using the MSA-MD method, which turned out to be significantly more efficient in reaching the native structure compared to continuous MD and conventional SA-MD simulation. PMID:26492886

Las Palmeras Molecular Dynamics: A flexible and modular molecular dynamics code

NASA Astrophysics Data System (ADS)

Davis, Sergio; Loyola, Claudia; González, Felipe; Peralta, Joaquín

2010-12-01

Las Palmeras Molecular Dynamics (LPMD) is a highly modular and extensible molecular dynamics (MD) code using interatomic potential functions. LPMD is able to perform equilibrium MD simulations of bulk crystalline solids, amorphous solids and liquids, as well as non-equilibrium MD (NEMD) simulations such as shock wave propagation, projectile impacts, cluster collisions, shearing, deformation under load, heat conduction, heterogeneous melting, among others, which involve unusual MD features like non-moving atoms and walls, unstoppable atoms with constant-velocity, and external forces like electric fields. LPMD is written in C++ as a compromise between efficiency and clarity of design, and its architecture is based on separate components or plug-ins, implemented as modules which are loaded on demand at runtime. The advantage of this architecture is the ability to completely link together the desired components involved in the simulation in different ways at runtime, using a user-friendly control file language which describes the simulation work-flow. As an added bonus, the plug-in API (Application Programming Interface) makes it possible to use the LPMD components to analyze data coming from other simulation packages, convert between input file formats, apply different transformations to saved MD atomic trajectories, and visualize dynamical processes either in real-time or as a post-processing step. Individual components, such as a new potential function, a new integrator, a new file format, new properties to calculate, new real-time visualizers, and even a new algorithm for handling neighbor lists can be easily coded, compiled and tested within LPMD by virtue of its object-oriented API, without the need to modify the rest of the code. LPMD includes already several pair potential functions such as Lennard-Jones, Morse, Buckingham, MCY and the harmonic potential, as well as embedded-atom model (EAM) functions such as the Sutton-Chen and Gupta potentials. Integrators to choose include Euler (if only for demonstration purposes), Verlet and Velocity Verlet, Leapfrog and Beeman, among others. Electrostatic forces are treated as another potential function, by default using the plug-in implementing the Ewald summation method. Program summaryProgram title: LPMD Catalogue identifier: AEHG_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEHG_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License version 3 No. of lines in distributed program, including test data, etc.: 509 490 No. of bytes in distributed program, including test data, etc.: 6 814 754 Distribution format: tar.gz Programming language: C++ Computer: 32-bit and 64-bit workstation Operating system: UNIX RAM: Minimum 1024 bytes Classification: 7.7 External routines: zlib, OpenGL Nature of problem: Study of Statistical Mechanics and Thermodynamics of condensed matter systems, as well as kinetics of non-equilibrium processes in the same systems. Solution method: Equilibrium and non-equilibrium molecular dynamics method, Monte Carlo methods. Restrictions: Rigid molecules are not supported. Polarizable atoms and chemical bonds (proteins) either. Unusual features: The program is able to change the temperature of the simulation cell, the pressure, cut regions of the cell, color the atoms by properties, even during the simulation. It is also possible to fix the positions and/or velocity of groups of atoms. Visualization of atoms and some physical properties during the simulation. Additional comments: The program does not only perform molecular dynamics and Monte Carlo simulations, it is also able to filter and manipulate atomic configurations, read and write different file formats, convert between them, evaluate different structural and dynamical properties. Running time: 50 seconds on a 1000-step simulation of 4000 argon atoms, running on a single 2.67 GHz Intel processor.

Analysis of the contribution of experimental bias, experimental noise, and inter-subject biological variability on the assessment of developmental trajectories in diffusion MRI studies of the brain.

PubMed

Sadeghi, Neda; Nayak, Amritha; Walker, Lindsay; Okan Irfanoglu, M; Albert, Paul S; Pierpaoli, Carlo

2015-04-01

Metrics derived from the diffusion tensor, such as fractional anisotropy (FA) and mean diffusivity (MD) have been used in many studies of postnatal brain development. A common finding of previous studies is that these tensor-derived measures vary widely even in healthy populations. This variability can be due to inherent inter-individual biological differences as well as experimental noise. Moreover, when comparing different studies, additional variability can be introduced by different acquisition protocols. In this study we examined scans of 61 individuals (aged 4-22 years) from the NIH MRI study of normal brain development. Two scans were collected with different protocols (low and high resolution). Our goal was to separate the contributions of biological variability and experimental noise to the overall measured variance, as well as to assess potential systematic effects related to the use of different protocols. We analyzed FA and MD in seventeen regions of interest. We found that biological variability for both FA and MD varies widely across brain regions; biological variability is highest for FA in the lateral part of the splenium and body of the corpus callosum along with the cingulum and the superior longitudinal fasciculus, and for MD in the optic radiations and the lateral part of the splenium. These regions with high inter-individual biological variability are the most likely candidates for assessing genetic and environmental effects in the developing brain. With respect to protocol-related effects, the lower resolution acquisition resulted in higher MD and lower FA values for the majority of regions compared with the higher resolution protocol. However, the majority of the regions did not show any age-protocol interaction, indicating similar trajectories were obtained irrespective of the protocol used. Published by Elsevier Inc.

Accelerated Molecular Dynamics Simulations with the AMOEBA Polarizable Force Field on Graphics Processing Units

PubMed Central

2013-01-01

The accelerated molecular dynamics (aMD) method has recently been shown to enhance the sampling of biomolecules in molecular dynamics (MD) simulations, often by several orders of magnitude. Here, we describe an implementation of the aMD method for the OpenMM application layer that takes full advantage of graphics processing units (GPUs) computing. The aMD method is shown to work in combination with the AMOEBA polarizable force field (AMOEBA-aMD), allowing the simulation of long time-scale events with a polarizable force field. Benchmarks are provided to show that the AMOEBA-aMD method is efficiently implemented and produces accurate results in its standard parametrization. For the BPTI protein, we demonstrate that the protein structure described with AMOEBA remains stable even on the extended time scales accessed at high levels of accelerations. For the DNA repair metalloenzyme endonuclease IV, we show that the use of the AMOEBA force field is a significant improvement over fixed charged models for describing the enzyme active-site. The new AMOEBA-aMD method is publicly available (http://wiki.simtk.org/openmm/VirtualRepository) and promises to be interesting for studying complex systems that can benefit from both the use of a polarizable force field and enhanced sampling. PMID:24634618

QwikMD — Integrative Molecular Dynamics Toolkit for Novices and Experts

PubMed Central

Ribeiro, João V.; Bernardi, Rafael C.; Rudack, Till; Stone, John E.; Phillips, James C.; Freddolino, Peter L.; Schulten, Klaus

2016-01-01

The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services. PMID:27216779

QwikMD — Integrative Molecular Dynamics Toolkit for Novices and Experts

NASA Astrophysics Data System (ADS)

Ribeiro, João V.; Bernardi, Rafael C.; Rudack, Till; Stone, John E.; Phillips, James C.; Freddolino, Peter L.; Schulten, Klaus

2016-05-01

The proper functioning of biomolecules in living cells requires them to assume particular structures and to undergo conformational changes. Both biomolecular structure and motion can be studied using a wide variety of techniques, but none offers the level of detail as do molecular dynamics (MD) simulations. Integrating two widely used modeling programs, namely NAMD and VMD, we have created a robust, user-friendly software, QwikMD, which enables novices and experts alike to address biomedically relevant questions, where often only molecular dynamics simulations can provide answers. Performing both simple and advanced MD simulations interactively, QwikMD automates as many steps as necessary for preparing, carrying out, and analyzing simulations while checking for common errors and enabling reproducibility. QwikMD meets also the needs of experts in the field, increasing the efficiency and quality of their work by carrying out tedious or repetitive tasks while enabling easy control of every step. Whether carrying out simulations within the live view mode on a small laptop or performing complex and large simulations on supercomputers or Cloud computers, QwikMD uses the same steps and user interface. QwikMD is freely available by download on group and personal computers. It is also available on the cloud at Amazon Web Services.

Crystal-melt interface mobility in bcc Fe: Linking molecular dynamics to phase-field and phase-field crystal modeling

NASA Astrophysics Data System (ADS)

Guerdane, M.; Berghoff, M.

2018-04-01

By combining molecular dynamics (MD) simulations with phase-field (PF) and phase-field crystal (PFC) modeling we study collision-controlled growth kinetics from the melt for pure Fe. The MD/PF comparison shows, on the one hand, that the PF model can be properly designed to reproduce quantitatively different aspects of the growth kinetics and anisotropy of planar and curved solid-liquid interfaces. On the other hand, this comparison demonstrates the ability of classical MD simulations to predict morphology and dynamics of moving curved interfaces up to a length scale of about 0.15 μ m . After mapping the MD model to the PF one, the latter permits to analyze the separate contribution of different anisotropies to the interface morphology. The MD/PFC agreement regarding the growth anisotropy and morphology extends the trend already observed for the here used PFC model in describing structural and elastic properties of bcc Fe.

Querying databases of trajectories of differential equations: Data structures for trajectories

NASA Technical Reports Server (NTRS)

Grossman, Robert

1989-01-01

One approach to qualitative reasoning about dynamical systems is to extract qualitative information by searching or making queries on databases containing very large numbers of trajectories. The efficiency of such queries depends crucially upon finding an appropriate data structure for trajectories of dynamical systems. Suppose that a large number of parameterized trajectories gamma of a dynamical system evolving in R sup N are stored in a database. Let Eta is contained in set R sup N denote a parameterized path in Euclidean Space, and let the Euclidean Norm denote a norm on the space of paths. A data structure is defined to represent trajectories of dynamical systems, and an algorithm is sketched which answers queries.

New Developments in the Embedded Statistical Coupling Method: Atomistic/Continuum Crack Propagation

NASA Technical Reports Server (NTRS)

Saether, E.; Yamakov, V.; Glaessgen, E.

2008-01-01

A concurrent multiscale modeling methodology that embeds a molecular dynamics (MD) region within a finite element (FEM) domain has been enhanced. The concurrent MD-FEM coupling methodology uses statistical averaging of the deformation of the atomistic MD domain to provide interface displacement boundary conditions to the surrounding continuum FEM region, which, in turn, generates interface reaction forces that are applied as piecewise constant traction boundary conditions to the MD domain. The enhancement is based on the addition of molecular dynamics-based cohesive zone model (CZM) elements near the MD-FEM interface. The CZM elements are a continuum interpretation of the traction-displacement relationships taken from MD simulations using Cohesive Zone Volume Elements (CZVE). The addition of CZM elements to the concurrent MD-FEM analysis provides a consistent set of atomistically-based cohesive properties within the finite element region near the growing crack. Another set of CZVEs are then used to extract revised CZM relationships from the enhanced embedded statistical coupling method (ESCM) simulation of an edge crack under uniaxial loading.

Molecular Dynamics Simulation of Calbindin D9k in Apo, Singly and Doubly Loaded States in Various Side-Chains

NASA Astrophysics Data System (ADS)

Thapa, Mahendra Bahadur

Calbindin D9k (CAB) is a single domain calcium-binding protein and is the smallest members of the calmodulin superfamily, possessing a pair of calcium-binding EF-hands, and structures for all four states have been determined and extensively characterized experimentally. Because of the tremendous advancement in hardware and software computer technologies in recent years, longer and more realistic molecular dynamics (MD) simulations of a protein are possible now in reasonable periods of time. These advances were exploited to generate multiple, all-atom MD simulations of CAB via the AMBER software package, and the resulting trajectories were employed to calculate backbone order parameters of the apo, the singly and the doubly loaded states of calcium in CAB. The results are in very good agreement with corresponding experimental NMR-based (Nuclear Magnetic Resonance spectroscopy) results, and are improved in comparison to those calculated over a decade ago; use of modified force fields played a key role in the observed improvements. The apo state is the most flexible, and the singly loaded and the doubly loaded states are similar, thus supporting positive cooperativity in line with the experimental results. Further, B-factor calculations of backbone atoms for these calcium-binding states of calbindin D9k also support such cooperativity. Although changes in side-chain motions are not necessarily correlated to changes in protein backbone mobility, past studies on the comparison of experimental and simulated methyl side-chain NMR relaxation parameters of CAB for the doubly-loaded state reported significant improvements in the quantitative representation of side-chain motion by MD simulation. In this project, the order parameters for various side chains in apo, singly loaded and doubly loaded states of CAB were calculated. The primary goal of this work was to determine whether or not the allosteric effect of calcium binding, as observed via the backbone order parameters, also extended to the amino acid side chains, and if so, to what extent. Such information could be useful in better understanding the physical basis of cooperative calcium binding in CAB. Most of the residues which provide ligands to bind calcium at the binding sites support positive cooperativity, as observed when Ca-Cß, Cß-C?, C-C bond and C-O bonds of COO groups of aspartic and glutamic acid residues, the C-N bond of the side-chain amide group in asparagine and glutamine residues, and the N-H bonds of amide (NH2) group order parameters were studied. There are only a few residues containing methyl groups that are involved in providing ligands to the calcium, and the studies of order parameters of C-C bond and C-H bond of these methyl groups did not exhibit the cooperativity effect upon calcium binding; the simulated C-C bond order parameter of the methyl group symmetry axis did correlate well with the experimental results for the fully loaded state of CAB (4ICB). Analysis of the MD trajectories using GSATools and MutInf, provided valuable insights into possible pathways for communicating allosteric effects between the two calcium-binding sites of CAB.

Coupling CP-MD simulations and X-ray absorption spectroscopy: exploring the structure of oxaliplatin in aqueous solution.

PubMed

Beret, Elizabeth C; Provost, Karine; Müller, Diane; Marcos, Enrique Sánchez

2009-09-10

A combined experimental-theoretical approach applying X-ray absorption spectroscopy and ab initio molecular dynamics (CP-MD) simulations is used to get insight into the structural determination of oxaliplatin, a third-generation anticancer drug of the cisplatin family, in aqueous solution. Experimental Pt L(III)-edge EXAFS and XANES spectra of oxaliplatin in water are compared with theoretical XAS spectra. The latter are obtained as statistically averaged spectra computed for a set of selected snapshots extracted from the MD trajectory of ethyldiamineoxalatoplatinum(II) (EDO-Pt) in liquid water. This compound is a simplified structure of oxaliplatin, where the outer part of the cyclohexane ring contained in the cyclohexanediamine ligand of oxaliplatin has been removed. We show that EDO-Pt is an appropriate model to simulate the spectroscopical properties of oxaliplatin given that the cyclohexane ring does not generate particular features in neither the EXAFS nor the XANES spectra. The computation of average EXAFS spectra using structures from the MD simulation in which atoms are selected according to different cutoff radii around the Pt center allows the assignment of spectral features to particular structural motifs, both in k and R-spaces. The outer oxygen atoms of the oxalate ligand (R(Pt-O(II)) = 3.97 +/- 0.03 A) are responsible for a well-defined hump at around 6.5 A(-1) in the k(2)-weighted EXAFS spectrum. The conventional EXAFS analysis data procedure is reexamined by its application to the simulated average EXAFS spectra. The structural parameters resulting from the fit may then be compared with those obtained from the simulation, providing an estimation of the methodological error associated with the global fitting procedure. A thorough discussion on the synergy between the experimental and theoretical XAS approaches is presented, and evidence for the detection of a slight hydration structure around the Pt complex is shown, leading to the suggestion of a new challenge to experimental XAS measurements.

Improved Statistical Sampling and Accuracy with Accelerated Molecular Dynamics on Rotatable Torsions.

PubMed

Doshi, Urmi; Hamelberg, Donald

2012-11-13

In enhanced sampling techniques, the precision of the reweighted ensemble properties is often decreased due to large variation in statistical weights and reduction in the effective sampling size. To abate this reweighting problem, here, we propose a general accelerated molecular dynamics (aMD) approach in which only the rotatable dihedrals are subjected to aMD (RaMD), unlike the typical implementation wherein all dihedrals are boosted (all-aMD). Nonrotatable and improper dihedrals are marginally important to conformational changes or the different rotameric states. Not accelerating them avoids the sharp increases in the potential energies due to small deviations from their minimum energy conformations and leads to improvement in the precision of RaMD. We present benchmark studies on two model dipeptides, Ace-Ala-Nme and Ace-Trp-Nme, simulated with normal MD, all-aMD, and RaMD. We carry out a systematic comparison between the performances of both forms of aMD using a theory that allows quantitative estimation of the effective number of sampled points and the associated uncertainty. Our results indicate that, for the same level of acceleration and simulation length, as used in all-aMD, RaMD results in significantly less loss in the effective sample size and, hence, increased accuracy in the sampling of φ-ψ space. RaMD yields an accuracy comparable to that of all-aMD, from simulation lengths 5 to 1000 times shorter, depending on the peptide and the acceleration level. Such improvement in speed and accuracy over all-aMD is highly remarkable, suggesting RaMD as a promising method for sampling larger biomolecules.

Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations.

PubMed

Kandel, Saugat; Salomon-Ferrer, Romelia; Larsen, Adrien B; Jain, Abhinandan; Vaidehi, Nagarajan

2016-01-28

The Internal Coordinate Molecular Dynamics (ICMD) method is an attractive molecular dynamics (MD) method for studying the dynamics of bonded systems such as proteins and polymers. It offers a simple venue for coarsening the dynamics model of a system at multiple hierarchical levels. For example, large scale protein dynamics can be studied using torsional dynamics, where large domains or helical structures can be treated as rigid bodies and the loops connecting them as flexible torsions. ICMD with such a dynamic model of the protein, combined with enhanced conformational sampling method such as temperature replica exchange, allows the sampling of large scale domain motion involving high energy barrier transitions. Once these large scale conformational transitions are sampled, all-torsion, or even all-atom, MD simulations can be carried out for the low energy conformations sampled via coarse grained ICMD to calculate the energetics of distinct conformations. Such hierarchical MD simulations can be carried out with standard all-atom forcefields without the need for compromising on the accuracy of the forces. Using constraints to treat bond lengths and bond angles as rigid can, however, distort the potential energy landscape of the system and reduce the number of dihedral transitions as well as conformational sampling. We present here a two-part solution to overcome such distortions of the potential energy landscape with ICMD models. To alleviate the intrinsic distortion that stems from the reduced phase space in torsional MD, we use the Fixman compensating potential. To additionally alleviate the extrinsic distortion that arises from the coupling between the dihedral angles and bond angles within a force field, we propose a hybrid ICMD method that allows the selective relaxing of bond angles. This hybrid ICMD method bridges the gap between all-atom MD and torsional MD. We demonstrate with examples that these methods together offer a solution to eliminate the potential energy distortions encountered in constrained ICMD simulations of peptide molecules.

Overcoming potential energy distortions in constrained internal coordinate molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Kandel, Saugat; Salomon-Ferrer, Romelia; Larsen, Adrien B.; Jain, Abhinandan; Vaidehi, Nagarajan

2016-01-01

The Internal Coordinate Molecular Dynamics (ICMD) method is an attractive molecular dynamics (MD) method for studying the dynamics of bonded systems such as proteins and polymers. It offers a simple venue for coarsening the dynamics model of a system at multiple hierarchical levels. For example, large scale protein dynamics can be studied using torsional dynamics, where large domains or helical structures can be treated as rigid bodies and the loops connecting them as flexible torsions. ICMD with such a dynamic model of the protein, combined with enhanced conformational sampling method such as temperature replica exchange, allows the sampling of large scale domain motion involving high energy barrier transitions. Once these large scale conformational transitions are sampled, all-torsion, or even all-atom, MD simulations can be carried out for the low energy conformations sampled via coarse grained ICMD to calculate the energetics of distinct conformations. Such hierarchical MD simulations can be carried out with standard all-atom forcefields without the need for compromising on the accuracy of the forces. Using constraints to treat bond lengths and bond angles as rigid can, however, distort the potential energy landscape of the system and reduce the number of dihedral transitions as well as conformational sampling. We present here a two-part solution to overcome such distortions of the potential energy landscape with ICMD models. To alleviate the intrinsic distortion that stems from the reduced phase space in torsional MD, we use the Fixman compensating potential. To additionally alleviate the extrinsic distortion that arises from the coupling between the dihedral angles and bond angles within a force field, we propose a hybrid ICMD method that allows the selective relaxing of bond angles. This hybrid ICMD method bridges the gap between all-atom MD and torsional MD. We demonstrate with examples that these methods together offer a solution to eliminate the potential energy distortions encountered in constrained ICMD simulations of peptide molecules.

Structure of a tethered polymer under flow using molecular dynamics and hybrid molecular-continuum simulations

NASA Astrophysics Data System (ADS)

Delgado-Buscalioni, Rafael; Coveney, Peter V.

2006-03-01

We analyse the structure of a single polymer tethered to a solid surface undergoing a Couette flow. We study the problem using molecular dynamics (MD) and hybrid MD-continuum simulations, wherein the polymer and the surrounding solvent are treated via standard MD, and the solvent flow farther away from the polymer is solved by continuum fluid dynamics (CFD). The polymer represents a freely jointed chain (FJC) and is modelled by Lennard-Jones (LJ) beads interacting through the FENE potential. The solvent (modelled as a LJ fluid) and a weakly attractive wall are treated at the molecular level. At large shear rates the polymer becomes more elongated than predicted by existing theoretical scaling laws. Also, along the normal-to-wall direction the structure observed for the FJC is, surprisingly, very similar to that predicted for a semiflexible chain. Comparison with previous Brownian dynamics simulations (which exclude both solvent and wall potential) indicates that these effects are due to the polymer-solvent and polymer-wall interactions. The hybrid simulations are in perfect agreement with the MD simulations, showing no trace of finite size effects. Importantly, the extra cost required to couple the MD and CFD domains is negligible.

Self-Consistent Determination of Atomic Charges of Ionic Liquid through a Combination of Molecular Dynamics Simulation and Density Functional Theory.

PubMed

Ishizuka, Ryosuke; Matubayasi, Nobuyuki

2016-02-09

A self-consistent scheme is developed to determine the atomic partial charges of ionic liquid. Molecular dynamics (MD) simulation was conducted to sample a set of ion configurations, and these configurations were subject to density functional theory (DFT) calculations to determine the partial charges. The charges were then averaged and used as inputs for the subsequent MD simulation, and MD and DFT calculations were repeated until the MD results are not altered any more. We applied this scheme to 1,3-dimethylimidazolium bis(trifluoromethylsulfonyl) imide ([C1mim][NTf2]) and investigated its structure and dynamics as a function of temperature. At convergence, the average ionic charges were ±0.84 e at 350 K due to charge transfer among ions, where e is the elementary charge, while the reduced ionic charges do not affect strongly the density of [C1mim][NTf2] and radial distribution function. Instead, major effects are found on the energetics and dynamics, with improvements of the overestimated heat of vaporization and the too slow motions of ions observed in MD simulations using commonly used force fields.

Complexity analysis of spontaneous brain activity in mood disorders: A magnetoencephalography study of bipolar disorder and major depression.

PubMed

Fernández, Alberto; Al-Timemy, Ali H; Ferre, Francisco; Rubio, Gabriel; Escudero, Javier

2018-04-26

The lack of a biomarker for Bipolar Disorder (BD) causes problems in the differential diagnosis with other mood disorders such as major depression (MD), and misdiagnosis frequently occurs. Bearing this in mind, we investigated non-linear magnetoencephalography (MEG) patterns in BD and MD. Lempel-Ziv Complexity (LZC) was used to evaluate the resting-state MEG activity in a cross-sectional sample of 60 subjects, including 20 patients with MD, 16 patients with BD type-I, and 24 control (CON) subjects. Particular attention was paid to the role of age. The results were aggregated by scalp region. Overall, MD patients showed significantly higher LZC scores than BD patients and CONs. Linear regression analyses demonstrated distinct tendencies of complexity progression as a function of age, with BD patients showing a divergent tendency as compared with MD and CON groups. Logistic regressions confirmed such distinct relationship with age, which allowed the classification of diagnostic groups. The patterns of neural complexity in BD and MD showed not only quantitative differences in their non-linear MEG characteristics but also divergent trajectories of progression as a function of age. Moreover, neural complexity patterns in BD patients resembled those previously observed in schizophrenia, thus supporting preceding evidence of common neuropathological processes. Copyright © 2018 Elsevier Inc. All rights reserved.

Examining Summer Laboratory Research Apprenticeships for High School Students as a Factor in Entry to MD/PhD Programs at Matriculation.

PubMed

Tai, Robert H; Kong, Xiaoqing; Mitchell, Claire E; Dabney, Katherine P; Read, Daniel M; Jeffe, Donna B; Andriole, Dorothy A; Wathington, Heather D

2017-01-01

Do summer laboratory research apprenticeships during high school have an impact on entry into MD/PhD programs? Apart from the nearly decade-long span of time between high school and matriculation into an MD/PhD program, young people have many life-shaping experiences that presumably impact their education and career trajectories. This quantitative study ( n = 236,432) examines the connection between early laboratory research apprenticeship experiences at the high school level and matriculation into one of the more rigorous educational programs for scientific research training. The span of time covered by this analysis reaches across more than a decade, examining the potential importance of research experiences during the precollege years in the educational trajectory of young people. Intertwined with this question on research experiences is a second major concern regarding diversity in the life sciences research corps. Diversity in this wide-ranging discipline refers specifically to the underrepresentation of Blacks/African Americans, Hispanics/Latino/as, and American Indians/Alaska Natives among the ranks of research scientists. Thus, this study includes analyses that specifically focus on research apprenticeships of Blacks/African Americans and Hispanics/Latino/as and their entrance into MD/PhD programs. © 2017 R. H. Tai et al. CBE—Life Sciences Education © 2017 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

General Trends of Dihedral Conformational Transitions in a Globular Protein

PubMed Central

Miao, Yinglong; Baudry, Jerome; Smith, Jeremy C.; McCammon, J. Andrew

2017-01-01

Dihedral conformational transitions are analyzed systematically in a model globular protein, cytochrome P450cam, to examine their structural and chemical dependences through combined conventional molecular dynamics (cMD), accelerated molecular dynamics (aMD) and Adaptive Biasing Force (ABF) simulations. The aMD simulations are performed at two acceleration levels, using dihedral and dual boost, respectively. In comparison with cMD, aMD samples protein dihedral transitions ~2 times faster on average using dihedral boost, and ~3.5 times faster using dual boost. In the protein backbone, significantly higher dihedral transition rates are observed in the Bend, Coil and Turn flexible regions, followed by the β bridge and β sheet, and then the helices. Moreover, protein sidechains of greater length exhibit higher transition rates on average in the aMD-enhanced sampling. Sidechains of the same length (particularly Nχ = 2) exhibit decreasing transition rates with residues when going from hydrophobic to polar, then charged and aromatic chemical types. The reduction of dihedral transition rates is found to be correlated with increasing energy barriers as identified through ABF free energy calculations. These general trends of dihedral conformational transitions provide important insights into the hierarchical dynamics and complex free energy landscapes of functional proteins. PMID:26799251

Cross-scale MD simulations of dynamic strength of tantalum

NASA Astrophysics Data System (ADS)

Bulatov, Vasily

2017-06-01

Dislocations are ubiquitous in metals where their motion presents the dominant and often the only mode of plastic response to straining. Over the last 25 years computational prediction of plastic response in metals has relied on Discrete Dislocation Dynamics (DDD) as the most fundamental method to account for collective dynamics of moving dislocations. Here we present first direct atomistic MD simulations of dislocation-mediated plasticity that are sufficiently large and long to compute plasticity response of single crystal tantalum while tracing the underlying dynamics of dislocations in all atomistic details. Where feasible, direct MD simulations sidestep DDD altogether thus reducing uncertainties of strength predictions to those of the interatomic potential. In the specific context of shock-induced material dynamics, the same MD models predict when, under what conditions and how dislocations interact and compete with other fundamental mechanisms of dynamic response, e.g. twinning, phase-transformations, fracture. In collaboration with: Luis Zepeda-Ruiz, Lawrence Livermore National Laboratory; Alexander Stukowski, Technische Universitat Darmstadt; Tomas Oppelstrup, Lawrence Livermore National Laboratory. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

Correlation of chemical shifts predicted by molecular dynamics simulations for partially disordered proteins.

PubMed

Karp, Jerome M; Eryilmaz, Ertan; Erylimaz, Ertan; Cowburn, David

2015-01-01

There has been a longstanding interest in being able to accurately predict NMR chemical shifts from structural data. Recent studies have focused on using molecular dynamics (MD) simulation data as input for improved prediction. Here we examine the accuracy of chemical shift prediction for intein systems, which have regions of intrinsic disorder. We find that using MD simulation data as input for chemical shift prediction does not consistently improve prediction accuracy over use of a static X-ray crystal structure. This appears to result from the complex conformational ensemble of the disordered protein segments. We show that using accelerated molecular dynamics (aMD) simulations improves chemical shift prediction, suggesting that methods which better sample the conformational ensemble like aMD are more appropriate tools for use in chemical shift prediction for proteins with disordered regions. Moreover, our study suggests that data accurately reflecting protein dynamics must be used as input for chemical shift prediction in order to correctly predict chemical shifts in systems with disorder.

A multi-state trajectory method for non-adiabatic dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tao, Guohua, E-mail: taogh@pkusz.edu.cn

2016-03-07

A multi-state trajectory approach is proposed to describe nuclear-electron coupled dynamics in nonadiabatic simulations. In this approach, each electronic state is associated with an individual trajectory, among which electronic transition occurs. The set of these individual trajectories constitutes a multi-state trajectory, and nuclear dynamics is described by one of these individual trajectories as the system is on the corresponding state. The total nuclear-electron coupled dynamics is obtained from the ensemble average of the multi-state trajectories. A variety of benchmark systems such as the spin-boson system have been tested and the results generated using the quasi-classical version of the method showmore » reasonably good agreement with the exact quantum calculations. Featured in a clear multi-state picture, high efficiency, and excellent numerical stability, the proposed method may have advantages in being implemented to realistic complex molecular systems, and it could be straightforwardly applied to general nonadiabatic dynamics involving multiple states.« less

Calculation and Visualization of Atomistic Mechanical Stresses in Nanomaterials and Biomolecules

PubMed Central

Gilson, Michael K.

2014-01-01

Many biomolecules have machine-like functions, and accordingly are discussed in terms of mechanical properties like force and motion. However, the concept of stress, a mechanical property that is of fundamental importance in the study of macroscopic mechanics, is not commonly applied in the biomolecular context. We anticipate that microscopical stress analyses of biomolecules and nanomaterials will provide useful mechanistic insights and help guide molecular design. To enable such applications, we have developed Calculator of Atomistic Mechanical Stress (CAMS), an open-source software package for computing atomic resolution stresses from molecular dynamics (MD) simulations. The software also enables decomposition of stress into contributions from bonded, nonbonded and Generalized Born potential terms. CAMS reads GROMACS topology and trajectory files, which are easily generated from AMBER files as well; and time-varying stresses may be animated and visualized in the VMD viewer. Here, we review relevant theory and present illustrative applications. PMID:25503996

Calculation and visualization of atomistic mechanical stresses in nanomaterials and biomolecules.

PubMed

Fenley, Andrew T; Muddana, Hari S; Gilson, Michael K

2014-01-01

Many biomolecules have machine-like functions, and accordingly are discussed in terms of mechanical properties like force and motion. However, the concept of stress, a mechanical property that is of fundamental importance in the study of macroscopic mechanics, is not commonly applied in the biomolecular context. We anticipate that microscopical stress analyses of biomolecules and nanomaterials will provide useful mechanistic insights and help guide molecular design. To enable such applications, we have developed Calculator of Atomistic Mechanical Stress (CAMS), an open-source software package for computing atomic resolution stresses from molecular dynamics (MD) simulations. The software also enables decomposition of stress into contributions from bonded, nonbonded and Generalized Born potential terms. CAMS reads GROMACS topology and trajectory files, which are easily generated from AMBER files as well; and time-varying stresses may be animated and visualized in the VMD viewer. Here, we review relevant theory and present illustrative applications.

Insight into the grain boundary effect on the ionic transport of yttria-stabilized zirconia at elevated temperatures from a molecular modeling perspective

NASA Astrophysics Data System (ADS)

Chang, Kai-Shiun; Lin, Yi-Feng; Tung, Kuo-Lun

A molecular dynamics (MD) simulation is used to reveal the grain boundary effect on the ionic transport of yttria-stabilized zirconia (YSZ). The oxygen ion displacements and diffusivities of the ideal and grain boundary-inserted YSZ models are analyzed at elevated temperatures. An optimized Y 2O 3 concentration within YSZ for the best ionic conductivity is achieved by balancing the trade-off between the increased vacancies and the decreased accessible free space. The mass transfer resistance of the grain boundary in YSZ can be more easily found at higher temperatures by observing the oxygen ion diffusivities or traveling trajectories. At lower temperatures, the grain interior and the grain boundary control the ionic transport. In contrast, the grain boundary effect on the diffusion barrier is gradually eliminated at elevated temperatures. The modeled results in this work agree well with previous experimental data.

Phase transitions in trajectories of a superconducting single-electron transistor coupled to a resonator.

PubMed

Genway, Sam; Garrahan, Juan P; Lesanovsky, Igor; Armour, Andrew D

2012-05-01

Recent progress in the study of dynamical phase transitions has been made with a large-deviation approach to study trajectories of stochastic jumps using a thermodynamic formalism. We study this method applied to an open quantum system consisting of a superconducting single-electron transistor, near the Josephson quasiparticle resonance, coupled to a resonator. We find that the dynamical behavior shown in rare trajectories can be rich even when the mean dynamical activity is small, and thus the formalism gives insights into the form of fluctuations. The structure of the dynamical phase diagram found from the quantum-jump trajectories of the resonator is studied, and we see that sharp transitions in the dynamical activity may be related to the appearance and disappearance of bistabilities in the state of the resonator as system parameters are changed. We also demonstrate that for a fast resonator, the trajectories of quasiparticles are similar to the resonator trajectories.

A novel molecular dynamics approach to evaluate the effect of phosphorylation on multimeric protein interface: the αB-Crystallin case study.

PubMed

Chiappori, Federica; Mattiazzi, Luca; Milanesi, Luciano; Merelli, Ivan

2016-03-02

Phosphorylation is one of the most important post-translational modifications (PTM) employed by cells to regulate several cellular processes. Studying the effects of phosphorylations on protein structures allows to investigate the modulation mechanisms of several proteins including chaperones, like the small HSPs, which display different multimeric structures according to the phosphorylation of a few serine residues. In this context, the proposed study is aimed at finding a method to correlate different PTM patterns (in particular phosphorylations at the monomers interface of multimeric complexes) with the dynamic behaviour of the complex, using physicochemical parameters derived from molecular dynamics simulations in the timescale of nanoseconds. We have developed a methodology relying on computing nine physicochemical parameters, derived from the analysis of short MD simulations, and combined with N identifiers that characterize the PTMs of the analysed protein. The nine general parameters were validated on three proteins, with known post-translational modified conformation and unmodified conformation. Then, we applied this approach to the case study of αB-Crystallin, a chaperone which multimeric state (up to 40 units) is supposed to be controlled by phosphorylation of Ser45 and Ser59. Phosphorylation of serines at the dimer interface induces the release of hexamers, the active state of αB-Crystallin. 30 ns of MD simulation were obtained for each possible combination of dimer phosphorylation state and average values of structural, dynamic, energetic and functional features were calculated on the equilibrated portion of the trajectories. Principal Component Analysis was applied to the parameters and the first five Principal Components, which summed up to 84 % of the total variance, were finally considered. The validation of this approach on multimeric proteins, which structures were known both modified and unmodified, allowed us to propose a new approach that can be used to predict the impact of PTM patterns in multi-modified proteins using data collected from short molecular dynamics simulations. Analysis on the αB-Crystallin case study clusters together all-P dimers with all-P hexamers and no-P dimer with no-P hexamer and results suggest a great influence of Ser59 phosphorylation on chain B.

Molecular Dynamics Simulations with Quantum Mechanics/Molecular Mechanics and Adaptive Neural Networks.

PubMed

Shen, Lin; Yang, Weitao

2018-03-13

Direct molecular dynamics (MD) simulation with ab initio quantum mechanical and molecular mechanical (QM/MM) methods is very powerful for studying the mechanism of chemical reactions in a complex environment but also very time-consuming. The computational cost of QM/MM calculations during MD simulations can be reduced significantly using semiempirical QM/MM methods with lower accuracy. To achieve higher accuracy at the ab initio QM/MM level, a correction on the existing semiempirical QM/MM model is an attractive idea. Recently, we reported a neural network (NN) method as QM/MM-NN to predict the potential energy difference between semiempirical and ab initio QM/MM approaches. The high-level results can be obtained using neural network based on semiempirical QM/MM MD simulations, but the lack of direct MD samplings at the ab initio QM/MM level is still a deficiency that limits the applications of QM/MM-NN. In the present paper, we developed a dynamic scheme of QM/MM-NN for direct MD simulations on the NN-predicted potential energy surface to approximate ab initio QM/MM MD. Since some configurations excluded from the database for NN training were encountered during simulations, which may cause some difficulties on MD samplings, an adaptive procedure inspired by the selection scheme reported by Behler [ Behler Int. J. Quantum Chem. 2015 , 115 , 1032 ; Behler Angew. Chem., Int. Ed. 2017 , 56 , 12828 ] was employed with some adaptions to update NN and carry out MD iteratively. We further applied the adaptive QM/MM-NN MD method to the free energy calculation and transition path optimization on chemical reactions in water. The results at the ab initio QM/MM level can be well reproduced using this method after 2-4 iteration cycles. The saving in computational cost is about 2 orders of magnitude. It demonstrates that the QM/MM-NN with direct MD simulations has great potentials not only for the calculation of thermodynamic properties but also for the characterization of reaction dynamics, which provides a useful tool to study chemical or biochemical systems in solution or enzymes.

Application of low energy ion blocking for adsorption site determination of Na Atoms on a Cu(111) surface

NASA Astrophysics Data System (ADS)

Zhang, R.; Makarenko, B.; Bahrim, B.; Rabalais, J. W.

2010-07-01

Ion blocking in the low keV energy range is demonstrated to be a sensitive method for probing surface adsorption sites by means of the technique of time-of-flight scattering and recoiling spectroscopy (TOF-SARS). Adsorbed atoms can block the nearly isotropic backscattering of primary ions from surface atoms in the outmost layers of a crystal. The relative adsorption site position can be derived unambiguously by simple geometrical constructs between the adsorbed atom site and the surface atom sites. Classical ion trajectory simulations using the scattering and recoiling imaging code (SARIC) and molecular dynamics (MD) simulations provide the detailed ion trajectories. Herein we present a quantitative analysis of the blocking effects produced by sub-monolayer Na adsorbed on a Cu(111) surface at room temperature. The results show that the Na adsorption site preferences are different at different Na coverages. At a coverage θ = 0.25 monolayer, Na atoms preferentially populate the fcc threefold surface sites with a height of 2.7 ± 0.1 Å above the 1st layer Cu atoms. At a lower coverage of θ = 0.10 monolayer, there is no adsorption site preference for the Na atoms on the Cu(111) surface.

A Molecular Dynamics Simulation of the Turbulent Couette Minimal Flow Unit

NASA Astrophysics Data System (ADS)

Smith, Edward

2016-11-01

What happens to turbulent motions below the Kolmogorov length scale? In order to explore this question, a 300 million molecule Molecular Dynamics (MD) simulation is presented for the minimal Couette channel in which turbulence can be sustained. The regeneration cycle and turbulent statistics show excellent agreement to continuum based computational fluid dynamics (CFD) at Re=400. As MD requires only Newton's laws and a form of inter-molecular potential, it captures a much greater range of phenomena without requiring the assumptions of Newton's law of viscosity, thermodynamic equilibrium, fluid isotropy or the limitation of grid resolution. The fundamental nature of MD means it is uniquely placed to explore the nature of turbulent transport. A number of unique insights from MD are presented, including energy budgets, sub-grid turbulent energy spectra, probability density functions, Lagrangian statistics and fluid wall interactions. EPSRC Post Doctoral Prize Fellowship.

Crystal MD: The massively parallel molecular dynamics software for metal with BCC structure

NASA Astrophysics Data System (ADS)

Hu, Changjun; Bai, He; He, Xinfu; Zhang, Boyao; Nie, Ningming; Wang, Xianmeng; Ren, Yingwen

2017-02-01

Material irradiation effect is one of the most important keys to use nuclear power. However, the lack of high-throughput irradiation facility and knowledge of evolution process, lead to little understanding of the addressed issues. With the help of high-performance computing, we could make a further understanding of micro-level-material. In this paper, a new data structure is proposed for the massively parallel simulation of the evolution of metal materials under irradiation environment. Based on the proposed data structure, we developed the new molecular dynamics software named Crystal MD. The simulation with Crystal MD achieved over 90% parallel efficiency in test cases, and it takes more than 25% less memory on multi-core clusters than LAMMPS and IMD, which are two popular molecular dynamics simulation software. Using Crystal MD, a two trillion particles simulation has been performed on Tianhe-2 cluster.

Comparison of kinematic and dynamic leg trajectory optimization techniques for biped robot locomotion

NASA Astrophysics Data System (ADS)

Khusainov, R.; Klimchik, A.; Magid, E.

2017-01-01

The paper presents comparison analysis of two approaches in defining leg trajectories for biped locomotion. The first one operates only with kinematic limitations of leg joints and finds the maximum possible locomotion speed for given limits. The second approach defines leg trajectories from the dynamic stability point of view and utilizes ZMP criteria. We show that two methods give different trajectories and demonstrate that trajectories based on pure dynamic optimization cannot be realized due to joint limits. Kinematic optimization provides unstable solution which can be balanced by upper body movement.

Molecular dynamics simulations and novel drug discovery.

PubMed

Liu, Xuewei; Shi, Danfeng; Zhou, Shuangyan; Liu, Hongli; Liu, Huanxiang; Yao, Xiaojun

2018-01-01

Molecular dynamics (MD) simulations can provide not only plentiful dynamical structural information on biomacromolecules but also a wealth of energetic information about protein and ligand interactions. Such information is very important to understanding the structure-function relationship of the target and the essence of protein-ligand interactions and to guiding the drug discovery and design process. Thus, MD simulations have been applied widely and successfully in each step of modern drug discovery. Areas covered: In this review, the authors review the applications of MD simulations in novel drug discovery, including the pathogenic mechanisms of amyloidosis diseases, virtual screening and the interaction mechanisms between drugs and targets. Expert opinion: MD simulations have been used widely in investigating the pathogenic mechanisms of diseases caused by protein misfolding, in virtual screening, and in investigating drug resistance mechanisms caused by mutations of the target. These issues are very difficult to solve by experimental methods alone. Thus, in the future, MD simulations will have wider application with the further improvement of computational capacity and the development of better sampling methods and more accurate force fields together with more efficient analysis methods.

Algorithms of GPU-enabled reactive force field (ReaxFF) molecular dynamics.

PubMed

Zheng, Mo; Li, Xiaoxia; Guo, Li

2013-04-01

Reactive force field (ReaxFF), a recent and novel bond order potential, allows for reactive molecular dynamics (ReaxFF MD) simulations for modeling larger and more complex molecular systems involving chemical reactions when compared with computation intensive quantum mechanical methods. However, ReaxFF MD can be approximately 10-50 times slower than classical MD due to its explicit modeling of bond forming and breaking, the dynamic charge equilibration at each time-step, and its one order smaller time-step than the classical MD, all of which pose significant computational challenges in simulation capability to reach spatio-temporal scales of nanometers and nanoseconds. The very recent advances of graphics processing unit (GPU) provide not only highly favorable performance for GPU enabled MD programs compared with CPU implementations but also an opportunity to manage with the computing power and memory demanding nature imposed on computer hardware by ReaxFF MD. In this paper, we present the algorithms of GMD-Reax, the first GPU enabled ReaxFF MD program with significantly improved performance surpassing CPU implementations on desktop workstations. The performance of GMD-Reax has been benchmarked on a PC equipped with a NVIDIA C2050 GPU for coal pyrolysis simulation systems with atoms ranging from 1378 to 27,283. GMD-Reax achieved speedups as high as 12 times faster than Duin et al.'s FORTRAN codes in Lammps on 8 CPU cores and 6 times faster than the Lammps' C codes based on PuReMD in terms of the simulation time per time-step averaged over 100 steps. GMD-Reax could be used as a new and efficient computational tool for exploiting very complex molecular reactions via ReaxFF MD simulation on desktop workstations. Copyright © 2013 Elsevier Inc. All rights reserved.

Conformational Transition Pathway in the Activation Process of Allosteric Glucokinase

PubMed Central

Shi, Ting; Zhao, Yaxue; Chen, Yingyi; Li, Xiaobai; Liu, Xinyi; Huang, Zhimin; Zhang, Jian

2013-01-01

Glucokinase (GK) is a glycolytic enzyme that plays an important role in regulating blood glucose level, thus acting as a potentially attractive target for drug discovery in the treatment of diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the activation mechanism of GK from the super-open state (inactive state) to the closed state (active state), a series of conventional molecular dynamics (MD) and targeted MD (TMD) simulations were performed on this enzyme. Conventional MD simulation showed a specific conformational ensemble of GK when the enzyme is inactive. Seven TMD simulations depicted a reliably conformational transition pathway of GK from the inactive state to the active state, and the components important to the conformational change of GK were identified by analyzing the detailed structures of the TMD trajectories. In combination with the inactivation process, our findings showed that the whole conformational pathway for the activation-inactivation-activation of GK is a one-direction circulation, and the active state is less stable than the inactive state in the circulation. Additionally, glucose was demonstrated to gradually modulate its binding pose with the help of residues in the large domain and connecting region of GK during the activation process. Furthermore, the obtained energy barriers were used to explain the preexisting equilibrium and the slow binding kinetic process of the substrate by GK. The simulated results are in accordance with the recent findings from the mutagenesis experiments and kinetic analyses. Our observations reveal a complicated conformational process in the allosteric protein, resulting in new knowledge about the delicate mechanisms for allosteric biological macromolecules that will be useful in drug design for targeting allosteric proteins. PMID:23409066

Secondary structure inducing potential of beta-amino acids: torsion angle clustering facilitates comparison and analysis of the conformation during MD trajectories.

PubMed

Guthöhrlein, E W; Malesević, M; Majer, Z; Sewald, N

2007-01-01

While numerous examples of beta-peptides--exclusively composed of beta-amino acids--have been investigated during the past decade, there are only few reports on the conformational preference of a single beta-amino acid when incorporated into a cyclopeptide. The conformational bias of beta-amino acids on the secondary structure of cyclopeptides has been investigated by NMR spectroscopy in combination with distance geometry (DG) and molecular dynamics (MD) calculations using experimental constraints. The atomic coordinate RMSD criterion usually employed for clustering of conformations after DG and MD calculations does not necessarily group similar peptide conformations, as there is an insufficient correlation between atomic coordinates and torsion angles. To improve on this shortcoming and to eliminate any arbitrary decisions during this process, a torsion angle clustering procedure has been implemented. For the cyclic pentapeptides cyclo-(-Val-beta-Hala-Phe-Leu-Ile-) 1 and cyclo-(-Ser-Pro-Leu-beta-Hasn-Asp-) 3, the beta-amino acid is found in the central position of an extended gamma-turn (pseudo gamma-turn, Psigamma-turn), while the beta-Hpro residue in the cyclic hexapeptide cyclo-(-Ser-beta-Hpro-Leu-Asn-Ile-Asp-) 5 preferentially occupies position i+1 of a pseudo beta-turn (Psibeta-turn). These results further corroborate the hypothesis of beta-amino acids being reliable inducers of secondary structure in cyclic penta- and hexapeptides. They can be employed in the de novo design of biologically active cyclopeptides in pharmaceutical research, since the three-dimensional presentation of pharmacophoric groups in the side chains can be tailored by incorporation of beta-amino acids in strategic sequential positions. (c) 2007 Wiley Periodicals, Inc.

Efficiency in nonequilibrium molecular dynamics Monte Carlo simulations

DOE PAGES

Radak, Brian K.; Roux, Benoît

2016-10-07

Hybrid algorithms combining nonequilibrium molecular dynamics and Monte Carlo (neMD/MC) offer a powerful avenue for improving the sampling efficiency of computer simulations of complex systems. These neMD/MC algorithms are also increasingly finding use in applications where conventional approaches are impractical, such as constant-pH simulations with explicit solvent. However, selecting an optimal nonequilibrium protocol for maximum efficiency often represents a non-trivial challenge. This work evaluates the efficiency of a broad class of neMD/MC algorithms and protocols within the theoretical framework of linear response theory. The approximations are validated against constant pH-MD simulations and shown to provide accurate predictions of neMD/MC performance.more » An assessment of a large set of protocols confirms (both theoretically and empirically) that a linear work protocol gives the best neMD/MC performance. Lastly, a well-defined criterion for optimizing the time parameters of the protocol is proposed and demonstrated with an adaptive algorithm that improves the performance on-the-fly with minimal cost.« less

The Hugoniot adiabat of crystalline copper based on molecular dynamics simulation and semiempirical equation of state

NASA Astrophysics Data System (ADS)

Gubin, S. A.; Maklashova, I. V.; Mel'nikov, I. N.

2018-01-01

The molecular dynamics (MD) method was used for prediction of properties of copper under shock-wave compression and clarification of the melting region of crystal copper. The embedded atom potential was used for the interatomic interaction. Parameters of Hugonoit adiabats of solid and liquid phases of copper calculated by the semiempirical Grüneisen equation of state are consistent with the results of MD simulations and experimental data. MD simulation allows to visualize the structure of cooper on the atomistic level. The analysis of the radial distribution function and the standard deviation by MD modeling allows to predict the melting area behind the shock wave front. These MD simulation data are required to verify the wide-range equation of state of metals. The melting parameters of copper based on MD simulations and semiempirical equations of state are consistent with experimental and theoretical data, including the region of the melting point of copper.

Conformational dynamics of a crystalline protein from microsecond-scale molecular dynamics simulations and diffuse X-ray scattering.

PubMed

Wall, Michael E; Van Benschoten, Andrew H; Sauter, Nicholas K; Adams, Paul D; Fraser, James S; Terwilliger, Thomas C

2014-12-16

X-ray diffraction from protein crystals includes both sharply peaked Bragg reflections and diffuse intensity between the peaks. The information in Bragg scattering is limited to what is available in the mean electron density. The diffuse scattering arises from correlations in the electron density variations and therefore contains information about collective motions in proteins. Previous studies using molecular-dynamics (MD) simulations to model diffuse scattering have been hindered by insufficient sampling of the conformational ensemble. To overcome this issue, we have performed a 1.1-μs MD simulation of crystalline staphylococcal nuclease, providing 100-fold more sampling than previous studies. This simulation enables reproducible calculations of the diffuse intensity and predicts functionally important motions, including transitions among at least eight metastable states with different active-site geometries. The total diffuse intensity calculated using the MD model is highly correlated with the experimental data. In particular, there is excellent agreement for the isotropic component of the diffuse intensity, and substantial but weaker agreement for the anisotropic component. Decomposition of the MD model into protein and solvent components indicates that protein-solvent interactions contribute substantially to the overall diffuse intensity. We conclude that diffuse scattering can be used to validate predictions from MD simulations and can provide information to improve MD models of protein motions.

General trends of dihedral conformational transitions in a globular protein.

PubMed

Miao, Yinglong; Baudry, Jerome; Smith, Jeremy C; McCammon, J Andrew

2016-04-01

Dihedral conformational transitions are analyzed systematically in a model globular protein, cytochrome P450cam, to examine their structural and chemical dependences through combined conventional molecular dynamics (cMD), accelerated molecular dynamics (aMD) and adaptive biasing force (ABF) simulations. The aMD simulations are performed at two acceleration levels, using dihedral and dual boost, respectively. In comparison with cMD, aMD samples protein dihedral transitions approximately two times faster on average using dihedral boost, and ∼ 3.5 times faster using dual boost. In the protein backbone, significantly higher dihedral transition rates are observed in the bend, coil, and turn flexible regions, followed by the β bridge and β sheet, and then the helices. Moreover, protein side chains of greater length exhibit higher transition rates on average in the aMD-enhanced sampling. Side chains of the same length (particularly Nχ = 2) exhibit decreasing transition rates with residues when going from hydrophobic to polar, then charged and aromatic chemical types. The reduction of dihedral transition rates is found to be correlated with increasing energy barriers as identified through ABF free energy calculations. These general trends of dihedral conformational transitions provide important insights into the hierarchical dynamics and complex free energy landscapes of functional proteins. © 2016 Wiley Periodicals, Inc.

General trends of dihedral conformational transitions in a globular protein

DOE PAGES

Miao, Yinglong; Baudry, Jerome; Smith, Jeremy C.; ...

2016-02-15

In this paper, dihedral conformational transitions are analyzed systematically in a model globular protein, cytochrome P450cam, to examine their structural and chemical dependences through combined conventional molecular dynamics (cMD), accelerated molecular dynamics (aMD) and adaptive biasing force (ABF) simulations. The aMD simulations are performed at two acceleration levels, using dihedral and dual boost, respectively. In comparison with cMD, aMD samples protein dihedral transitions approximately two times faster on average using dihedral boost, and ~3.5 times faster using dual boost. In the protein backbone, significantly higher dihedral transition rates are observed in the bend, coil, and turn flexible regions, followed bymore » the β bridge and β sheet, and then the helices. Moreover, protein side chains of greater length exhibit higher transition rates on average in the aMD-enhanced sampling. Side chains of the same length (particularly Nχ = 2) exhibit decreasing transition rates with residues when going from hydrophobic to polar, then charged and aromatic chemical types. The reduction of dihedral transition rates is found to be correlated with increasing energy barriers as identified through ABF free energy calculations. In conclusion, these general trends of dihedral conformational transitions provide important insights into the hierarchical dynamics and complex free energy landscapes of functional proteins.« less

Comparing the Ability of Enhanced Sampling Molecular Dynamics Methods To Reproduce the Behavior of Fluorescent Labels on Proteins.

PubMed

Walczewska-Szewc, Katarzyna; Deplazes, Evelyne; Corry, Ben

2015-07-14

Adequately sampling the large number of conformations accessible to proteins and other macromolecules is one of the central challenges in molecular dynamics (MD) simulations; this activity can be difficult, even for relatively simple systems. An example where this problem arises is in the simulation of dye-labeled proteins, which are now being widely used in the design and interpretation of Förster resonance energy transfer (FRET) experiments. In this study, MD simulations are used to characterize the motion of two commonly used FRET dyes attached to an immobilized chain of polyproline. Even in this simple system, the dyes exhibit complex behavior that is a mixture of fast and slow motions. Consequently, very long MD simulations are required to sufficiently sample the entire range of dye motion. Here, we compare the ability of enhanced sampling methods to reproduce the behavior of fluorescent labels on proteins. In particular, we compared Accelerated Molecular Dynamics (AMD), metadynamics, Replica Exchange Molecular Dynamics (REMD), and High Temperature Molecular Dynamics (HTMD) to equilibrium MD simulations. We find that, in our system, all of these methods improve the sampling of the dye motion, but the most significant improvement is achieved using REMD.

In Silico Analyses of Substrate Interactions with Human Serum Paraoxonase 1

DTIC Science & Technology

2008-01-01

substrate interactions of HuPON1 remains elusive. In this study, we apply homology modeling, docking, and molecular dynamic (MD) simulations to probe the...mod- eling; docking; molecular dynamics simulations ; binding free energy decomposition. 486 PROTEINS Published 2008 WILEY-LISS, INC. yThis article is a...apply homology modeling, docking, and molecular dynamic (MD) simulations to probe the binding interactions of HuPON1 with representative substrates. The

COFFDROP: A Coarse-Grained Nonbonded Force Field for Proteins Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of Amino Acids.

PubMed

Andrews, Casey T; Elcock, Adrian H

2014-11-11

We describe the derivation of a set of bonded and nonbonded coarse-grained (CG) potential functions for use in implicit-solvent Brownian dynamics (BD) simulations of proteins derived from all-atom explicit-solvent molecular dynamics (MD) simulations of amino acids. Bonded potential functions were derived from 1 μs MD simulations of each of the 20 canonical amino acids, with histidine modeled in both its protonated and neutral forms; nonbonded potential functions were derived from 1 μs MD simulations of every possible pairing of the amino acids (231 different systems). The angle and dihedral probability distributions and radial distribution functions sampled during MD were used to optimize a set of CG potential functions through use of the iterative Boltzmann inversion (IBI) method. The optimized set of potential functions-which we term COFFDROP (COarse-grained Force Field for Dynamic Representation Of Proteins)-quantitatively reproduced all of the "target" MD distributions. In a first test of the force field, it was used to predict the clustering behavior of concentrated amino acid solutions; the predictions were directly compared with the results of corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement. In a second test, BD simulations of the small protein villin headpiece were carried out at concentrations that have recently been studied in all-atom explicit-solvent MD simulations by Petrov and Zagrovic ( PLoS Comput. Biol. 2014 , 5 , e1003638). The anomalously strong intermolecular interactions seen in the MD study were reproduced in the COFFDROP simulations; a simple scaling of COFFDROP's nonbonded parameters, however, produced results in better accordance with experiment. Overall, our results suggest that potential functions derived from simulations of pairwise amino acid interactions might be of quite broad applicability, with COFFDROP likely to be especially useful for modeling unfolded or intrinsically disordered proteins.

COFFDROP: A Coarse-Grained Nonbonded Force Field for Proteins Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of Amino Acids

PubMed Central

2015-01-01

We describe the derivation of a set of bonded and nonbonded coarse-grained (CG) potential functions for use in implicit-solvent Brownian dynamics (BD) simulations of proteins derived from all-atom explicit-solvent molecular dynamics (MD) simulations of amino acids. Bonded potential functions were derived from 1 μs MD simulations of each of the 20 canonical amino acids, with histidine modeled in both its protonated and neutral forms; nonbonded potential functions were derived from 1 μs MD simulations of every possible pairing of the amino acids (231 different systems). The angle and dihedral probability distributions and radial distribution functions sampled during MD were used to optimize a set of CG potential functions through use of the iterative Boltzmann inversion (IBI) method. The optimized set of potential functions—which we term COFFDROP (COarse-grained Force Field for Dynamic Representation Of Proteins)—quantitatively reproduced all of the “target” MD distributions. In a first test of the force field, it was used to predict the clustering behavior of concentrated amino acid solutions; the predictions were directly compared with the results of corresponding all-atom explicit-solvent MD simulations and found to be in excellent agreement. In a second test, BD simulations of the small protein villin headpiece were carried out at concentrations that have recently been studied in all-atom explicit-solvent MD simulations by Petrov and Zagrovic (PLoS Comput. Biol.2014, 5, e1003638). The anomalously strong intermolecular interactions seen in the MD study were reproduced in the COFFDROP simulations; a simple scaling of COFFDROP’s nonbonded parameters, however, produced results in better accordance with experiment. Overall, our results suggest that potential functions derived from simulations of pairwise amino acid interactions might be of quite broad applicability, with COFFDROP likely to be especially useful for modeling unfolded or intrinsically disordered proteins. PMID:25400526

Multi-state trajectory approach to non-adiabatic dynamics: General formalism and the active state trajectory approximation

NASA Astrophysics Data System (ADS)

Tao, Guohua

2017-07-01

A general theoretical framework is derived for the recently developed multi-state trajectory (MST) approach from the time dependent Schrödinger equation, resulting in equations of motion for coupled nuclear-electronic dynamics equivalent to Hamilton dynamics or Heisenberg equation based on a new multistate Meyer-Miller (MM) model. The derived MST formalism incorporates both diabatic and adiabatic representations as limiting cases and reduces to Ehrenfest or Born-Oppenheimer dynamics in the mean-field or the single-state limits, respectively. In the general multistate formalism, nuclear dynamics is represented in terms of a set of individual state-specific trajectories, while in the active state trajectory (AST) approximation, only one single nuclear trajectory on the active state is propagated with its augmented images running on all other states. The AST approximation combines the advantages of consistent nuclear-coupled electronic dynamics in the MM model and the single nuclear trajectory in the trajectory surface hopping (TSH) treatment and therefore may provide a potential alternative to both Ehrenfest and TSH methods. The resulting algorithm features in a consistent description of coupled electronic-nuclear dynamics and excellent numerical stability. The implementation of the MST approach to several benchmark systems involving multiple nonadiabatic transitions and conical intersection shows reasonably good agreement with exact quantum calculations, and the results in both representations are similar in accuracy. The AST treatment also reproduces the exact results reasonably, sometimes even quantitatively well, with a better performance in the adiabatic representation.

Conformational flexibility of the ErbB2 ectodomain and trastuzumab antibody complex as revealed by molecular dynamics and principal component analysis.

PubMed

Franco-Gonzalez, Juan Felipe; Cruz, Victor L; Ramos, Javier; Martínez-Salazar, Javier

2013-03-01

Human epidermal growth factor receptor 2 (ErbB2) is a transmembrane oncoprotein that is over expressed in breast cancer. A successful therapeutic treatment is a monoclonal antibody called trastuzumab which interacts with the ErbB2 extracellular domain (ErbB2-ECD). A better understanding of the detailed structure of the receptor-antibody interaction is indeed of prime interest for the design of more effective anticancer therapies. In order to discuss the flexibility of the complex ErbB2-ECD/trastuzumab, we present, in this study, a multi-nanosecond molecular dynamics simulation (MD) together with an analysis of fluctuations, through a principal component analysis (PCA) of this system. Previous to this step and in order to validate the simulations, we have performed a detailed analysis of the variable antibody domain interactions with the extracellular domain IV of ErbB2. This structure has been statically elucidated by x-ray studies. Indeed, the simulation results are in excellent agreement with the available experimental information during the full trajectory. The PCA shows eigenvector fluctuations resulting in a hinge motion in which domain II and C(H) domains approach each other. This move is likely stabilized by the formation of H-bonds and salt bridge interactions between residues of the dimerization arm in the domain II and trastuzumab residues located in the C(H) domain. Finally, we discuss the flexibility of the MD/PCA model in relation with the static x-ray structure. A movement of the antibody toward the dimerization domain of the ErbB2 receptor is reported for the first time. This finding could have important consequences on the biological action of the monoclonal antibody.

Turn-Directed α-β Conformational Transition of α-syn12 Peptide at Different pH Revealed by Unbiased Molecular Dynamics Simulations

PubMed Central

Liu, Lei; Cao, Zanxia

2013-01-01

The transition from α-helical to β-hairpin conformations of α-syn12 peptide is characterized here using long timescale, unbiased molecular dynamics (MD) simulations in explicit solvent models at physiological and acidic pH values. Four independent normal MD trajectories, each 2500 ns, are performed at 300 K using the GROMOS 43A1 force field and SPC water model. The most clustered structures at both pH values are β-hairpin but with different turns and hydrogen bonds. Turn9-6 and four hydrogen bonds (HB9-6, HB6-9, HB11-4 and HB4-11) are formed at physiological pH; turn8-5 and five hydrogen bonds (HB8-5, HB5-8, HB10-3, HB3-10 and HB12-1) are formed at acidic pH. A common folding mechanism is observed: the formation of the turn is always before the formation of the hydrogen bonds, which means the turn is always found to be the major determinant in initiating the transition process. Furthermore, two transition paths are observed at physiological pH. One of the transition paths tends to form the most-clustered turn and improper hydrogen bonds at the beginning, and then form the most-clustered hydrogen bonds. Another transition path tends to form the most-clustered turn, and turn5-2 firstly, followed by the formation of part hydrogen bonds, then turn5-2 is extended and more hydrogen bonds are formed. The transition path at acidic pH is as the same as the first path described at physiological pH. PMID:23708094

Deciphering the GPER/GPR30-agonist and antagonists interactions using molecular modeling studies, molecular dynamics, and docking simulations.

PubMed

Méndez-Luna, D; Martínez-Archundia, M; Maroun, Rachid C; Ceballos-Reyes, G; Fragoso-Vázquez, M J; González-Juárez, D E; Correa-Basurto, J

2015-01-01

The G-protein coupled estrogen receptor 1 GPER/GPR30 is a transmembrane seven-helix (7TM) receptor involved in the growth and proliferation of breast cancer. Due to the absence of a crystal structure of GPER/GPR30, in this work, molecular modeling studies have been carried out to build a three-dimensional structure, which was subsequently refined by molecular dynamics (MD) simulations (up to 120 ns). Furthermore, we explored GPER/GPR30's molecular recognition properties by using reported agonist ligands (G1, estradiol (E2), tamoxifen, and fulvestrant) and the antagonist ligands (G15 and G36) in subsequent docking studies. Our results identified the E2 binding site on GPER/GPR30, as well as other receptor cavities for accepting large volume ligands, through GPER/GPR30 π-π, hydrophobic, and hydrogen bond interactions. Snapshots of the MD trajectory at 14 and 70 ns showed almost identical binding motifs for G1 and G15. It was also observed that C107 interacts with the acetyl oxygen of G1 (at 14 ns) and that at 70 ns the residue E275 interacts with the acetyl group and with the oxygen from the other agonist whereas the isopropyl group of G36 is oriented toward Met141, suggesting that both C107 and E275 could be involved in the protein activation. This contribution suggest that GPER1 has great structural changes which explain its great capacity to accept diverse ligands, and also, the same ligand could be recognized in different binding pose according to GPER structural conformations.

Electronic couplings and on-site energies for hole transfer in DNA: Systematic quantum mechanical/molecular dynamic study

NASA Astrophysics Data System (ADS)

Voityuk, Alexander A.

2008-03-01

The electron hole transfer (HT) properties of DNA are substantially affected by thermal fluctuations of the π stack structure. Depending on the mutual position of neighboring nucleobases, electronic coupling V may change by several orders of magnitude. In the present paper, we report the results of systematic QM/molecular dynamic (MD) calculations of the electronic couplings and on-site energies for the hole transfer. Based on 15ns MD trajectories for several DNA oligomers, we calculate the average coupling squares ⟨V2⟩ and the energies of basepair triplets XG +Y and XA +Y, where X, Y =G, A, T, and C. For each of the 32 systems, 15 000 conformations separated by 1ps are considered. The three-state generalized Mulliken-Hush method is used to derive electronic couplings for HT between neighboring basepairs. The adiabatic energies and dipole moment matrix elements are computed within the INDO/S method. We compare the rms values of V with the couplings estimated for the idealized B-DNA structure and show that in several important cases the couplings calculated for the idealized B-DNA structure are considerably underestimated. The rms values for intrastrand couplings G-G, A-A, G-A, and A-G are found to be similar, ˜0.07eV, while the interstrand couplings are quite different. The energies of hole states G+ and A+ in the stack depend on the nature of the neighboring pairs. The XG +Y are by 0.5eV more stable than XA +Y. The thermal fluctuations of the DNA structure facilitate the HT process from guanine to adenine. The tabulated couplings and on-site energies can be used as reference parameters in theoretical and computational studies of HT processes in DNA.

Molecular dynamics as a foundation for flux prediction through nanoporous membranes: A vectorized, constraint-free approach to conservative simulations

NASA Astrophysics Data System (ADS)

Inman, Matthew Clay

A novel, open-cathode direct methanol fuel cell (DMFC ) has been designed and built by researchers at the University of North Florida and University of Florida. Foremost among the advances of this system over previous DMFC architectures is a passive water recovery system which allows product water to replenish that consumed at the anode. This is enabled by a specially-designed water pathway combined with a liquid barrier layer (LBL ). The LBL membrane is positioned between the cathode catalyst layer and the cathode gas diffusion layer, and must exhibit high permeability and low diffusive resistance to both oxygen and water vapor, bulk hydrophobicity to hold back the product liquid water, and must remain electrically conductive. Maintaining water balance at optimum operating temperatures is problematic with the current LBL design, forcing the system to run at lower temperatures decreasing the overall system efficiency. This research presents a novel approach to nanoporous membrane design whereby flux of a given species is determined based upon the molecular properties of said species and those of the diffusing medium, the pore geometry, and the membrane thickness. A molecular dynamics (MD ) model is developed for tracking Knudsen regime flows of a Lennard-Jones (LJ ) fluid through an atomistic pore structure, hundreds of thousands of wall collision simulations are performed on the University of Florida HiPerGator supercomputer, and the generated trajectory information is used to develop number density and axial velocity profiles for use in a rigorous approach to total flux calculation absent in previously attempted MD models. Results are compared to other published approaches and diffusion data available in the literature. The impact of this study on various applications of membrane design is discussed and additional simulations and model improvements are outlined for future consideration.

Mutagenesis and molecular dynamics simulations revealed the chitooligosaccharide entry and exit points for chitinase D from Serratia proteamaculans.

PubMed

Madhuprakash, Jogi; Tanneeru, Karunakar; Karlapudi, Bhavana; Guruprasad, Lalitha; Podile, Appa Rao

2014-09-01

Transglycosylation (TG) activity is a property of glycosyl hydrolases (GHs) with which new glycosidic bonds are introduced between donor and acceptor sugar molecules. This special property of the GHs has potential to generate longer chain chitooligosaccharides (CHOS) that show elicitor activity in plants. We hypothesize that TG activity could be improved by retaining the substrate for a longer duration in the catalytic site. Four variants of chitinase D from Serratia proteamaculans (SpChiD) i.e. G119S, G119W, W120A and G201W were analyzed in detail for improved TG activity using high performance liquid chromatography (HPLC) and high resolution mass spectrometry (HRMS). The results were strongly supported by 50ns molecular dynamics (MD) simulations and estimated solvated interaction energies (SIE). The mutant G119W lost much of both hydrolytic and TG activities, while the mutant G201W displayed increased TG. The trajectory of MD simulations of the mutant G119W showed that the indole rings of two adjacent Trp residues create a major hindrance for the DP4 movement towards the catalytic center. Increased van der Waals (vdW) and coulombic interactions between DP4 substrate and the Trp-201 resulted in enhanced TG activity with the mutant G201W. The average number of hydrogen bonds observed for the DP4 substrate was increased for the mutants G119W and G201W compared to SpChiD. The increase in TG activity could be due to partial blocking of product exit of SpChiD. This new approach can be used for generating mutants of GHs with improved TG activity to produce longer chain oligosaccharides. Copyright © 2014 Elsevier B.V. All rights reserved.

Molecular dynamics simulations and principal component analysis on human laforin mutation W32G and W32G/K87A.

PubMed

Srikumar, P S; Rohini, K; Rajesh, Perumbilavil Kaithamanakallam

2014-06-01

Mutations in human laforin lead to an autosomal neurodegenerative disorder Lafora disease. In N-terminal carbohydrate binding domain of laforin, two mutations W32G and K87A are reported as highly disease causing laforin mutants. Experimental studies reported that mutations are responsible for the abolishment of glycogen binding which is a critical function of laforin. Our current computational study focused on the role of conformational changes in human laforin structure due to existing single mutation W32G and prepared double mutation W32G/K87A related to loss of glycogen binding. We performed 10 ns molecular dynamics (MD) simulation studies in the Gromacs package for both mutations and analyzed the trajectories. From the results, the global properties like root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and hydrogen bonds showed structural changes in atomic level observed in W32G and W32G/K87A laforin mutants. The conformational change induced by mutants influenced the loss of the overall stability of the native laforin. Moreover, the change in overall motion of protein was analyzed by principal component analysis and results showed protein clusters expanded more than native and also change in direction in case of double mutant in conformational space. Overall, our report provides theoretical information on loss of structure-function relationship due to flexible nature of laforin mutants. In conclusion, comparative MD simulation studies support the experimental data on W32G and W32G/K87A related to the lafora disease mechanism on glycogen binding.

Modeling of three dimensional structure of human alpha-fetoprotein complexed with diethylstilbestrol: docking and molecular dynamics simulation study.

PubMed

Terentiev, Alexander A; Moldogazieva, Nurbubu T; Levtsova, Olga V; Maximenko, Dmitry M; Borozdenko, Denis A; Shaitan, Konstantin V

2012-04-01

It has been long experimentally demonstrated that human alpha-fetoprotein (HAFP) has an ability to bind immobilized estrogens with the most efficiency for synthetic estrogen analog - diethylstilbestrol (DES). However, the question remains why the human AFP (HAFP), unlike rodent AFP, cannot bind free estrogens. Moreover, despite the fact that AFP was first discovered more than 50 years ago and is presently recognized as a "golden standard" among onco-biomarkers, its three-dimensional (3D) structure has not been experimentally solved yet. In this work using MODELLER program, we generated 3D model of HAFP on the basis of homology with human serum albumin (HSA) and Vitamin D-binding protein (VTDB) with subsequent molecular docking of DES to the model structure and molecular dynamics (MD) simulation study of the complex obtained. The model constructed has U-shaped structure in which a cavity may be distinguished. In this cavity the putative estrogen-binding site is localized. Validation by RMSD calculation and with the use of PROCHECK program showed good quality of the model and stability of extended region of four alpha-helical structures that contains putative hormone-binding residues. Data extracted from MD simulation trajectory allow proposing two types of interactions between amino acid residues of HAFP and DES molecule: (1) hydrogen bonding with involvement of residues S445, R452, and E551; (2) hydrophobic interactions with participation of L138, M448, and M548 residues. A suggestion is made that immobilization of the hormone using a long spacer provides delivery of the estrogen molecule to the binding site and, thereby, facilitates interaction between HAFP and the hormone.

Multi-scale characterization of the energy landscape of proteins with application to the C3D/Efb-C complex.

PubMed

Haspel, Nurit; Geisbrecht, Brian V; Lambris, John; Kavraki, Lydia

2010-03-01

We present a novel multi-level methodology to explore and characterize the low energy landscape and the thermodynamics of proteins. Traditional conformational search methods typically explore only a small portion of the conformational space of proteins and are hard to apply to large proteins due to the large amount of calculations required. In our multi-scale approach, we first provide an initial characterization of the equilibrium state ensemble of a protein using an efficient computational conformational sampling method. We then enrich the obtained ensemble by performing short Molecular Dynamics (MD) simulations on selected conformations from the ensembles as starting points. To facilitate the analysis of the results, we project the resulting conformations on a low-dimensional landscape to efficiently focus on important interactions and examine low energy regions. This methodology provides a more extensive sampling of the low energy landscape than an MD simulation starting from a single crystal structure as it explores multiple trajectories of the protein. This enables us to obtain a broader view of the dynamics of proteins and it can help in understanding complex binding, improving docking results and more. In this work, we apply the methodology to provide an extensive characterization of the bound complexes of the C3d fragment of human Complement component C3 and one of its powerful bacterial inhibitors, the inhibitory domain of Staphylococcus aureus extra-cellular fibrinogen-binding domain (Efb-C) and two of its mutants. We characterize several important interactions along the binding interface and define low free energy regions in the three complexes. Proteins 2010. (c) 2009 Wiley-Liss, Inc.

Molecular Dynamics Simulations of Novel Potential Inhibitors for Penicillin Binding Protein 2B of the Resistant 5204 Strain of Streptococcus Pneumoniae.

PubMed

Suvaithenamudhan, Suvaiyarasan; Parthasarathy, Subbiah

2017-01-01

Top five best hit compounds (ZINC59376795, ZINC60175365, ZINC36922620, ZINC39550705 and ZINC36953975) were obtained through our high throughput virtual screening (HTVS) analysis with resistant 5204-PBP2B (5204 Penicillin Binding Protein 2B) and sensitive R6-PBP2B (R6 Penicillin Binding Protein 2B) proteins of Streptococcus pneumoniae. To gain insight in molecular docking and dynamics simulations of these top five best hit compounds with both resistant 5204-PBP2B and sensitive R6-PBP2B targets. We have employed Glide XP docking and molecular dynamics simulations of these five best hit compounds with 5204-PBP2B and R6-PBP2B targets. The stability analysis has been carried out through DFT, prime-MM/GBSA binding free energy, RMSD, RMSF and Principal Component Analysis. The reference drug, penicillin G forms stable complex with sensitive R6-PBP2B protein. Similar stability is observed for the mutant resistant 5204-PBP2B with the top scoring compound ZINC592376795 which implies that this compound may act as an effective potential inhibitor. The compound ZINC59376795 forms a total of five hydrogen bonds with resistant 5204-PBP2B protein of which three are with mutated residues. Similarly, the other four compounds including penicillin G also form hydrogen bonds with mutated residue. The MD simulations and stability analysis of the complexes of wild and mutant forms are evaluated for a trajectory period of 16ns and further MD simulations of ZINC59376795 with resistant 5204-PBP2B and sensitive R6-PBP2B confirmed the stability for 50 ns. These results suggest that the top five best hit compounds are found to be a promising gateway for the further development of anti-pneumococcal therapeutics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Insights from Molecular Dynamics Simulations: Structural Basis for the V567D Mutation-Induced Instability of Zebrafish Alpha-Dystroglycan and Comparison with the Murine Model

PubMed Central

Pirolli, Davide; Sciandra, Francesca; Bozzi, Manuela; Giardina, Bruno; Brancaccio, Andrea; De Rosa, Maria Cristina

2014-01-01

A missense amino acid mutation of valine to aspartic acid in 567 position of alpha-dystroglycan (DG), identified in dag1-mutated zebrafish, results in a reduced transcription and a complete absence of the protein. Lacking experimental structural data for zebrafish DG domains, the detailed mechanism for the observed mutation-induced destabilization of the DG complex and membrane damage, remained unclear. With the aim to contribute to a better clarification of the structure-function relationships featuring the DG complex, three-dimensional structural models of wild-type and mutant (V567D) C-terminal domain of alpha-DG from zebrafish were constructed by a template-based modelling approach. We then ran extensive molecular dynamics (MD) simulations to reveal the structural and dynamic properties of the C-terminal domain and to evaluate the effect of the single mutation on alpha-DG stability. A comparative study has been also carried out on our previously generated model of murine alpha-DG C-terminal domain including the I591D mutation, which is topologically equivalent to the V567D mutation found in zebrafish. Trajectories from MD simulations were analyzed in detail, revealing extensive structural disorder involving multiple beta-strands in the mutated variant of the zebrafish protein whereas local effects have been detected in the murine protein. A biochemical analysis of the murine alpha-DG mutant I591D confirmed a pronounced instability of the protein. Taken together, the computational and biochemical analysis suggest that the V567D/I591D mutation, belonging to the G beta-strand, plays a key role in inducing a destabilization of the alpha-DG C-terminal Ig-like domain that could possibly affect and propagate to the entire DG complex. The structural features herein identified may be of crucial help to understand the molecular basis of primary dystroglycanopathies. PMID:25078606

Insights from molecular dynamics simulations: structural basis for the V567D mutation-induced instability of zebrafish alpha-dystroglycan and comparison with the murine model.

PubMed

Pirolli, Davide; Sciandra, Francesca; Bozzi, Manuela; Giardina, Bruno; Brancaccio, Andrea; De Rosa, Maria Cristina

2014-01-01

A missense amino acid mutation of valine to aspartic acid in 567 position of alpha-dystroglycan (DG), identified in dag1-mutated zebrafish, results in a reduced transcription and a complete absence of the protein. Lacking experimental structural data for zebrafish DG domains, the detailed mechanism for the observed mutation-induced destabilization of the DG complex and membrane damage, remained unclear. With the aim to contribute to a better clarification of the structure-function relationships featuring the DG complex, three-dimensional structural models of wild-type and mutant (V567D) C-terminal domain of alpha-DG from zebrafish were constructed by a template-based modelling approach. We then ran extensive molecular dynamics (MD) simulations to reveal the structural and dynamic properties of the C-terminal domain and to evaluate the effect of the single mutation on alpha-DG stability. A comparative study has been also carried out on our previously generated model of murine alpha-DG C-terminal domain including the I591D mutation, which is topologically equivalent to the V567D mutation found in zebrafish. Trajectories from MD simulations were analyzed in detail, revealing extensive structural disorder involving multiple beta-strands in the mutated variant of the zebrafish protein whereas local effects have been detected in the murine protein. A biochemical analysis of the murine alpha-DG mutant I591D confirmed a pronounced instability of the protein. Taken together, the computational and biochemical analysis suggest that the V567D/I591D mutation, belonging to the G beta-strand, plays a key role in inducing a destabilization of the alpha-DG C-terminal Ig-like domain that could possibly affect and propagate to the entire DG complex. The structural features herein identified may be of crucial help to understand the molecular basis of primary dystroglycanopathies.

Computer Simulations and Theoretical Studies of Complex Systems: from complex fluids to frustrated magnets

NASA Astrophysics Data System (ADS)

Choi, Eunsong

Computer simulations are an integral part of research in modern condensed matter physics; they serve as a direct bridge between theory and experiment by systemactically applying a microscopic model to a collection of particles that effectively imitate a macroscopic system. In this thesis, we study two very differnt condensed systems, namely complex fluids and frustrated magnets, primarily by simulating classical dynamics of each system. In the first part of the thesis, we focus on ionic liquids (ILs) and polymers--the two complementary classes of materials that can be combined to provide various unique properties. The properties of polymers/ILs systems, such as conductivity, viscosity, and miscibility, can be fine tuned by choosing an appropriate combination of cations, anions, and polymers. However, designing a system that meets a specific need requires a concrete understanding of physics and chemistry that dictates a complex interplay between polymers and ionic liquids. In this regard, molecular dynamics (MD) simulation is an efficient tool that provides a molecular level picture of such complex systems. We study the behavior of Poly (ethylene oxide) (PEO) and the imidazolium based ionic liquids, using MD simulations and statistical mechanics. We also discuss our efforts to develop reliable and efficient classical force-fields for PEO and the ionic liquids. The second part is devoted to studies on geometrically frustrated magnets. In particular, a microscopic model, which gives rise to an incommensurate spiral magnetic ordering observed in a pyrochlore antiferromagnet is investigated. The validation of the model is made via a comparison of the spin-wave spectra with the neutron scattering data. Since the standard Holstein-Primakoff method is difficult to employ in such a complex ground state structure with a large unit cell, we carry out classical spin dynamics simulations to compute spin-wave spectra directly from the Fourier transform of spin trajectories. We conclude the study by showing an excellent agreement between the simulation and the experiment.

Mathematical difficulties as decoupling of expectation and developmental trajectories

PubMed Central

McLean, Janet F.; Rusconi, Elena

2014-01-01

Recent years have seen an increase in research articles and reviews exploring mathematical difficulties (MD). Many of these articles have set out to explain the etiology of the problems, the possibility of different subtypes, and potential brain regions that underlie many of the observable behaviors. These articles are very valuable in a research field, which many have noted, falls behind that of reading and language disabilities. Here will provide a perspective on the current understanding of MD from a different angle, by outlining the school curriculum of England and the US and connecting these to the skills needed at different stages of mathematical understanding. We will extend this to explore the cognitive skills which most likely underpin these different stages and whose impairment may thus lead to mathematics difficulties at all stages of mathematics development. To conclude we will briefly explore interventions that are currently available, indicating whether these can be used to aid the different children at different stages of their mathematical development and what their current limitations may be. The principal aim of this review is to establish an explicit connection between the academic discourse, with its research base and concepts, and the developmental trajectory of abstract mathematical skills that is expected (and somewhat dictated) in formal education. This will possibly help to highlight and make sense of the gap between the complexity of the MD range in real life and the state of its academic science. PMID:24567712

Exploring Hamiltonian dielectric solvent molecular dynamics

NASA Astrophysics Data System (ADS)

Bauer, Sebastian; Tavan, Paul; Mathias, Gerald

2014-09-01

Hamiltonian dielectric solvent (HADES) is a recent method [7,25], which enables Hamiltonian molecular dynamics (MD) simulations of peptides and proteins in dielectric continua. Sample simulations of an α-helical decapeptide with and without explicit solvent demonstrate the high efficiency of HADES-MD. Addressing the folding of this peptide by replica exchange MD we study the properties of HADES by comparing melting curves, secondary structure motifs and salt bridges with explicit solvent results. Despite the unoptimized ad hoc parametrization of HADES, calculated reaction field energies correlate well with numerical grid solutions of the dielectric Poisson equation.

Hybrid classical/quantum simulation for infrared spectroscopy of water

NASA Astrophysics Data System (ADS)

Maekawa, Yuki; Sasaoka, Kenji; Ube, Takuji; Ishiguro, Takashi; Yamamoto, Takahiro

2018-05-01

We have developed a hybrid classical/quantum simulation method to calculate the infrared (IR) spectrum of water. The proposed method achieves much higher accuracy than conventional classical molecular dynamics (MD) simulations at a much lower computational cost than ab initio MD simulations. The IR spectrum of water is obtained as an ensemble average of the eigenvalues of the dynamical matrix constructed by ab initio calculations, using the positions of oxygen atoms that constitute water molecules obtained from the classical MD simulation. The calculated IR spectrum is in excellent agreement with the experimental IR spectrum.

Symmetrical Windowing for Quantum States in Quasi-Classical Trajectory Simulations

NASA Astrophysics Data System (ADS)

Cotton, Stephen Joshua

An approach has been developed for extracting approximate quantum state-to-state information from classical trajectory simulations which "quantizes" symmetrically both the initial and final classical actions associated with the degrees of freedom of interest using quantum number bins (or "window functions") which are significantly narrower than unit-width. This approach thus imposes a more stringent quantization condition on classical trajectory simulations than has been traditionally employed, while doing so in a manner that is time-symmetric and microscopically reversible. To demonstrate this "symmetric quasi-classical" (SQC) approach for a simple real system, collinear H + H2 reactive scattering calculations were performed [S.J. Cotton and W.H. Miller, J. Phys. Chem. A 117, 7190 (2013)] with SQC-quantization applied to the H 2 vibrational degree of freedom (DOF). It was seen that the use of window functions of approximately 1/2-unit width led to calculated reaction probabilities in very good agreement with quantum mechanical results over the threshold energy region, representing a significant improvement over what is obtained using the traditional quasi-classical procedure. The SQC approach was then applied [S.J. Cotton and W.H. Miller, J. Chem. Phys. 139, 234112 (2013)] to the much more interesting and challenging problem of incorporating non-adiabatic effects into what would otherwise be standard classical trajectory simulations. To do this, the classical Meyer-Miller (MM) Hamiltonian was used to model the electronic DOFs, with SQC-quantization applied to the classical "electronic" actions of the MM model---representing the occupations of the electronic states---in order to extract the electronic state population dynamics. It was demonstrated that if one ties the zero-point energy (ZPE) of the electronic DOFs to the SQC windowing function's width parameter this very simple SQC/MM approach is capable of quantitatively reproducing quantum mechanical results for a range of standard benchmark models of electronically non-adiabatic processes, including applications where "quantum" coherence effects are significant. Notably, among these benchmarks was the well-studied "spin-boson" model of condensed phase non-adiabatic dynamics, in both its symmetric and asymmetric forms---the latter of which many classical approaches fail to treat successfully. The SQC/MM approach to the treatment of non-adiabatic dynamics was next applied [S.J. Cotton, K. Igumenshchev, and W.H. Miller, J. Chem. Phys., 141, 084104 (2014)] to several recently proposed models of condensed phase electron transfer (ET) processes. For these problems, a flux-side correlation function framework modified for consistency with the SQC approach was developed for the calculation of thermal ET rate constants, and excellent accuracy was seen over wide ranges of non-adiabatic coupling strength and energetic bias/exothermicity. Significantly, the "inverted regime" in thermal rate constants (with increasing bias) known from Marcus Theory was reproduced quantitatively for these models---representing the successful treatment of another regime that classical approaches generally have difficulty in correctly describing. Relatedly, a model of photoinduced proton coupled electron transfer (PCET) was also addressed, and it was shown that the SQC/MM approach could reasonably model the explicit population dynamics of the photoexcited electron donor and acceptor states over the four parameter regimes considered. The potential utility of the SQC/MM technique lies in its stunning simplicity and the ease by which it may readily be incorporated into "ordinary" molecular dynamics (MD) simulations. In short, a typical MD simulation may be augmented to take non-adiabatic effects into account simply by introducing an auxiliary pair of classical "electronic" action-angle variables for each energetically viable Born-Oppenheimer surface, and time-evolving these auxiliary variables via Hamilton's equations (using the MM electronic Hamiltonian) in the same manner that the other classical variables---i.e., the coordinates of all the nuclei---are evolved forward in time. In a complex molecular system involving many hundreds or thousands of nuclear DOFs, the propagation of these extra "electronic" variables represents a modest increase in computational effort, and yet, the examples presented herein suggest that in many instances the SQC/MM approach will describe the true non-adiabatic quantum dynamics to a reasonable and useful degree of quantitative accuracy.

Dose calculation of dynamic trajectory radiotherapy using Monte Carlo.

PubMed

Manser, P; Frauchiger, D; Frei, D; Volken, W; Terribilini, D; Fix, M K

2018-04-06

Using volumetric modulated arc therapy (VMAT) delivery technique gantry position, multi-leaf collimator (MLC) as well as dose rate change dynamically during the application. However, additional components can be dynamically altered throughout the dose delivery such as the collimator or the couch. Thus, the degrees of freedom increase allowing almost arbitrary dynamic trajectories for the beam. While the dose delivery of such dynamic trajectories for linear accelerators is technically possible, there is currently no dose calculation and validation tool available. Thus, the aim of this work is to develop a dose calculation and verification tool for dynamic trajectories using Monte Carlo (MC) methods. The dose calculation for dynamic trajectories is implemented in the previously developed Swiss Monte Carlo Plan (SMCP). SMCP interfaces the treatment planning system Eclipse with a MC dose calculation algorithm and is already able to handle dynamic MLC and gantry rotations. Hence, the additional dynamic components, namely the collimator and the couch, are described similarly to the dynamic MLC by defining data pairs of positions of the dynamic component and the corresponding MU-fractions. For validation purposes, measurements are performed with the Delta4 phantom and film measurements using the developer mode on a TrueBeam linear accelerator. These measured dose distributions are then compared with the corresponding calculations using SMCP. First, simple academic cases applying one-dimensional movements are investigated and second, more complex dynamic trajectories with several simultaneously moving components are compared considering academic cases as well as a clinically motivated prostate case. The dose calculation for dynamic trajectories is successfully implemented into SMCP. The comparisons between the measured and calculated dose distributions for the simple as well as for the more complex situations show an agreement which is generally within 3% of the maximum dose or 3mm. The required computation time for the dose calculation remains the same when the additional dynamic moving components are included. The results obtained for the dose comparisons for simple and complex situations suggest that the extended SMCP is an accurate dose calculation and efficient verification tool for dynamic trajectory radiotherapy. This work was supported by Varian Medical Systems. Copyright © 2018. Published by Elsevier GmbH.

Curcumin Binding to Beta Amyloid: A Computational Study.

PubMed

Rao, Praveen P N; Mohamed, Tarek; Teckwani, Karan; Tin, Gary

2015-10-01

Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper β-sheet assembly and (ii) full-length Aβ fibril β-sheet assembly. Curcumin binding in these models was evaluated by molecular docking and molecular dynamics (MD) simulation studies. In both the models, curcumin was oriented in a linear extended conformation parallel to fiber axis and exhibited better stability in the Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper model (Ebinding  = -10.05 kcal/mol) compared to full-length Aβ fibril model (Ebinding  = -3.47 kcal/mol). Analysis of MD trajectories of curcumin bound to full-length Aβ fibril shows good stability with minimum Cα-atom RMSD shifts. Interestingly, curcumin binding led to marked fluctuations in the (14) HQKLVFFA(21) region that constitute the fibril spine with RMSF values ranging from 1.4 to 3.6 Å. These results show that curcumin binding to Aβ shifts the equilibrium in the aggregation pathway by promoting the formation of non-toxic aggregates. © 2015 John Wiley & Sons A/S.

Structural Phase Transformation in Strained Monolayer MoWSe2 Alloy.

PubMed

Apte, Amey; Kochat, Vidya; Rajak, Pankaj; Krishnamoorthy, Aravind; Manimunda, Praveena; Hachtel, Jordan A; Idrobo, Juan Carlos; Syed Amanulla, Syed Asif; Vashishta, Priya; Nakano, Aiichiro; Kalia, Rajiv K; Tiwary, Chandra Sekhar; Ajayan, Pulickel M

2018-04-24

Two-dimensional (2D) materials exhibit different mechanical properties from their bulk counterparts owing to their monolayer atomic thickness. Here, we have examined the mechanical behavior of 2D molybdenum tungsten diselenide (MoWSe 2 ) precipitation alloy grown using chemical vapor deposition and composed of numerous nanoscopic MoSe 2 and WSe 2 regions. Applying a bending strain blue-shifted the MoSe 2 and WSe 2 A 1g Raman modes with the stress concentrated near the precipitate interfaces predominantly affecting the WSe 2 modes. In situ local Raman measurements suggested that the crack propagated primarily thorough MoSe 2 -rich regions in the monolayer alloy. Molecular dynamics (MD) simulations were performed to study crack propagation in an MoSe 2 monolayer containing nanoscopic WSe 2 regions akin to the experiment. Raman spectra calculated from MD trajectories of crack propagation confirmed the emergence of intermediate peaks in the strained monolayer alloy, mirroring experimental results. The simulations revealed that the stress buildup around the crack tip caused an irreversible structural transformation from the 2H to 1T phase both in the MoSe 2 matrix and WSe 2 patches. This was corroborated by high-angle annular dark-field images. Crack branching and subsequent healing of a crack branch were also observed in WSe 2 , indicating the increased toughness and crack propagation resistance of the alloyed 2D MoWSe 2 over the unalloyed counterparts.

Development of a two-dimensional binning model for N{sub 2}–N relaxation in hypersonic shock conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Tong, E-mail: tongzhu2@illinois.edu; Levin, Deborah A., E-mail: deblevin@illinois.edu; Li, Zheng, E-mail: zul107@psu.edu

2016-08-14

A high fidelity internal energy relaxation model for N{sub 2}–N suitable for use in direct simulation Monte Carlo (DSMC) modeling of chemically reacting flows is proposed. A novel two-dimensional binning approach with variable bin energy resolutions in the rotational and vibrational modes is developed for treating the internal mode of N{sub 2}. Both bin-to-bin and state-specific relaxation cross sections are obtained using the molecular dynamics/quasi-classical trajectory (MD/QCT) method with two potential energy surfaces as well as the state-specific database of Jaffe et al. The MD/QCT simulations of inelastic energy exchange between N{sub 2} and N show that there is amore » strong forward-preferential scattering behavior at high collision velocities. The 99 bin model is used in homogeneous DSMC relaxation simulations and is found to be able to recover the state-specific master equation results of Panesi et al. when the Jaffe state-specific cross sections are used. Rotational relaxation energy profiles and relaxation times obtained using the ReaxFF and Jaffe potential energy surfaces (PESs) are in general agreement but there are larger differences between the vibrational relaxation times. These differences become smaller as the translational temperature increases because the difference in the PES energy barrier becomes less important.« less

LQTA-QSAR: a new 4D-QSAR methodology.

PubMed

Martins, João Paulo A; Barbosa, Euzébio G; Pasqualoto, Kerly F M; Ferreira, Márcia M C

2009-06-01

A novel 4D-QSAR approach which makes use of the molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package is presented in this study. This new methodology, named LQTA-QSAR (LQTA, Laboratório de Quimiometria Teórica e Aplicada), has a module (LQTAgrid) that calculates intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from MD simulations. These interaction energies are the independent variables or descriptors employed in a QSAR analysis. The comparison of the proposed methodology to other 4D-QSAR and CoMFA formalisms was performed using a set of forty-seven glycogen phosphorylase b inhibitors (data set 1) and a set of forty-four MAP p38 kinase inhibitors (data set 2). The QSAR models for both data sets were built using the ordered predictor selection (OPS) algorithm for variable selection. Model validation was carried out applying y-randomization and leave-N-out cross-validation in addition to the external validation. PLS models for data set 1 and 2 provided the following statistics: q(2) = 0.72, r(2) = 0.81 for 12 variables selected and 2 latent variables and q(2) = 0.82, r(2) = 0.90 for 10 variables selected and 5 latent variables, respectively. Visualization of the descriptors in 3D space was successfully interpreted from the chemical point of view, supporting the applicability of this new approach in rational drug design.

Crystal Structure of a Ube2S-Ubiquitin Conjugate

PubMed Central

Lorenz, Sonja; Bhattacharyya, Moitrayee; Feiler, Christian; Rape, Michael; Kuriyan, John

2016-01-01

Protein ubiquitination occurs through the sequential formation and reorganization of specific protein-protein interfaces. Ubiquitin-conjugating (E2) enzymes, such as Ube2S, catalyze the formation of an isopeptide linkage between the C-terminus of a “donor” ubiquitin and a primary amino group of an “acceptor” ubiquitin molecule. This reaction involves an intermediate, in which the C-terminus of the donor ubiquitin is thioester-bound to the active site cysteine of the E2 and a functionally important interface is formed between the two proteins. A docked model of a Ube2S-donor ubiquitin complex was generated previously, based on chemical shift mapping by NMR, and predicted contacts were validated in functional studies. We now present the crystal structure of a covalent Ube2S-ubiquitin complex. The structure contains an interface between Ube2S and ubiquitin in trans that resembles the earlier model in general terms, but differs in detail. The crystallographic interface is more hydrophobic than the earlier model and is stable in molecular dynamics (MD) simulations. Remarkably, the docked Ube2S-donor complex converges readily to the configuration seen in the crystal structure in 3 out of 8 MD trajectories. Since the crystallographic interface is fully consistent with mutational effects, this indicates that the structure provides an energetically favorable representation of the functionally critical Ube2S-donor interface. PMID:26828794

Modeling of diatomic molecule using the Morse potential and the Verlet algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fidiani, Elok

Performing molecular modeling usually uses special software for Molecular Dynamics (MD) such as: GROMACS, NAMD, JMOL etc. Molecular dynamics is a computational method to calculate the time dependent behavior of a molecular system. In this work, MATLAB was used as numerical method for a simple modeling of some diatomic molecules: HCl, H{sub 2} and O{sub 2}. MATLAB is a matrix based numerical software, in order to do numerical analysis, all the functions and equations describing properties of atoms and molecules must be developed manually in MATLAB. In this work, a Morse potential was generated to describe the bond interaction betweenmore » the two atoms. In order to analyze the simultaneous motion of molecules, the Verlet Algorithm derived from Newton’s Equations of Motion (classical mechanics) was operated. Both the Morse potential and the Verlet algorithm were integrated using MATLAB to derive physical properties and the trajectory of the molecules. The data computed by MATLAB is always in the form of a matrix. To visualize it, Visualized Molecular Dynamics (VMD) was performed. Such method is useful for development and testing some types of interaction on a molecular scale. Besides, this can be very helpful for describing some basic principles of molecular interaction for educational purposes.« less

Symplectic molecular dynamics simulations on specially designed parallel computers.

PubMed

Borstnik, Urban; Janezic, Dusanka

2005-01-01

We have developed a computer program for molecular dynamics (MD) simulation that implements the Split Integration Symplectic Method (SISM) and is designed to run on specialized parallel computers. The MD integration is performed by the SISM, which analytically treats high-frequency vibrational motion and thus enables the use of longer simulation time steps. The low-frequency motion is treated numerically on specially designed parallel computers, which decreases the computational time of each simulation time step. The combination of these approaches means that less time is required and fewer steps are needed and so enables fast MD simulations. We study the computational performance of MD simulation of molecular systems on specialized computers and provide a comparison to standard personal computers. The combination of the SISM with two specialized parallel computers is an effective way to increase the speed of MD simulations up to 16-fold over a single PC processor.

Surface segregation in a binary mixture of ionic liquids: Comparison between high-resolution RBS measurements and molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Nakajima, Kaoru; Nakanishi, Shunto; Chval, Zdeněk; Lísal, Martin; Kimura, Kenji

2016-11-01

Surface structure of equimolar mixture of 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([C2C1Im][Tf2N]) and 1-ethyl-3-methylimidazolium tetrafluoroborate ([C2C1Im][BF4]) is studied using high-resolution Rutherford backscattering spectroscopy (HRBS) and molecular dynamics (MD) simulations. Both HRBS and MD simulations show enrichment of [Tf2N] in the first molecular layer although the degree of enrichment observed by HRBS is more pronounced than that predicted by the MD simulation. In the subsurface region, MD simulation shows a small depletion of [Tf2N] while HRBS shows a small enrichment here. This discrepancy is partially attributed to the artifact of the MD simulations. Since the number of each ion is fixed in a finite-size simulation box, surface enrichment of particular ion results in its artificial depletion in the subsurface region.

Quantum trajectory phase transitions in the micromaser.

PubMed

Garrahan, Juan P; Armour, Andrew D; Lesanovsky, Igor

2011-08-01

We study the dynamics of the single-atom maser, or micromaser, by means of the recently introduced method of thermodynamics of quantum jump trajectories. We find that the dynamics of the micromaser displays multiple space-time phase transitions, i.e., phase transitions in ensembles of quantum jump trajectories. This rich dynamical phase structure becomes apparent when trajectories are classified by dynamical observables that quantify dynamical activity, such as the number of atoms that have changed state while traversing the cavity. The space-time transitions can be either first order or continuous, and are controlled not just by standard parameters of the micromaser but also by nonequilibrium "counting" fields. We discuss how the dynamical phase behavior relates to the better known stationary-state properties of the micromaser.

Structure and Dynamics of Helical Protein Fragments Investigated by Theory and Experiment

NASA Astrophysics Data System (ADS)

Karimi, Afshin

This work addresses the conformation and dynamics of model peptides using spectroscopy and molecular dynamics simulations. Experimentally, we investigate the structure and dynamics of peptide fragments taken from coiled coil and three helical bundle motifs of bacterial coat proteins. Theoretically, we use molecular dynamics simulations of isolated helices with explicit water molecules to derive trajectories which reveal features about picosecond dynamics and local unfolding events. The assignment of the ^1H, ^{15}N, and ^ {13}C resonances, secondary structure, backbone dynamics, hydration and other biophysical parameters of a 30 residue recombinant peptide corresponding to an immunogenic site on the coiled coil region of Streptococcus pyogenes 24M protein are reported. Our results suggest that this peptide is a symmetric parallel dimeric alpha-helical coiled coil with local defects within the helix and fraying at the termini. The ^1H and ^ {15}N assignments, the hydration, the overall fold, and other biophysical parameters of a recombinant B domain of Staphylococcal protein A (FB) are reported. Our results indicate FB is a highly stable monomeric three helical bundle. A symmetric two domain construct was used to probe the modular assembly of two B domains. Here, spectroscopic results suggest weak interactions between the two domains. The folding pathway of FB was investigated using amide exchange data of the native protein and peptide models. We propose that the helical hairpin consisting of helices II and III is an on-pathway intermediate in the folding of FB. Two 1 ns molecular dynamics simulations (MD) on two mainly helical peptides--an 18 residue peptide corresponding to a portion of the H helix of myoglobin (MBH) and a 14 residue analogue of the C-peptide of ribonuclease A (CRNA) --were carried out in water using the united atom AMBER/OPLS force-field. In the case of MBH, the initial helical conformation progressively frays to a more disordered structure. A common motif in the unfolding mechanism involves the formation of transient turn structures involving several water molecules. In contrast to the MBH simulation, the CRNA trajectory was characterized by the presence of fairly stable i ... i+4 (alpha-helical) hydrogen bonds throughout the simulation, except at the N-terminus where some fraying was observed.

Molecular dynamics simulations and applications in computational toxicology and nanotoxicology.

PubMed

Selvaraj, Chandrabose; Sakkiah, Sugunadevi; Tong, Weida; Hong, Huixiao

2018-02-01

Nanotoxicology studies toxicity of nanomaterials and has been widely applied in biomedical researches to explore toxicity of various biological systems. Investigating biological systems through in vivo and in vitro methods is expensive and time taking. Therefore, computational toxicology, a multi-discipline field that utilizes computational power and algorithms to examine toxicology of biological systems, has gained attractions to scientists. Molecular dynamics (MD) simulations of biomolecules such as proteins and DNA are popular for understanding of interactions between biological systems and chemicals in computational toxicology. In this paper, we review MD simulation methods, protocol for running MD simulations and their applications in studies of toxicity and nanotechnology. We also briefly summarize some popular software tools for execution of MD simulations. Published by Elsevier Ltd.

Review of the fundamental theories behind small angle X-ray scattering, molecular dynamics simulations, and relevant integrated application.

PubMed

Boldon, Lauren; Laliberte, Fallon; Liu, Li

2015-01-01

In this paper, the fundamental concepts and equations necessary for performing small angle X-ray scattering (SAXS) experiments, molecular dynamics (MD) simulations, and MD-SAXS analyses were reviewed. Furthermore, several key biological and non-biological applications for SAXS, MD, and MD-SAXS are presented in this review; however, this article does not cover all possible applications. SAXS is an experimental technique used for the analysis of a wide variety of biological and non-biological structures. SAXS utilizes spherical averaging to produce one- or two-dimensional intensity profiles, from which structural data may be extracted. MD simulation is a computer simulation technique that is used to model complex biological and non-biological systems at the atomic level. MD simulations apply classical Newtonian mechanics' equations of motion to perform force calculations and to predict the theoretical physical properties of the system. This review presents several applications that highlight the ability of both SAXS and MD to study protein folding and function in addition to non-biological applications, such as the study of mechanical, electrical, and structural properties of non-biological nanoparticles. Lastly, the potential benefits of combining SAXS and MD simulations for the study of both biological and non-biological systems are demonstrated through the presentation of several examples that combine the two techniques.

Experimental Evidence for a Structural-Dynamical Transition in Trajectory Space.

PubMed

Pinchaipat, Rattachai; Campo, Matteo; Turci, Francesco; Hallett, James E; Speck, Thomas; Royall, C Patrick

2017-07-14

Among the key insights into the glass transition has been the identification of a nonequilibrium phase transition in trajectory space which reveals phase coexistence between the normal supercooled liquid (active phase) and a glassy state (inactive phase). Here, we present evidence that such a transition occurs in experiments. In colloidal hard spheres, we find a non-Gaussian distribution of trajectories leaning towards those rich in locally favored structures (LFSs), associated with the emergence of slow dynamics. This we interpret as evidence for a nonequilibrium transition to an inactive LFS-rich phase. Reweighting trajectories reveals a first-order phase transition in trajectory space between a normal liquid and a LFS-rich phase. We also find evidence for a purely dynamical transition in trajectory space.

Constant-pH molecular dynamics using stochastic titration

NASA Astrophysics Data System (ADS)

Baptista, António M.; Teixeira, Vitor H.; Soares, Cláudio M.

2002-09-01

A new method is proposed for performing constant-pH molecular dynamics (MD) simulations, that is, MD simulations where pH is one of the external thermodynamic parameters, like the temperature or the pressure. The protonation state of each titrable site in the solute is allowed to change during a molecular mechanics (MM) MD simulation, the new states being obtained from a combination of continuum electrostatics (CE) calculations and Monte Carlo (MC) simulation of protonation equilibrium. The coupling between the MM/MD and CE/MC algorithms is done in a way that ensures a proper Markov chain, sampling from the intended semigrand canonical distribution. This stochastic titration method is applied to succinic acid, aimed at illustrating the method and examining the choice of its adjustable parameters. The complete titration of succinic acid, using constant-pH MD simulations at different pH values, gives a clear picture of the coupling between the trans/gauche isomerization and the protonation process, making it possible to reconcile some apparently contradictory results of previous studies. The present constant-pH MD method is shown to require a moderate increase of computational cost when compared to the usual MD method.

Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task

PubMed Central

Miller, Rikki L.A.

2017-01-01

Abstract The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior. PMID:29034318

Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task.

PubMed

Miller, Rikki L A; Francoeur, Miranda J; Gibson, Brett M; Mair, Robert G

2017-01-01

The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior.

Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers.

PubMed

Chew, G L; Huo, C W; Huang, D; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M C; Hopper, J L; Britt, K; Henderson, M A; Haviv, I; Thompson, E W

2014-11-01

Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD.

Rotational dynamics of benzene and water in an ionic liquid explored via molecular dynamics simulations and NMR T1 measurements.

PubMed

Yasaka, Yoshiro; Klein, Michael L; Nakahara, Masaru; Matubayasi, Nobuyuki

2012-02-21

The rotational dynamics of benzene and water in the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride are studied using molecular dynamics (MD) simulation and NMR T(1) measurements. MD trajectories based on an effective potential are used to calculate the (2)H NMR relaxation time, T(1) via Fourier transform of the relevant rotational time correlation function, C(2R)(t). To compensate for the lack of polarization in the standard fixed-charge modeling of the IL, an effective ionic charge, which is smaller than the elementary charge is employed. The simulation results are in closest agreement with NMR experiments with respect to the temperature and Larmor frequency dependencies of T(1) when an effective charge of ±0.5e is used for the anion and the cation, respectively. The computed C(2R)(t) of both solutes shows a bi-modal nature, comprised of an initial non-diffusive ps relaxation plus a long-time ns tail extending to the diffusive regime. Due to the latter component, the solute dynamics is not under the motional narrowing condition with respect to the prevalent Larmor frequency. It is shown that the diffusive tail of the C(2R)(t) is most important to understand frequency and temperature dependencies of T(1) in ILs. On the other hand, the effect of the initial ps relaxation is an increase of T(1) by a constant factor. This is equivalent to an "effective" reduction of the quadrupolar coupling constant (QCC). Thus, in the NMR T(1) analysis, the rotational time correlation function can be modeled analytically in the form of aexp (-t/τ) (Lipari-Szabo model), where the constant a, the Lipari-Szabo factor, contains the integrated contribution of the short-time relaxation and τ represents the relaxation time of the exponential (diffusive) tail. The Debye model is a special case of the Lipari-Szabo model with a = 1, and turns out to be inappropriate to represent benzene and water dynamics in ILs since a is as small as 0.1. The use of the Debye model would result in an underestimation of the QCC by a factor of 2-3 as a compensation for the neglect of the Lipari-Szabo factor. © 2012 American Institute of Physics

Rotational dynamics of benzene and water in an ionic liquid explored via molecular dynamics simulations and NMR T1 measurements

NASA Astrophysics Data System (ADS)

Yasaka, Yoshiro; Klein, Michael L.; Nakahara, Masaru; Matubayasi, Nobuyuki

2012-02-01

The rotational dynamics of benzene and water in the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride are studied using molecular dynamics (MD) simulation and NMR T1 measurements. MD trajectories based on an effective potential are used to calculate the 2H NMR relaxation time, T1 via Fourier transform of the relevant rotational time correlation function, C2R(t). To compensate for the lack of polarization in the standard fixed-charge modeling of the IL, an effective ionic charge, which is smaller than the elementary charge is employed. The simulation results are in closest agreement with NMR experiments with respect to the temperature and Larmor frequency dependencies of T1 when an effective charge of ±0.5e is used for the anion and the cation, respectively. The computed C2R(t) of both solutes shows a bi-modal nature, comprised of an initial non-diffusive ps relaxation plus a long-time ns tail extending to the diffusive regime. Due to the latter component, the solute dynamics is not under the motional narrowing condition with respect to the prevalent Larmor frequency. It is shown that the diffusive tail of the C2R(t) is most important to understand frequency and temperature dependencies of T1 in ILs. On the other hand, the effect of the initial ps relaxation is an increase of T1 by a constant factor. This is equivalent to an "effective" reduction of the quadrupolar coupling constant (QCC). Thus, in the NMR T1 analysis, the rotational time correlation function can be modeled analytically in the form of aexp (-t/τ) (Lipari-Szabo model), where the constant a, the Lipari-Szabo factor, contains the integrated contribution of the short-time relaxation and τ represents the relaxation time of the exponential (diffusive) tail. The Debye model is a special case of the Lipari-Szabo model with a = 1, and turns out to be inappropriate to represent benzene and water dynamics in ILs since a is as small as 0.1. The use of the Debye model would result in an underestimation of the QCC by a factor of 2-3 as a compensation for the neglect of the Lipari-Szabo factor.

Dynamics and Structure of Point Defects in Forsterite: ab initio calculations

NASA Astrophysics Data System (ADS)

Churakov, S.; Khisina, N.; Urusov, V.; Wirth, R.

2001-12-01

OH-bearing fluid inclusions in Fo92 forsterite samples from peridotite nodule 9206 (Udachnaja kimberlite pipe)[1] were documented recently based on TEM and IR studies. The Fourier transform of diffraction pattern from the inclusions exhibited a pattern, which is interpreted as ordered planar (2H)xMg defects. In this study the structure and dynamics of protons associated with Mg(1), Mg(2) vacancies and interstitial polyhedrons ordered in a (100) plane corresponding to double unite cell periodicity of the forsterite lattice has been investigated by ab initio quantum mechanic calculations. Static structure optimizations and ab-initio molecular dynamics (MD) simulations have been performed using the CPMD density functional code[2]. The calculations were accomplished with the BLYP-functional utilizing the generalized gradient approximation. Non-local Goedecker-type pseudopotentials[3] have been applied to account for core electrons. Valence electron orbitals were approximated by plane wave expansion up to 70 Ry energy cutoff. The energy of static structures was sampled on 2x2x2 Monkhorst-Pack mesh[4]. During the structure relaxation parameters of an orthorhombic 2x1x2 supercell contaning 116 atoms corresponding to Mg28Si16O64H8 hydrous olivine was fixed at experimental values of a=9.524Å b=10.225Å and c=11.988Å relative to the Pbnm space group. Series of NVT-MD calculations were performed at 1000 K on 2x1x1 supercell with 58 atoms using four chain Nose thermostat. Randomly disturbed optimized structures were used as initial configuration for MD runs. The 1ps system equilibration is followed by trajectory production over 5 ps interval. A point energy sampling was applied in all MD calculations. A series of geometry optimizations, starting with various initial position of protons in Mg(1), Mg(2) and interstitial sites were carried out to obtain a structure with the lowest lattice energy. It was found that structures with protons completely located within the M1-polyhedron vacancies have lower energies then any other associated with M2 and interstitial polyhedrons. For protons associated with vacancies several configurations with small energy difference have been found. These configurations suggest a possible binding of the protons to O1, O2 and O3 sites including the formation of water-like HOH complexes. The MD simulations shows that protons can move easily within the vacant polyhedron to form covalent OH bonds at various oxygen sites. The protons initially located in interstitial positions of fosterite lattice were found to migrate in vacant polyhedra. References [1] Khisina, N.R. & Wirth, R. (2001): Hydrous olivine (Mg,Fe)2-xvxSiO4H2x - a new DHMS phase of variable composition observed as nanometer-size precipitation in mantle olivine. PCM, submitted [2] Hutter J. et al.: CPMD v. 4.0, MPI fuer Festkoerperforschung and IBM Zuerich Research Laboratory 1995-2000 [3] Goedecker S., Teter M. and Hutter J. (1996) Separable dual-space Gaussian pseudopotentials. Phys.Rev. B, 54(3) 1703-1710 [4] Monkhorst H.J. and Pack D. 1975 Special points for Brellouin-zone intagration. Phys. Rev B,13,5188-5192

Using molecular simulation to explore the nanoscale dynamics of the plant kinome.

PubMed

Moffett, Alexander S; Shukla, Diwakar

2018-03-09

Eukaryotic protein kinases (PKs) are a large family of proteins critical for cellular response to external signals, acting as molecular switches. PKs propagate biochemical signals by catalyzing phosphorylation of other proteins, including other PKs, which can undergo conformational changes upon phosphorylation and catalyze further phosphorylations. Although PKs have been studied thoroughly across the domains of life, the structures of these proteins are sparsely understood in numerous groups of organisms, including plants. In addition to efforts towards determining crystal structures of PKs, research on human PKs has incorporated molecular dynamics (MD) simulations to study the conformational dynamics underlying the switching of PK function. This approach of experimental structural biology coupled with computational biophysics has led to improved understanding of how PKs become catalytically active and why mutations cause pathological PK behavior, at spatial and temporal resolutions inaccessible to current experimental methods alone. In this review, we argue for the value of applying MD simulation to plant PKs. We review the basics of MD simulation methodology, the successes achieved through MD simulation in animal PKs, and current work on plant PKs using MD simulation. We conclude with a discussion of the future of MD simulations and plant PKs, arguing for the importance of molecular simulation in the future of plant PK research. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Conformational dynamics of a crystalline protein from microsecond-scale molecular dynamics simulations and diffuse X-ray scattering

DOE PAGES

Wall, Michael E.; Van Benschoten, Andrew H.; Sauter, Nicholas K.; ...

2014-12-01

X-ray diffraction from protein crystals includes both sharply peaked Bragg reflections and diffuse intensity between the peaks. The information in Bragg scattering is limited to what is available in the mean electron density. The diffuse scattering arises from correlations in the electron density variations and therefore contains information about collective motions in proteins. Previous studies using molecular-dynamics (MD) simulations to model diffuse scattering have been hindered by insufficient sampling of the conformational ensemble. To overcome this issue, we have performed a 1.1-μs MD simulation of crystalline staphylococcal nuclease, providing 100-fold more sampling than previous studies. This simulation enables reproducible calculationsmore » of the diffuse intensity and predicts functionally important motions, including transitions among at least eight metastable states with different active-site geometries. The total diffuse intensity calculated using the MD model is highly correlated with the experimental data. In particular, there is excellent agreement for the isotropic component of the diffuse intensity, and substantial but weaker agreement for the anisotropic component. The decomposition of the MD model into protein and solvent components indicates that protein–solvent interactions contribute substantially to the overall diffuse intensity. In conclusion, diffuse scattering can be used to validate predictions from MD simulations and can provide information to improve MD models of protein motions.« less

Conformational dynamics of a crystalline protein from microsecond-scale molecular dynamics simulations and diffuse X-ray scattering

PubMed Central

Wall, Michael E.; Van Benschoten, Andrew H.; Sauter, Nicholas K.; Adams, Paul D.; Fraser, James S.; Terwilliger, Thomas C.

2014-01-01

X-ray diffraction from protein crystals includes both sharply peaked Bragg reflections and diffuse intensity between the peaks. The information in Bragg scattering is limited to what is available in the mean electron density. The diffuse scattering arises from correlations in the electron density variations and therefore contains information about collective motions in proteins. Previous studies using molecular-dynamics (MD) simulations to model diffuse scattering have been hindered by insufficient sampling of the conformational ensemble. To overcome this issue, we have performed a 1.1-μs MD simulation of crystalline staphylococcal nuclease, providing 100-fold more sampling than previous studies. This simulation enables reproducible calculations of the diffuse intensity and predicts functionally important motions, including transitions among at least eight metastable states with different active-site geometries. The total diffuse intensity calculated using the MD model is highly correlated with the experimental data. In particular, there is excellent agreement for the isotropic component of the diffuse intensity, and substantial but weaker agreement for the anisotropic component. Decomposition of the MD model into protein and solvent components indicates that protein–solvent interactions contribute substantially to the overall diffuse intensity. We conclude that diffuse scattering can be used to validate predictions from MD simulations and can provide information to improve MD models of protein motions. PMID:25453071

Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems

DOE PAGES

Radak, Brian K.; Chipot, Christophe; Suh, Donghyuk; ...

2017-11-07

We report that an increasingly important endeavor is to develop computational strategies that enable molecular dynamics (MD) simulations of biomolecular systems with spontaneous changes in protonation states under conditions of constant pH. The present work describes our efforts to implement the powerful constant-pH MD simulation method, based on a hybrid nonequilibrium MD/Monte Carlo (neMD/MC) technique within the highly scalable program NAMD. The constant-pH hybrid neMD/MC method has several appealing features; it samples the correct semigrand canonical ensemble rigorously, the computational cost increases linearly with the number of titratable sites, and it is applicable to explicit solvent simulations. The present implementationmore » of the constant-pH hybrid neMD/MC in NAMD is designed to handle a wide range of biomolecular systems with no constraints on the choice of force field. Furthermore, the sampling efficiency can be adaptively improved on-the-fly by adjusting algorithmic parameters during the simulation. Finally, illustrative examples emphasizing medium- and large-scale applications on next-generation supercomputing architectures are provided.« less

Hybrid particle-field molecular dynamics simulation for polyelectrolyte systems.

PubMed

Zhu, You-Liang; Lu, Zhong-Yuan; Milano, Giuseppe; Shi, An-Chang; Sun, Zhao-Yan

2016-04-14

To achieve simulations on large spatial and temporal scales with high molecular chemical specificity, a hybrid particle-field method was proposed recently. This method is developed by combining molecular dynamics and self-consistent field theory (MD-SCF). The MD-SCF method has been validated by successfully predicting the experimentally observable properties of several systems. Here we propose an efficient scheme for the inclusion of electrostatic interactions in the MD-SCF framework. In this scheme, charged molecules are interacting with the external fields that are self-consistently determined from the charge densities. This method is validated by comparing the structural properties of polyelectrolytes in solution obtained from the MD-SCF and particle-based simulations. Moreover, taking PMMA-b-PEO and LiCF3SO3 as examples, the enhancement of immiscibility between the ion-dissolving block and the inert block by doping lithium salts into the copolymer is examined by using the MD-SCF method. By employing GPU-acceleration, the high performance of the MD-SCF method with explicit treatment of electrostatics facilitates the simulation study of many problems involving polyelectrolytes.

Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radak, Brian K.; Chipot, Christophe; Suh, Donghyuk

We report that an increasingly important endeavor is to develop computational strategies that enable molecular dynamics (MD) simulations of biomolecular systems with spontaneous changes in protonation states under conditions of constant pH. The present work describes our efforts to implement the powerful constant-pH MD simulation method, based on a hybrid nonequilibrium MD/Monte Carlo (neMD/MC) technique within the highly scalable program NAMD. The constant-pH hybrid neMD/MC method has several appealing features; it samples the correct semigrand canonical ensemble rigorously, the computational cost increases linearly with the number of titratable sites, and it is applicable to explicit solvent simulations. The present implementationmore » of the constant-pH hybrid neMD/MC in NAMD is designed to handle a wide range of biomolecular systems with no constraints on the choice of force field. Furthermore, the sampling efficiency can be adaptively improved on-the-fly by adjusting algorithmic parameters during the simulation. Finally, illustrative examples emphasizing medium- and large-scale applications on next-generation supercomputing architectures are provided.« less

Why should biochemistry students be introduced to molecular dynamics simulations--and how can we introduce them?

PubMed

Elmore, Donald E

2016-01-01

Molecular dynamics (MD) simulations play an increasingly important role in many aspects of biochemical research but are often not part of the biochemistry curricula at the undergraduate level. This article discusses the pedagogical value of exposing students to MD simulations and provides information to help instructors consider what software and hardware resources are necessary to successfully introduce these simulations into their courses. In addition, a brief review of the MD-based activities in this issue and other sources are provided. © 2016 The International Union of Biochemistry and Molecular Biology.

Generalized Gaussian wave packet dynamics: Integrable and chaotic systems.

PubMed

Pal, Harinder; Vyas, Manan; Tomsovic, Steven

2016-01-01

The ultimate semiclassical wave packet propagation technique is a complex, time-dependent Wentzel-Kramers-Brillouin method known as generalized Gaussian wave packet dynamics (GGWPD). It requires overcoming many technical difficulties in order to be carried out fully in practice. In its place roughly twenty years ago, linearized wave packet dynamics was generalized to methods that include sets of off-center, real trajectories for both classically integrable and chaotic dynamical systems that completely capture the dynamical transport. The connections between those methods and GGWPD are developed in a way that enables a far more practical implementation of GGWPD. The generally complex saddle-point trajectories at its foundation are found using a multidimensional Newton-Raphson root search method that begins with the set of off-center, real trajectories. This is possible because there is a one-to-one correspondence. The neighboring trajectories associated with each off-center, real trajectory form a path that crosses a unique saddle; there are exceptions that are straightforward to identify. The method is applied to the kicked rotor to demonstrate the accuracy improvement as a function of ℏ that comes with using the saddle-point trajectories.

Preserving correlations between trajectories for efficient path sampling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gingrich, Todd R.; Geissler, Phillip L.; Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

2015-06-21

Importance sampling of trajectories has proved a uniquely successful strategy for exploring rare dynamical behaviors of complex systems in an unbiased way. Carrying out this sampling, however, requires an ability to propose changes to dynamical pathways that are substantial, yet sufficiently modest to obtain reasonable acceptance rates. Satisfying this requirement becomes very challenging in the case of long trajectories, due to the characteristic divergences of chaotic dynamics. Here, we examine schemes for addressing this problem, which engineer correlation between a trial trajectory and its reference path, for instance using artificial forces. Our analysis is facilitated by a modern perspective onmore » Markov chain Monte Carlo sampling, inspired by non-equilibrium statistical mechanics, which clarifies the types of sampling strategies that can scale to long trajectories. Viewed in this light, the most promising such strategy guides a trial trajectory by manipulating the sequence of random numbers that advance its stochastic time evolution, as done in a handful of existing methods. In cases where this “noise guidance” synchronizes trajectories effectively, as the Glauber dynamics of a two-dimensional Ising model, we show that efficient path sampling can be achieved for even very long trajectories.« less

Molecular dynamics-driven drug discovery: leaping forward with confidence.

PubMed

Ganesan, Aravindhan; Coote, Michelle L; Barakat, Khaled

2017-02-01

Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities that enable in silico approaches to expedite drug discovery processes. Molecular dynamics (MD) has become a particularly important tool in drug design and discovery. From classical MD methods to more sophisticated hybrid classical/quantum mechanical (QM) approaches, MD simulations are now able to offer extraordinary insights into ligand-receptor interactions. In this review, we discuss how the applications of MD approaches are significantly transforming current drug discovery and development efforts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structural modeling of Ge6.25As32.5Se61.25 using a combination of reverse Monte Carlo and Ab initio molecular dynamics.

PubMed

Opletal, George; Drumm, Daniel W; Wang, Rong P; Russo, Salvy P

2014-07-03

Ternary glass structures are notoriously difficult to model accurately, and yet prevalent in several modern endeavors. Here, a novel combination of Reverse Monte Carlo (RMC) modeling and ab initio molecular dynamics (MD) is presented, rendering these complicated structures computationally tractable. A case study (Ge6.25As32.5Se61.25 glass) illustrates the effects of ab initio MD quench rates and equilibration temperatures, and the combined approach's efficacy over standard RMC or random insertion methods. Submelting point MD quenches achieve the most stable, realistic models, agreeing with both experimental and fully ab initio results. The simple approach of RMC followed by ab initio geometry optimization provides similar quality to the RMC-MD combination, for far fewer resources.

From force-fields to photons: MD simulations of dye-labeled nucleic acids and Monte Carlo modeling of FRET

NASA Astrophysics Data System (ADS)

Milas, Peker; Gamari, Ben; Parrot, Louis; Buckman, Richard; Goldner, Lori

2011-11-01

Fluorescence resonance energy transfer (FRET) is a powerful experimental technique for understanding the structural fluctuations and transformations of RNA, DNA and proteins. Molecular dynamics (MD) simulations provide a window into the nature of these fluctuations on a faster time scale inaccessible to experiment. We use Monte Carlo methods to model and compare FRET data from dye-labeled RNA with what might be predicted from the MD simulation. With a few notable exceptions, the contribution of fluorophore and linker dynamics to these FRET measurements has not been investigated. We include the dynamics of the ground state dyes and linkers along with an explicit water solvent in our study of a 16mer double-stranded RNA. Cyanine dyes are attached at either the 3' or 5' ends with a three carbon linker, providing a basis for contrasting the dynamics of similar but not identical molecular structures.

Distribution and Dynamic Properties of Xenon Dissolved in the Ionic Smectic Phase of [C16mim][NO3]: MD Simulation and Theoretical Model.

PubMed

Frezzato, Diego; Saielli, Giacomo

2016-03-10

We have investigated the structural and dynamic properties of Xe dissolved in the ionic liquid crystal (ILC) phase of 1-hexadecyl-3-methylimidazolium nitrate using classical molecular dynamics (MD) simulations. Xe is found to be preferentially dissolved within the hydrophobic environment of the alkyl chains rather than in the ionic layers of the smectic phase. The structural parameters and the estimated local diffusion coefficients concerning the short-time motion of Xe are used to parametrize a theoretical model based on the Smoluchowski equation for the macroscopic dynamics across the smectic layers, a feature which cannot be directly obtained from the relatively short MD simulations. This protocol represents an efficient combination of computational and theoretical tools to obtain information on slow processes concerning the permeability and diffusivity of the xenon in smectic ILCs.

Steinberg ``AUDIOMAPS'' Music Appreciation-Via-Understanding: Special-Relativity + Expectations ``Quantum-Theory'': a Quantum-ACOUSTO/MUSICO-Dynamics (QA/MD)

NASA Astrophysics Data System (ADS)

Fender, Lee; Steinberg, Russell; Siegel, Edward Carl-Ludwig

2011-03-01

Steinberg wildly popular "AUDIOMAPS" music enjoyment/appreciation-via-understanding methodology, versus art, music-dynamics evolves, telling a story in (3+1)-dimensions: trails, frames, timbres, + dynamics amplitude vs. music-score time-series (formal-inverse power-spectrum) surprisingly closely parallels (3+1)-dimensional Einstein(1905) special-relativity "+" (with its enjoyment-expectations) a manifestation of quantum-theory expectation-values, together a music quantum-ACOUSTO/MUSICO-dynamics(QA/MD). Analysis via Derrida deconstruction enabled Siegel-Baez "Category-Semantics" "FUZZYICS"="CATEGORYICS ('TRIZ") Aristotle SoO DEduction , irrespective of Boon-Klimontovich vs. Voss-Clark[PRL(77)] music power-spectrum analysis sampling-time/duration controversy: part versus whole, shows QA/MD reigns supreme as THE music appreciation-via-analysis tool for the listener in musicology!!! Connection to Deutsch-Hartmann-Levitin[This is Your Brain on Music, (06)] brain/mind-barrier brain/mind-music connection is subtle/compelling/immediate!!!

Molecular Dynamics Simulation of Salt Diffusion in Polyelectrolyte Assemblies.

PubMed

Zhang, Ran; Duan, Xiaozheng; Ding, Mingming; Shi, Tongfei

2018-06-05

The diffusion of salt ions and charged probe molecules in polyelectrolyte assemblies is often assumed to follow a theoretical hopping model, in which the diffusing ion is hopping between charged sites of chains based on electroneutrality. However, experimental verification of diffusing pathway at such microscales is difficult, and the corresponding molecular mechanisms remain elusive. In this study, we perform all-atom molecular dynamics (MD) simulations of salt diffusion in polyelectrolyte (PE) assembly of poly (sodium 4-styrenesulfonate) (PSS) and poly (diallyldimethylammonium chloride) (PDAC). Besides the ion hopping mode, the diffusing trajectories are found presenting common features of a jump process, i.e., subjecting to PE relaxation, water pockets in the structure open and close, thus the ion can move from one pocket to another. Anomalous subdiffusion of ions and water is observed due to the trapping scenarios in these water pockets. The jump events are much rarer compared with ion hopping but significantly increases salt diffusion with increasing temperature. Our result strongly indicates that salt diffusion in hydrated PDAC/PSS is a combined process of ion hopping and jump motion. This provides new molecular explanation for the coupling of salt motion with chain motion and the nonlinear increase of salt diffusion at glass transition temperature.

Quantitative Predictions of Binding Free Energy Changes in Drug-Resistant Influenza Neuraminidase

DTIC Science & Technology

2012-08-30

drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and...conformations that are virtually identical to WT [10]. Molecular simulations that rigorously model the microscopic structure and thermodynamics PLOS...influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with

Quantum dynamics modeled by interacting trajectories

NASA Astrophysics Data System (ADS)

Cruz-Rodríguez, L.; Uranga-Piña, L.; Martínez-Mesa, A.; Meier, C.

2018-03-01

We present quantum dynamical simulations based on the propagation of interacting trajectories where the effect of the quantum potential is mimicked by effective pseudo-particle interactions. The method is applied to several quantum systems, both for bound and scattering problems. For the bound systems, the quantum ground state density and zero point energy are shown to be perfectly obtained by the interacting trajectories. In the case of time-dependent quantum scattering, the Eckart barrier and uphill ramp are considered, with transmission coefficients in very good agreement with standard quantum calculations. Finally, we show that via wave function synthesis along the trajectories, correlation functions and energy spectra can be obtained based on the dynamics of interacting trajectories.

Lane changing trajectory planning and tracking control for intelligent vehicle on curved road.

PubMed

Wang, Lukun; Zhao, Xiaoying; Su, Hao; Tang, Gongyou

2016-01-01

This paper explores lane changing trajectory planning and tracking control for intelligent vehicle on curved road. A novel arcs trajectory is planned for the desired lane changing trajectory. A kinematic controller and a dynamics controller are designed to implement the trajectory tracking control. Firstly, the kinematic model and dynamics model of intelligent vehicle with non-holonomic constraint are established. Secondly, two constraints of lane changing on curved road in practice (LCCP) are proposed. Thirdly, two arcs with same curvature are constructed for the desired lane changing trajectory. According to the geometrical characteristics of arcs trajectory, equations of desired state can be calculated. Finally, the backstepping method is employed to design a kinematic trajectory tracking controller. Then the sliding-mode dynamics controller is designed to ensure that the motion of the intelligent vehicle can follow the desired velocity generated by kinematic controller. The stability of control system is proved by Lyapunov theory. Computer simulation demonstrates that the desired arcs trajectory and state curves with B-spline optimization can meet the requirements of LCCP constraints and the proposed control schemes can make tracking errors to converge uniformly.

Towards an explanation of orbits in the extreme trans-Neptunian region: The effect of Milgromian dynamics

NASA Astrophysics Data System (ADS)

Paučo, R.

2017-06-01

Context. Milgromian dynamics (MD or MOND) uniquely predicts motion in a galaxy from the distribution of its stars and gas in a remarkable agreement with observations so far. In the solar system, MD predicts the existence of some possibly non-negligible dynamical effects, which can be used to constrain the freedom in MD theories. Known extreme trans-Neptunian objects (ETNOs) have their argument of perihelion, longitude of ascending node, and inclination distributed in highly non-uniform fashion; ETNOs are bodies with perihelion distances greater than the orbit of Neptune and with semimajor axes greater than 150 au and less than 1500 au. It is as if these bodies have been systematically perturbed by some external force. Aims: We investigated a hypothesis that the puzzling orbital characteristics of ETNOs are a consequence of MD. Methods: We set up a dynamical model of the solar system incorporating the external field effect (EFE), which is anticipated to be the dominant effect of MD in the ETNOs region. We used constraints available on the strength of EFE coming from radio tracking of the Cassini spacecraft. We performed several numerical experiments, concentrating on the long-term orbital evolution of primordial (randomised) ETNOs in MD. Results: The EFE could produce distinct non-uniform distributions of the orbital elements of ETNOs that are related to the orientation of an orbit in space. If we demand that EFE is solely responsible for the detachment of Sedna and 2012 VP113, then these distributions are at odds with the currently observed statistics on ETNOs unless the EFE quadrupole strength parameter Q2 has values that are unlikely (with probability <1%) in light of the Cassini data.

Internal Coordinate Molecular Dynamics: A Foundation for Multiscale Dynamics

PubMed Central

2015-01-01

Internal coordinates such as bond lengths, bond angles, and torsion angles (BAT) are natural coordinates for describing a bonded molecular system. However, the molecular dynamics (MD) simulation methods that are widely used for proteins, DNA, and polymers are based on Cartesian coordinates owing to the mathematical simplicity of the equations of motion. However, constraints are often needed with Cartesian MD simulations to enhance the conformational sampling. This makes the equations of motion in the Cartesian coordinates differential-algebraic, which adversely impacts the complexity and the robustness of the simulations. On the other hand, constraints can be easily placed in BAT coordinates by removing the degrees of freedom that need to be constrained. Thus, the internal coordinate MD (ICMD) offers an attractive alternative to Cartesian coordinate MD for developing multiscale MD method. The torsional MD method is a special adaptation of the ICMD method, where all the bond lengths and bond angles are kept rigid. The advantages of ICMD simulation methods are the longer time step size afforded by freezing high frequency degrees of freedom and performing a conformational search in the more important low frequency torsional degrees of freedom. However, the advancements in the ICMD simulations have been slow and stifled by long-standing mathematical bottlenecks. In this review, we summarize the recent mathematical advancements we have made based on spatial operator algebra, in developing a robust long time scale ICMD simulation toolkit useful for various applications. We also present the applications of ICMD simulations to study conformational changes in proteins and protein structure refinement. We review the advantages of the ICMD simulations over the Cartesian simulations when used with enhanced sampling methods and project the future use of ICMD simulations in protein dynamics. PMID:25517406

Virtual synthesis of crystals using ab initio MD: Case study on LiFePO4

NASA Astrophysics Data System (ADS)

Mishra, S. B.; Nanda, B. R. K.

2017-05-01

Molecular dynamics simulation technique is fairly successful in studying the structural aspects and dynamics of fluids. Here we study the ability of ab initio molecular dynamics (ab initio MD) to carry out virtual experiments to synthesize new crystalline materials and to predict their structures. For this purpose the olivine phosphate LiFePO4 (LFPO) is used as an example. As transition metal oxides in general are stabilized with layered geometry, we carried out ab initio MD simulations over a hypothetical layered configuration consisting of alternate LiPO2 and FeO2 layers. With intermittent steps of electron minimization, the resulted equilibrium lattice consist of PO4 tetrahedra and distorted Fe-O complexes similar to the one observed in the experimental lattice.

First principles molecular dynamics of molten NaCl

NASA Astrophysics Data System (ADS)

Galamba, N.; Costa Cabral, B. J.

2007-03-01

First principles Hellmann-Feynman molecular dynamics (HFMD) results for molten NaCl at a single state point are reported. The effect of induction forces on the structure and dynamics of the system is studied by comparison of the partial radial distribution functions and the velocity and force autocorrelation functions with those calculated from classical MD based on rigid-ion and shell-model potentials. The first principles results reproduce the main structural features of the molten salt observed experimentally, whereas they are incorrectly described by both rigid-ion and shell-model potentials. Moreover, HFMD Green-Kubo self-diffusion coefficients are in closer agreement with experimental data than those predicted by classical MD. A comprehensive discussion of MD results for molten NaCl based on different ab initio parametrized polarizable interionic potentials is also given.

Review of the fundamental theories behind small angle X-ray scattering, molecular dynamics simulations, and relevant integrated application

PubMed Central

Boldon, Lauren; Laliberte, Fallon; Liu, Li

2015-01-01

In this paper, the fundamental concepts and equations necessary for performing small angle X-ray scattering (SAXS) experiments, molecular dynamics (MD) simulations, and MD-SAXS analyses were reviewed. Furthermore, several key biological and non-biological applications for SAXS, MD, and MD-SAXS are presented in this review; however, this article does not cover all possible applications. SAXS is an experimental technique used for the analysis of a wide variety of biological and non-biological structures. SAXS utilizes spherical averaging to produce one- or two-dimensional intensity profiles, from which structural data may be extracted. MD simulation is a computer simulation technique that is used to model complex biological and non-biological systems at the atomic level. MD simulations apply classical Newtonian mechanics’ equations of motion to perform force calculations and to predict the theoretical physical properties of the system. This review presents several applications that highlight the ability of both SAXS and MD to study protein folding and function in addition to non-biological applications, such as the study of mechanical, electrical, and structural properties of non-biological nanoparticles. Lastly, the potential benefits of combining SAXS and MD simulations for the study of both biological and non-biological systems are demonstrated through the presentation of several examples that combine the two techniques. PMID:25721341

Comparison of Phase Field Crystal and Molecular Dynamics Simulations for a Shrinking Grain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radhakrishnan, Balasubramaniam; Gorti, Sarma B; Nicholson, Don M

2012-01-01

The Phase-Field Crystal (PFC) model represents the atomic density as a continuous function, whose spatial distribution evolves at diffusional, rather than vibrational time scales. PFC provides a tool to study defect interactions at the atomistic level but over longer time scales than in molecular dynamics (MD). We examine the behavior of the PFC model with the goal of relating the PFC parameters to physical parameters of real systems, derived from MD simulations. For this purpose we model the phenomenon of the shrinking of a spherical grain situated in a matrix. By comparing the rate of shrinking of the central grainmore » using MD and PFC we obtain a relationship between PFC and MD time scales for processes driven by grain boundary diffusion. The morphological changes in the central grain including grain shape and grain rotation are also examined in order to assess the accuracy of the PFC in capturing the evolution path predicted by MD.« less

The ONIOM molecular dynamics method for biochemical applications: cytidine deaminase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsubara, Toshiaki; Dupuis, Michel; Aida, Misako

2007-03-22

Abstract We derived and implemented the ONIOM-molecular dynamics (MD) method for biochemical applications. The implementation allows the characterization of the functions of the real enzymes taking account of their thermal motion. In this method, the direct MD is performed by calculating the ONIOM energy and gradients of the system on the fly. We describe the first application of this ONOM-MD method to cytidine deaminase. The environmental effects on the substrate in the active site are examined. The ONIOM-MD simulations show that the product uridine is strongly perturbed by the thermal motion of the environment and dissociates easily from the activemore » site. TM and MA were supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan. MD was supported by the Division of Chemical Sciences, Office of Basic Energy Sciences, and by the Office of Biological and Environmental Research of the U.S. Department of Energy DOE. Battelle operates Pacific Northwest National Laboratory for DOE.« less

Combined Molecular Dynamics Simulation-Molecular-Thermodynamic Theory Framework for Predicting Surface Tensions.

PubMed

Sresht, Vishnu; Lewandowski, Eric P; Blankschtein, Daniel; Jusufi, Arben

2017-08-22

A molecular modeling approach is presented with a focus on quantitative predictions of the surface tension of aqueous surfactant solutions. The approach combines classical Molecular Dynamics (MD) simulations with a molecular-thermodynamic theory (MTT) [ Y. J. Nikas, S. Puvvada, D. Blankschtein, Langmuir 1992 , 8 , 2680 ]. The MD component is used to calculate thermodynamic and molecular parameters that are needed in the MTT model to determine the surface tension isotherm. The MD/MTT approach provides the important link between the surfactant bulk concentration, the experimental control parameter, and the surfactant surface concentration, the MD control parameter. We demonstrate the capability of the MD/MTT modeling approach on nonionic alkyl polyethylene glycol surfactants at the air-water interface and observe reasonable agreement of the predicted surface tensions and the experimental surface tension data over a wide range of surfactant concentrations below the critical micelle concentration. Our modeling approach can be extended to ionic surfactants and their mixtures with both ionic and nonionic surfactants at liquid-liquid interfaces.

Dynamic changes in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers during various murine peripartum states and over time.

PubMed

Chew, G L; Huang, D; Huo, C W; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M D; Hopper, J L; Henderson, M A; Haviv, I; Thompson, E W

2013-07-01

Mammographic density (MD) is a strong heritable risk factor for breast cancer, and may decrease with increasing parity. However, the biomolecular basis for MD-associated breast cancer remains unclear, and systemic hormonal effects on MD-associated risk is poorly understood. This study assessed the effect of murine peripartum states on high and low MD tissue maintained in a xenograft model of human MD. Method High and low MD human breast tissues were precisely sampled under radiographic guidance from prophylactic mastectomy specimens of women. The high and low MD tissues were maintained in separate vascularised biochambers in nulliparous or pregnant SCID mice for 4 weeks, or mice undergoing postpartum involution or lactation for three additional weeks. High and low MD biochamber material was harvested for histologic and radiographic comparisons during various murine peripartum states. High and low MD biochamber tissues in nulliparous mice were harvested at different timepoints for histologic and radiographic comparisons. Results High MD biochamber tissues had decreased stromal (p = 0.0027), increased adipose (p = 0.0003) and a trend to increased glandular tissue areas (p = 0.076) after murine postpartum involution. Stromal areas decreased (p = 0.042), while glandular (p = 0.001) and adipose areas (p = 0.009) increased in high MD biochamber tissues during lactation. A difference in radiographic density was observed in high (p = 0.0021) or low MD biochamber tissues (p = 0.004) between nulliparous, pregnant and involution groups. No differences in tissue composition were observed in high or low MD biochamber tissues maintained for different durations, although radiographic density increased over time. Conclusion High MD biochamber tissues had measurable histologic changes after postpartum involution or lactation. Alterations in radiographic density occurred in biochamber tissues between different peripartum states and over time. These findings demonstrate the dynamic nature of the human MD xenograft model, providing a platform for studying the biomolecular basis of MD-associated cancer risk.

E9-Im9 Colicin DNase−Immunity Protein Biomolecular Association in Water: A Multiple-Copy and Accelerated Molecular Dynamics Simulation Study

PubMed Central

2008-01-01

Protein−protein transient and dynamic interactions underlie all biological processes. The molecular dynamics (MD) of the E9 colicin DNase protein, its Im9 inhibitor protein, and their E9-Im9 recognition complex are investigated by combining multiple-copy (MC) MD and accelerated MD (aMD) explicit-solvent simulation approaches, after validation with crystalline-phase and solution experiments. Im9 shows higher flexibility than its E9 counterpart. Im9 displays a significant reduction of backbone flexibility and a remarkable increase in motional correlation upon E9 association. Im9 loops 23−31 and 54−64 open with respect to the E9-Im9 X-ray structure and show high conformational diversity. Upon association a large fraction (∼20 nm2) of E9 and Im9 protein surfaces become inaccessible to water. Numerous salt bridges transiently occurring throughout our six 50 ns long MC-MD simulations are not present in the X-ray model. Among these Im9 Glu31−E9 Arg96 and Im9 Glu41−Lys89 involve interface interactions. Through the use of 10 ns of Im9 aMD simulation, we reconcile the largest thermodynamic impact measured for Asp51Ala mutation with Im9 structure and dynamics. Lys57 acts as an essential molecular switch to shift Im9 surface loop towards an ideal configuration for E9 inhibition. This is achieved by switching Asp60−Lys57 and Asp62−Lys57 hydrogen bonds to Asp51−Lys57 salt bridge. E9-Im9 recognition involves shifts of conformational distributions, reorganization of intramolecular hydrogen bond patterns, and formation of new inter- and intramolecular interactions. The description of key transient biological interactions can be significantly enriched by the dynamic and atomic-level information provided by computer simulations. PMID:19053689

Trajectory optimization for the National Aerospace Plane

NASA Technical Reports Server (NTRS)

Lu, Ping

1993-01-01

The objective of this second phase research is to investigate the optimal ascent trajectory for the National Aerospace Plane (NASP) from runway take-off to orbital insertion and address the unique problems associated with the hypersonic flight trajectory optimization. The trajectory optimization problem for an aerospace plane is a highly challenging problem because of the complexity involved. Previous work has been successful in obtaining sub-optimal trajectories by using energy-state approximation and time-scale decomposition techniques. But it is known that the energy-state approximation is not valid in certain portions of the trajectory. This research aims at employing full dynamics of the aerospace plane and emphasizing direct trajectory optimization methods. The major accomplishments of this research include the first-time development of an inverse dynamics approach in trajectory optimization which enables us to generate optimal trajectories for the aerospace plane efficiently and reliably, and general analytical solutions to constrained hypersonic trajectories that has wide application in trajectory optimization as well as in guidance and flight dynamics. Optimal trajectories in abort landing and ascent augmented with rocket propulsion and thrust vectoring control were also investigated. Motivated by this study, a new global trajectory optimization tool using continuous simulated annealing and a nonlinear predictive feedback guidance law have been under investigation and some promising results have been obtained, which may well lead to more significant development and application in the near future.

Differential flap dynamics in l,d-transpeptidase2 from mycobacterium tuberculosis revealed by molecular dynamics.

PubMed

Fakhar, Zeynab; Govender, Thavendran; Maguire, Glenn E M; Lamichhane, Gyanu; Walker, Ross C; Kruger, Hendrik G; Honarparvar, Bahareh

2017-06-01

Despite the advances in tuberculosis treatment, TB is still one the most deadly infectious diseases and remains a major global health quandary. Mycobacterium tuberculosis (Mtb) is the only known mycobacterium with a high content of 3→3 crosslinks in the biosynthesis of peptidoglycan, which is negligible in most bacterial species. An Mtb lacking Ldt Mt2 leads to alteration of the colony morphology and loss of virulence which makes this enzyme an attractive target. Regardless of the vital role of Ldt Mt2 for cell wall survival, the impact of ligand binding on the dynamics of the β-hairpin flap is still unknown. Understanding the structural and dynamical behaviour of the flap regions provides clear insight into the design of the effective inhibitors against Ldt Mt2 . Carbapenems, an specific class of β-lactam family, have been shown to inactivate this enzyme. Herein a comprehensive investigation of the flap dynamics of Ldt Mt2 complex with substrate and three carbapenems namely, ertapenem, imipenem and meropenem is discussed and analyzed for the first account using 140 ns molecular dynamics simulations. The structural features (RMSD, RMSF and R g ) derived by MD trajectories were analyzed. Distance analysis, particularly tip-tip SER135-ASN167 index, identified conformational changes in terms of flap opening and closure within binding process. Principal component analysis (PCA) was employed to qualitatively understand the divergent effects of different inhibitors on the dominant motion of each residue. To probe different internal dynamics induced by ligand binding, dynamic cross-correlation marix (DCCM) analysis was used. The binding free energies of the selected complexes were assessed using MM-GBSA method and per residue free energy decomposition analysis were performed to characterize the contribution of the key residues to the total binding free energies.

Molecular dynamics study on glycolic acid in the physiological salt solution

NASA Astrophysics Data System (ADS)

Matsunaga, S.

2018-05-01

Molecular dynamics (MD) study on glycolic acid in the physiological salt solution has been performed, which is a model of a biofuel cell. The structure and charge distribution of glycolic acid in aqueous solution used in MD is beforehand optimized by Gaussian09 utilizing the density functional theory. MD is performed in the NTV constant condition, i.e. the number of particles, temperature, and volume of MD cell are definite. The structure difference of the glycolic acid and oxalic acid is detected by the water distribution around the molecules using the pair distribution functions, gij(r), and the frequency dependent diffusion coefficients, Di(ν). The anomalous dielectric constant of the solution, i.e. about 12 times larger than that of water, has been obtained, which may be attributed to the ion pair formation in the solution.

Conformational analysis of a condensed macrocyclic β-lactam by NMR and molecular dynamics calculations

NASA Astrophysics Data System (ADS)

Keserű, György M.; Vásárhelyi, Helga; Makara, Gergely

1994-09-01

The conformation of the new macrocyclic β-lactam ( 1) was investigated by NMR and molecular dynamics (MD) calculations. Restraints obtained from NOESY and ROESY experiments were introduced into MD simulations which led to well-defined conformations. The preference for the calculated minimum energy conformation was confirmed by the analysis of vicinal coupling constants. Experimental coupling constants agreed with computed values.

Regional Influences of Marcellus Shale Natural Gas Activity: Back-trajectory Analysis of Baltimore/Washington Ethane Concentrations

NASA Astrophysics Data System (ADS)

Vinciguerra, T.; Chittams, A.; Dadzie, J.; Deskins, T.; Goncalves, V.; M'Bagui Matsanga, C.; Zakaria, R.; Ehrman, S.; Dickerson, R. R.

2015-12-01

Over the past several years, the combined utilization of hydraulic fracturing and horizontal drilling has led to a rapid increase in natural gas production, especially from the Marcellus Shale. To explore the impact of this activity downwind on regions with no natural gas production, the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) Model was used to generate 48-hour back-trajectories for summer, daytime hours from the years 2007-2014 in the Baltimore, MD and Washington, D.C. areas where hourly ethane measurements are available from Photochemical Assessment Monitoring Stations (PAMS). For each of the years investigated, unconventional well counts were obtained for counties in the surrounding states of Pennsylvania, Ohio, West Virginia, and Virginia, and counties exceeding a threshold of 0.05 wells/km2 were designated as counties with a high density of wells. The back-trajectories for each year were separated into two groups: those which passed through counties containing a high density of wells, and those which did not. Back-trajectories passing through high-density counties were further screened by applying a height criterion where trajectories beyond 10% above the mixing layer were excluded. Preliminary results indicate that air parcels with back-trajectories passing within the boundary layer of counties with a high density of unconventional natural gas wells correspond to significantly greater concentrations of observed ethane at these downwind monitors.

A combined EPR and MD simulation study of a nitroxyl spin label with restricted internal mobility sensitive to protein dynamics.

PubMed

Oganesyan, Vasily S; Chami, Fatima; White, Gaye F; Thomson, Andrew J

2017-01-01

EPR studies combined with fully atomistic Molecular Dynamics (MD) simulations and an MD-EPR simulation method provide evidence for intrinsic low rotameric mobility of a nitroxyl spin label, Rn, compared to the more widely employed label MTSL (R1). Both experimental and modelling results using two structurally different sites of attachment to Myoglobin show that the EPR spectra of Rn are more sensitive to the local protein environment than that of MTSL. This study reveals the potential of using the Rn spin label as a reporter of protein motions. Copyright © 2016 Elsevier Inc. All rights reserved.

A combined molecular dynamics/micromechanics/finite element approach for multiscale constitutive modeling of nanocomposites with interface effects

NASA Astrophysics Data System (ADS)

Yang, B. J.; Shin, H.; Lee, H. K.; Kim, H.

2013-12-01

We introduce a multiscale framework based on molecular dynamic (MD) simulation, micromechanics, and finite element method (FEM). A micromechanical model, which considers influences of the interface properties, nanoparticle (NP) size, and microcracks, is developed. Then, we perform MD simulations to characterize the mechanical properties of the nanocomposite system (silica/nylon 6) with varying volume fraction and size of NPs. By comparing the MD with micromechanics results, intrinsic physical properties at interfacial region are derived. Finally, we implement the developed model in the FEM code with the derived interfacial parameters, and predict the mechanical behavior of the nanocomposite at the macroscopic scale.

Computation of shear viscosity of colloidal suspensions by SRD-MD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laganapan, A. M. K.; Videcoq, A., E-mail: arnaud.videcoq@unilim.fr; Bienia, M.

2015-04-14

The behaviour of sheared colloidal suspensions with full hydrodynamic interactions (HIs) is numerically studied. To this end, we use the hybrid stochastic rotation dynamics-molecular dynamics (SRD-MD) method. The shear viscosity of colloidal suspensions is computed for different volume fractions, both for dilute and concentrated cases. We verify that HIs help in the collisions and the streaming of colloidal particles, thereby increasing the overall shear viscosity of the suspension. Our results show a good agreement with known experimental, theoretical, and numerical studies. This work demonstrates the ability of SRD-MD to successfully simulate transport coefficients that require correct modelling of HIs.

NMR investigations of molecular dynamics

NASA Astrophysics Data System (ADS)

Palmer, Arthur

2011-03-01

NMR spectroscopy is a powerful experimental approach for characterizing protein conformational dynamics on multiple time scales. The insights obtained from NMR studies are complemented and by molecular dynamics (MD) simulations, which provide full atomistic details of protein dynamics. Homologous mesophilic (E. coli) and thermophilic (T. thermophilus) ribonuclease H (RNase H) enzymes serve to illustrate how changes in protein sequence and structure that affect conformational dynamic processes can be monitored and characterized by joint analysis of NMR spectroscopy and MD simulations. A Gly residue inserted within a putative hinge between helices B and C is conserved among thermophilic RNases H, but absent in mesophilic RNases H. Experimental spin relaxation measurements show that the dynamic properties of T. thermophilus RNase H are recapitulated in E. coli RNase H by insertion of a Gly residue between helices B and C. Additional specific intramolecular interactions that modulate backbone and sidechain dynamical properties of the Gly-rich loop and of the conserved Trp residue flanking the Gly insertion site have been identified using MD simulations and subsequently confirmed by NMR spin relaxation measurements. These results emphasize the importance of hydrogen bonds and local steric interactions in restricting conformational fluctuations, and the absence of such interactions in allowing conformational adaptation to substrate binding.

Dexterity-Enhanced Telerobotic Microsurgery

NASA Technical Reports Server (NTRS)

Charles, Steve; Das, Hari; Ohm, Timothy; Boswell, Curtis; Rodriguez, Guillermo; Steele, Robert; Istrate, Dan

1997-01-01

The work reported in this paper is the result, of a collaboration between researchers at the Jet Propulsion Laboratory and Steve Charles, MD, a vitreo-retinal surgeon. The Robot Assisted MicroSurgery (RAMS) telerobotic workstation developed at JPL is a prototype of a system that will be completely under the manual control of a surgeon. The system has a slave robot that will hold surgical instruments. The slave robot motions replicate in six degrees of freedom those of tile. surgeon's hand measured using a master input device with a surgical instrument, shaped handle. The surgeon commands motions for the instrument by moving the handle in the desired trajectories. The trajectories are measured, filtered, and scaled down then used to drive the slave robot.

Combining cell-based hydrodynamics with hybrid particle-field simulations: efficient and realistic simulation of structuring dynamics.

PubMed

Sevink, G J A; Schmid, F; Kawakatsu, T; Milano, G

2017-02-22

We have extended an existing hybrid MD-SCF simulation technique that employs a coarsening step to enhance the computational efficiency of evaluating non-bonded particle interactions. This technique is conceptually equivalent to the single chain in mean-field (SCMF) method in polymer physics, in the sense that non-bonded interactions are derived from the non-ideal chemical potential in self-consistent field (SCF) theory, after a particle-to-field projection. In contrast to SCMF, however, MD-SCF evolves particle coordinates by the usual Newton's equation of motion. Since collisions are seriously affected by the softening of non-bonded interactions that originates from their evaluation at the coarser continuum level, we have devised a way to reinsert the effect of collisions on the structural evolution. Merging MD-SCF with multi-particle collision dynamics (MPCD), we mimic particle collisions at the level of computational cells and at the same time properly account for the momentum transfer that is important for a realistic system evolution. The resulting hybrid MD-SCF/MPCD method was validated for a particular coarse-grained model of phospholipids in aqueous solution, against reference full-particle simulations and the original MD-SCF model. We additionally implemented and tested an alternative and more isotropic finite difference gradient. Our results show that efficiency is improved by merging MD-SCF with MPCD, as properly accounting for hydrodynamic interactions considerably speeds up the phase separation dynamics, with negligible additional computational costs compared to efficient MD-SCF. This new method enables realistic simulations of large-scale systems that are needed to investigate the applications of self-assembled structures of lipids in nanotechnologies.

Investigation of polarization effects in the gramicidin A channel from ab initio molecular dynamics simulations.

PubMed

Timko, Jeff; Kuyucak, Serdar

2012-11-28

Polarization is an important component of molecular interactions and is expected to play a particularly significant role in inhomogeneous environments such as pores and interfaces. Here we investigate the effects of polarization in the gramicidin A ion channel by performing quantum mechanics/molecular mechanics molecular dynamics (MD) simulations and comparing the results with those obtained from classical MD simulations with non-polarizable force fields. We consider the dipole moments of backbone carbonyl groups and channel water molecules as well as a number of structural quantities of interest. The ab initio results show that the dipole moments of the carbonyl groups and water molecules are highly sensitive to the hydrogen bonds (H-bonds) they participate in. In the absence of a K(+) ion, water molecules in the channel are quite mobile, making the H-bond network highly dynamic. A central K(+) ion acts as an anchor for the channel waters, stabilizing the H-bond network and thereby increasing their average dipole moments. In contrast, the K(+) ion has little effect on the dipole moments of the neighboring carbonyl groups. The weakness of the ion-peptide interactions helps to explain the near diffusion-rate conductance of K(+) ions through the channel. We also address the sampling issue in relatively short ab initio MD simulations. Results obtained from a continuous 20 ps ab initio MD simulation are compared with those generated by sampling ten windows from a much longer classical MD simulation and running each window for 2 ps with ab initio MD. Both methods yield similar results for a number of quantities of interest, indicating that fluctuations are fast enough to justify the short ab initio MD simulations.

DROIDS 1.20: A GUI-Based Pipeline for GPU-Accelerated Comparative Protein Dynamics.

PubMed

Babbitt, Gregory A; Mortensen, Jamie S; Coppola, Erin E; Adams, Lily E; Liao, Justin K

2018-03-13

Traditional informatics in comparative genomics work only with static representations of biomolecules (i.e., sequence and structure), thereby ignoring the molecular dynamics (MD) of proteins that define function in the cell. A comparative approach applied to MD would connect this very short timescale process, defined in femtoseconds, to one of the longest in the universe: molecular evolution measured in millions of years. Here, we leverage advances in graphics-processing-unit-accelerated MD simulation software to develop a comparative method of MD analysis and visualization that can be applied to any two homologous Protein Data Bank structures. Our open-source pipeline, DROIDS (Detecting Relative Outlier Impacts in Dynamic Simulations), works in conjunction with existing molecular modeling software to convert any Linux gaming personal computer into a "comparative computational microscope" for observing the biophysical effects of mutations and other chemical changes in proteins. DROIDS implements structural alignment and Benjamini-Hochberg-corrected Kolmogorov-Smirnov statistics to compare nanosecond-scale atom bond fluctuations on the protein backbone, color mapping the significant differences identified in protein MD with single-amino-acid resolution. DROIDS is simple to use, incorporating graphical user interface control for Amber16 MD simulations, cpptraj analysis, and the final statistical and visual representations in R graphics and UCSF Chimera. We demonstrate that DROIDS can be utilized to visually investigate molecular evolution and disease-related functional changes in MD due to genetic mutation and epigenetic modification. DROIDS can also be used to potentially investigate binding interactions of pharmaceuticals, toxins, or other biomolecules in a functional evolutionary context as well. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Effects of mutations on active site conformation and dynamics of RNA-dependent RNA polymerase from Coxsackievirus B3.

PubMed

Shen, Hujun; Deng, Mingsen; Zhang, Yachao

2017-10-01

Recent crystal structures of RNA-dependent RNA polymerase (3D pol ) from Coxsackievirus B3 (CVB3) revealed that a tyrosine mutation at Phe364 (F364Y) resulted in structures with open active site whereas a hydrophobic mutation at Phe364 (F364A) led to conformations with closed active site. Besides, the crystal structures showed that the F364W mutation had no preference between the open and closed active sites, similar to wild-type. In this paper, we present a molecular dynamics (MD) study on CVB3 3D pol in order to address some important questions raised by experiments. First, MD simulations of F364Y and F364A were carried out to explore how these mutations at Phe364 influence active site dynamics and conformations. Second, MD simulations of wild-type and mutants were performed to discover the connection between active site dynamics and polymerase function. MD simulations reveal that the effect of mutations on active site dynamics is associated with the interaction between the structural motifs A and D in CVB3 3D pol . Interestingly, we discover that the active site state is influenced by the formation of a hydrogen bond between backbone atoms of Ala231 (in motif A) and Ala358 (in motif D), which has never been revealed before. Copyright © 2017 Elsevier Inc. All rights reserved.

Marijuana use trajectories among drug-using youth presenting to an urban emergency department: Violence and social influences

PubMed Central

Walton, Maureen A.; Epstein-Ngo, Quyen; Carter, Patrick M.; Zimmerman, Marc A.; Blow, Frederic C.; Buu, Anne; Goldstick, Jason; Cunningham, Rebecca M.

2017-01-01

Aims This paper examined longitudinal marijuana use trajectories among drug-using youth presenting to the ED to inform intervention development. Methods Given interest in substance use and violence, this study oversampled those presenting with assault injuries. Assault-injured youth (ages 14-24) endorsing past 6-month drug use (n=349), and a sex and age proportionally-sampled comparison group (n=250) endorsing drug use, completed a baseline assessment and follow-ups at 6, 12, 18, and 24 months. Latent class trajectory analyses examined days of marijuana use over 2 years. Multinomial regression analyses examined baseline, 12-month and 24-month factors associated with substance use trajectory groups. Results Trajectory analyses identified 5 groups: Low (Low; 28.2%; n=169); Intermittent (INT; 16.2%; n=97); Moderate Decline (MD; 12.0%; n=72); High decline (HD, 13.2%; n=79) and Chronic (C; 30.4%; n=182). At baseline, as compared to the Low group, the other trajectory groups were more likely to be male and have greater levels of physical aggression. At 12- and 24-months, negative and positive peer influences, incarceration and community violence were additional characteristics associated with the greater marijuana use trajectories (as compared to the Low group). Conclusions Interventions for drug-using youth presenting to the urban ED should address peer influences, physical aggression and community violence exposure, given the association between these characteristics and greater marijuana use trajectories. PMID:28219802

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Haixuan; Osetskiy, Yury N; Stoller, Roger E

The fundamentals of the framework and the details of each component of the self-evolving atomistic kinetic Monte Carlo (SEAKMC) are presented. The strength of this new technique is the ability to simulate dynamic processes with atomistic fidelity that is comparable to molecular dynamics (MD) but on a much longer time scale. The observation that the dimer method preferentially finds the saddle point (SP) with the lowest energy is investigated and found to be true only for defects with high symmetry. In order to estimate the fidelity of dynamics and accuracy of the simulation time, a general criterion is proposed andmore » applied to two representative problems. Applications of SEAKMC for investigating the diffusion of interstitials and vacancies in bcc iron are presented and compared directly with MD simulations, demonstrating that SEAKMC provides results that formerly could be obtained only through MD. The correlation factor for interstitial diffusion in the dumbbell configuration, which is extremely difficult to obtain using MD, is predicted using SEAKMC. The limitations of SEAKMC are also discussed. The paper presents a comprehensive picture of the SEAKMC method in both its unique predictive capabilities and technically important details.« less

Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor.

PubMed

Kappel, Kalli; Miao, Yinglong; McCammon, J Andrew

2015-11-01

Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein-ligand binding, especially the drug recognition of GPCRs.

PuReMD-GPU: A reactive molecular dynamics simulation package for GPUs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kylasa, S.B., E-mail: skylasa@purdue.edu; Aktulga, H.M., E-mail: hmaktulga@lbl.gov; Grama, A.Y., E-mail: ayg@cs.purdue.edu

2014-09-01

We present an efficient and highly accurate GP-GPU implementation of our community code, PuReMD, for reactive molecular dynamics simulations using the ReaxFF force field. PuReMD and its incorporation into LAMMPS (Reax/C) is used by a large number of research groups worldwide for simulating diverse systems ranging from biomembranes to explosives (RDX) at atomistic level of detail. The sub-femtosecond time-steps associated with ReaxFF strongly motivate significant improvements to per-timestep simulation time through effective use of GPUs. This paper presents, in detail, the design and implementation of PuReMD-GPU, which enables ReaxFF simulations on GPUs, as well as various performance optimization techniques wemore » developed to obtain high performance on state-of-the-art hardware. Comprehensive experiments on model systems (bulk water and amorphous silica) are presented to quantify the performance improvements achieved by PuReMD-GPU and to verify its accuracy. In particular, our experiments show up to 16× improvement in runtime compared to our highly optimized CPU-only single-core ReaxFF implementation. PuReMD-GPU is a unique production code, and is currently available on request from the authors.« less

Leap-dynamics: efficient sampling of conformational space of proteins and peptides in solution.

PubMed

Kleinjung, J; Bayley, P; Fraternali, F

2000-03-31

A molecular simulation scheme, called Leap-dynamics, that provides efficient sampling of protein conformational space in solution is presented. The scheme is a combined approach using a fast sampling method, imposing conformational 'leaps' to force the system over energy barriers, and molecular dynamics (MD) for refinement. The presence of solvent is approximated by a potential of mean force depending on the solvent accessible surface area. The method has been successfully applied to N-acetyl-L-alanine-N-methylamide (alanine dipeptide), sampling experimentally observed conformations inaccessible to MD alone under the chosen conditions. The method predicts correctly the increased partial flexibility of the mutant Y35G compared to native bovine pancreatic trypsin inhibitor. In particular, the improvement over MD consists of the detection of conformational flexibility that corresponds closely to slow motions identified by nuclear magnetic resonance techniques.

Trajectory phase transitions and dynamical Lee-Yang zeros of the Glauber-Ising chain.

PubMed

Hickey, James M; Flindt, Christian; Garrahan, Juan P

2013-07-01

We examine the generating function of the time-integrated energy for the one-dimensional Glauber-Ising model. At long times, the generating function takes on a large-deviation form and the associated cumulant generating function has singularities corresponding to continuous trajectory (or "space-time") phase transitions between paramagnetic trajectories and ferromagnetically or antiferromagnetically ordered trajectories. In the thermodynamic limit, the singularities make up a whole curve of critical points in the complex plane of the counting field. We evaluate analytically the generating function by mapping the generator of the biased dynamics to a non-Hermitian Hamiltonian of an associated quantum spin chain. We relate the trajectory phase transitions to the high-order cumulants of the time-integrated energy which we use to extract the dynamical Lee-Yang zeros of the generating function. This approach offers the possibility to detect continuous trajectory phase transitions from the finite-time behavior of measurable quantities.

Trajectory control method of stratospheric airship based on the sliding mode control and prediction in wind field

NASA Astrophysics Data System (ADS)

Zhang, Jia-shi; Yang, Xi-xiang

2017-11-01

The stratospheric airship has the characteristics of large inertia, long time delay and large disturbance of wind field , so the trajectory control is very difficult .Build the lateral three degrees of freedom dynamic model which consider the wind interference , the dynamics equation is linearized by the small perturbation theory, propose a trajectory control method Combine with the sliding mode control and prediction, design the trajectory controller , takes the HAA airship as the reference to carry out simulation analysis. Results show that the improved sliding mode control with front-feedback method not only can solve well control problems of airship trajectory in wind field, but also can effectively improve the control accuracy of the traditional sliding mode control method, solved problems that using the traditional sliding mode control to control. It provides a useful reference for dynamic modeling and trajectory control of stratospheric airship.

Effectiveness of Telerehabilitation for OIF/OEF Returnees with Combat Related Trauma

DTIC Science & Technology

2015-02-01

Our telerehabilitation care coordination team is organized under Steve Scott, MD, Chief Physical Medicine and Rehabilitation Services VA at the...for communication between care coordinators and study enrollees. Separate “ virtual rooms” have been setup on the 5 VA server to facilitate care...characterize rehabilitation trajectories over time in the areas of function, cognition, psychosocial adjustment, integration into society and mental health

Molecular Dynamics of Hot Dense Plasmas: New Horizons

NASA Astrophysics Data System (ADS)

Graziani, Frank

2011-10-01

We describe the status of a new time-dependent simulation capability for hot dense plasmas. The backbone of this multi-institutional computational and experimental effort--the Cimarron Project--is the massively parallel molecular dynamics (MD) code ``ddcMD''. The project's focus is material conditions such as exist in inertial confinement fusion experiments, and in many stellar interiors: high temperatures, high densities, significant electromagnetic fields, mixtures of high- and low- Zelements, and non-Maxwellian particle distributions. Of particular importance is our ability to incorporate into this classical MD code key atomic, radiative, and nuclear processes, so that their interacting effects under non-ideal plasma conditions can be investigated. This talk summarizes progress in computational methodology, discusses strengths and weaknesses of quantum statistical potentials as effective interactions for MD, explains the model used for quantum events possibly occurring in a collision and highlights some significant results obtained to date. We describe the status of a new time-dependent simulation capability for hot dense plasmas. The backbone of this multi-institutional computational and experimental effort--the Cimarron Project--is the massively parallel molecular dynamics (MD) code ``ddcMD''. The project's focus is material conditions such as exist in inertial confinement fusion experiments, and in many stellar interiors: high temperatures, high densities, significant electromagnetic fields, mixtures of high- and low- Zelements, and non-Maxwellian particle distributions. Of particular importance is our ability to incorporate into this classical MD code key atomic, radiative, and nuclear processes, so that their interacting effects under non-ideal plasma conditions can be investigated. This talk summarizes progress in computational methodology, discusses strengths and weaknesses of quantum statistical potentials as effective interactions for MD, explains the model used for quantum events possibly occurring in a collision and highlights some significant results obtained to date. This work is performed under the auspices of the U. S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

Functional mechanism of C-terminal tail in the enzymatic role of porcine testicular carbonyl reductase: a combined experiment and molecular dynamics simulation study of the C-terminal tail in the enzymatic role of PTCR.

PubMed

Son, Minky; Bang, Woo Young; Park, Chanin; Lee, Yuno; Kwon, Seul Gi; Kim, Sam Woong; Kim, Chul Wook; Lee, Keun Woo

2014-01-01

Porcine testicular carbonyl reductase, PTCR which is one of the short chain dehydrogenases/reductases (SDR) superfamily catalyzes the NADPH-dependent reduction of carbonyl compounds including steroids and prostaglandins. Previously we reported C-terminal tail of PTCR was deleted due to a nonsynonymous single nucleotide variation (nsSNV). Here we identified from kinetic studies that the enzymatic properties for 5α-dihydrotestosterone (5α-DHT) were different between wild-type and C-terminal-deleted PTCRs. Compared to wild-type PTCR, C-terminal-deleted PTCR has much higher reduction rate. To investigate structural difference between wild-type and C-terminal-deleted PTCRs upon 5α-DHT binding, we performed molecular dynamics simulations for two complexes. Using trajectories, molecular interactions including hydrogen bonding patterns, distance between 5α-DHT and catalytic Tyr193, and interaction energies are analyzed and compared. During the MD simulation time, the dynamic behavior of C-terminal tail in wild-type PTCR is also examined using essential dynamics analysis. The results of our simulations reveal that the binding conformation of 5α-DHT in C-terminal-deleted PTCR is more favorable for reduction reaction in PTCR, which shows strong agreement with kinetic data. These structural findings provide valuable information to understand substrate specificity of PTCR and further kinetic properties of enzymes belonging to the SDR superfamily.

Functional Mechanism of C-Terminal Tail in the Enzymatic Role of Porcine Testicular Carbonyl Reductase: A Combined Experiment and Molecular Dynamics Simulation Study of the C-Terminal Tail in the Enzymatic Role of PTCR

PubMed Central

Park, Chanin; Lee, Yuno; Kwon, Seul Gi; Kim, Sam Woong; Kim, Chul Wook; Lee, Keun Woo

2014-01-01

Porcine testicular carbonyl reductase, PTCR which is one of the short chain dehydrogenases/reductases (SDR) superfamily catalyzes the NADPH-dependent reduction of carbonyl compounds including steroids and prostaglandins. Previously we reported C- terminal tail of PTCR was deleted due to a nonsynonymous single nucleotide variation (nsSNV). Here we identified from kinetic studies that the enzymatic properties for 5α-dihydrotestosterone (5α-DHT) were different between wild-type and C-terminal-deleted PTCRs. Compared to wild-type PTCR, C-terminal-deleted PTCR has much higher reduction rate. To investigate structural difference between wild-type and C-terminal-deleted PTCRs upon 5α-DHT binding, we performed molecular dynamics simulations for two complexes. Using trajectories, molecular interactions including hydrogen bonding patterns, distance between 5α-DHT and catalytic Tyr193, and interaction energies are analyzed and compared. During the MD simulation time, the dynamic behavior of C-terminal tail in wild-type PTCR is also examined using essential dynamics analysis. The results of our simulations reveal that the binding conformation of 5α-DHT in C-terminal-deleted PTCR is more favorable for reduction reaction in PTCR, which shows strong agreement with kinetic data. These structural findings provide valuable information to understand substrate specificity of PTCR and further kinetic properties of enzymes belonging to the SDR superfamily. PMID:24646606

Advances in Understanding of Swift Heavy-Ion Tracks in Complex Ceramics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lang, Maik; Devanathan, Ram; Toulemonde, Marcel

2015-02-01

Tracks produced by swift heavy ions in ceramics are of interest for fundamental science as well as for applications covering different fields such as nanotechnology or fission-track dating of minerals. In the case of pyrochlores with general formula A2B2O7, the track structure and radiation sensitivity shows a clear dependence on the composition. Ion irradiated Gd2Zr2O7, e.g., retains its crystallinity while amorphous tracks are produced in Gd2Ti2O7. Tracks in Ti-containing compositions have a complex morphology consisting of an amorphous core surrounded by a shell of a disordered, defect-fluorite phase. The size of the amorphous core decreases with decreasing energy loss andmore » with increasing Zr content, while the shell thickness seems to be similar over a wide range of energy loss values. The large data set and the complex track structure has made pyrochlore an interesting model system for a general theoretical description of track formation including thermal spike calculations (providing the spatial and temporal evolution of temperature around the ion trajectory) and molecular dynamics (MD) simulations (describing the response of the atomic system).Recent MD advances consider the sudden temperature increase by inserting data from the thermal spike. The combination allows the reproduction of the core-shell track characteristic and sheds light on the early stages of track formation including recrystallization of the molten material produced by the thermal spike.« less

Finite-temperature stress calculations in atomic models using moments of position.

PubMed

Parthasarathy, Ranganathan; Misra, Anil; Ouyang, Lizhi

2018-07-04

Continuum modeling of finite temperature mechanical behavior of atomic systems requires refined description of atomic motions. In this paper, we identify additional kinematical quantities that are relevant for a more accurate continuum description as the system is subjected to step-wise loading. The presented formalism avoids the necessity for atomic trajectory mapping with deformation, provides the definitions of the kinematic variables and their conjugates in real space, and simplifies local work conjugacy. The total work done on an atom under deformation is decomposed into the work corresponding to changing its equilibrium position and work corresponding to changing its second moment about equilibrium position. Correspondingly, we define two kinematic variables: a deformation gradient tensor and a vibration tensor, and derive their stress conjugates, termed here as static and vibration stresses, respectively. The proposed approach is validated using MD simulation in NVT ensembles for fcc aluminum subjected to uniaxial extension. The observed evolution of second moments in the MD simulation with macroscopic deformation is not directly related to the transformation of atomic trajectories through the deformation gradient using generator functions. However, it is noteworthy that deformation leads to a change in the second moment of the trajectories. Correspondingly, the vibration part of the Piola stress becomes particularly significant at high temperature and high tensile strain as the crystal approaches the softening limit. In contrast to the eigenvectors of the deformation gradient, the eigenvectors of the vibration tensor show strong spatial heterogeneity in the vicinity of softening. More importantly, the elliptic distribution of local atomic density transitions to a dumbbell shape, before significant non-affinity in equilibrium positions has occurred.

Finite-temperature stress calculations in atomic models using moments of position

NASA Astrophysics Data System (ADS)

Parthasarathy, Ranganathan; Misra, Anil; Ouyang, Lizhi

2018-07-01

Continuum modeling of finite temperature mechanical behavior of atomic systems requires refined description of atomic motions. In this paper, we identify additional kinematical quantities that are relevant for a more accurate continuum description as the system is subjected to step-wise loading. The presented formalism avoids the necessity for atomic trajectory mapping with deformation, provides the definitions of the kinematic variables and their conjugates in real space, and simplifies local work conjugacy. The total work done on an atom under deformation is decomposed into the work corresponding to changing its equilibrium position and work corresponding to changing its second moment about equilibrium position. Correspondingly, we define two kinematic variables: a deformation gradient tensor and a vibration tensor, and derive their stress conjugates, termed here as static and vibration stresses, respectively. The proposed approach is validated using MD simulation in NVT ensembles for fcc aluminum subjected to uniaxial extension. The observed evolution of second moments in the MD simulation with macroscopic deformation is not directly related to the transformation of atomic trajectories through the deformation gradient using generator functions. However, it is noteworthy that deformation leads to a change in the second moment of the trajectories. Correspondingly, the vibration part of the Piola stress becomes particularly significant at high temperature and high tensile strain as the crystal approaches the softening limit. In contrast to the eigenvectors of the deformation gradient, the eigenvectors of the vibration tensor show strong spatial heterogeneity in the vicinity of softening. More importantly, the elliptic distribution of local atomic density transitions to a dumbbell shape, before significant non-affinity in equilibrium positions has occurred.

A comparison between elastic network interpolation and MD simulation of 16S ribosomal RNA.

PubMed

Kim, Moon K; Li, Wen; Shapiro, Bruce A; Chirikjian, Gregory S

2003-12-01

In this paper a coarse-grained method called elastic network interpolation (ENI) is used to generate feasible transition pathways between two given conformations of the core central domain of 16S Ribosomal RNA (16S rRNA). The two given conformations are the extremes generated by a molecular dynamics (MD) simulation, which differ from each other by 10A in root-mean-square deviation (RMSD). It takes only several hours to build an ENI pathway on a 1.5GHz Pentium with 512 MB memory, while the MD takes several weeks on high-performance multi-processor servers such as the SGI ORIGIN 2000/2100. It is shown that multiple ENI pathways capture the essential anharmonic motions of millions of timesteps in a particular MD simulation. A coarse-grained normal mode analysis (NMA) is performed on each intermediate ENI conformation, and the lowest 1% of the normal modes (representing about 40 degrees of freedom (DOF)) are used to parameterize fluctuations. This combined ENI/NMA method captures all intermediate conformations in the MD run with 1.5A RMSD on average. In addition, if we restrict attention to the time interval of the MD run between the two extreme conformations, the RMSD between the closest ENI/NMA pathway and the MD results is about 1A. These results may serve as a paradigm for reduced-DOF dynamic simulations of large biological macromolecules as well as a method for the reduced-parameter interpretation of massive amounts of MD data.

Structural and Dynamic Characterization of Mutated Keap1 for Varied Affinity toward Nrf2: A Molecular Dynamics Simulation Study.

PubMed

Cheng, I-Chung; Chen, Ya-Jyun; Ku, Chia-Wei; Huang, Yu-Wen; Yang, Chia-Ning

2015-10-26

Keap1 is an adaptor protein that regulates Nrf2 in response to oxidative stress. Under basal conditions, Nrf2 is negatively regulated through ubiquitination by Keap1. However, upon exposure to oxidative stress, the ubiquitination of Nrf2 is inhibited, resulting in an increased steady-state level of Nrf2 in the nucleus and increased transcription of cytoprotective genes. A gene variant G364C and somatic mutation G430C on Keap1 have recently been reported to substantially impair the Keap1-Nrf2 interaction and to be associated with lung cancer. By contrast, alanine scanning experiments have shown that the mutations S363A, S508A, S555A, and S602A do not affect the ability of Keap1 to bind to Nrf2, regardless of the fact that G364 and G430 are not in contact with Nrf2 whereas the four serine residues are involved in the accommodation of Nrf2 with their hydroxy groups. In this study, molecular dynamics simulations were performed to investigate the structural and dynamic variances among wild-type (WT) Keap1 and the six mutants in unbound form. Principal component analysis of the collected MD trajectories was performed to provide dynamic diversity. Our dynamic and structural observations suggest that the G364C and G430C mutants possess a mobile D385 that moves toward R380, an anchor residue to accommodate an acidic residue in Nrf2, thereby hampering the Keap1-Nrf2 recognition of an electrostatic nature. By contrast, none of the four serine-to-alanine mutants alters the H-bond network formed by the serine backbone to its partner; accordingly, these mutants are almost as intact as the WT structurally and dynamically.

Unraveling Hydrophobic Interactions at the Molecular Scale Using Force Spectroscopy and Molecular Dynamics Simulations.

PubMed

Stock, Philipp; Monroe, Jacob I; Utzig, Thomas; Smith, David J; Shell, M Scott; Valtiner, Markus

2017-03-28

Interactions between hydrophobic moieties steer ubiquitous processes in aqueous media, including the self-organization of biologic matter. Recent decades have seen tremendous progress in understanding these for macroscopic hydrophobic interfaces. Yet, it is still a challenge to experimentally measure hydrophobic interactions (HIs) at the single-molecule scale and thus to compare with theory. Here, we present a combined experimental-simulation approach to directly measure and quantify the sequence dependence and additivity of HIs in peptide systems at the single-molecule scale. We combine dynamic single-molecule force spectroscopy on model peptides with fully atomistic, both equilibrium and nonequilibrium, molecular dynamics (MD) simulations of the same systems. Specifically, we mutate a flexible (GS) 5 peptide scaffold with increasing numbers of hydrophobic leucine monomers and measure the peptides' desorption from hydrophobic self-assembled monolayer surfaces. Based on the analysis of nonequilibrium work-trajectories, we measure an interaction free energy that scales linearly with 3.0-3.4 k B T per leucine. In good agreement, simulations indicate a similar trend with 2.1 k B T per leucine, while also providing a detailed molecular view into HIs. This approach potentially provides a roadmap for directly extracting qualitative and quantitative single-molecule interactions at solid/liquid interfaces in a wide range of fields, including interactions at biointerfaces and adhesive interactions in industrial applications.

Influence of C-terminal tail deletion on structure and stability of hyperthermophile Sulfolobus tokodaii RNase HI.

PubMed

Chen, Lin; Zhang, Ji-Long; Zheng, Qing-Chuan; Chu, Wen-Ting; Xue, Qiao; Zhang, Hong-Xing; Sun, Chia-Chung

2013-06-01

The C-terminus tail (G144-T149) of the hyperthermophile Sulfolobus tokodaii (Sto-RNase HI) plays an important role in this protein's hyperstabilization and may therefore be a good protein stability tag. Detailed understanding of the structural and dynamic effects of C-terminus tail deletion is required for gaining insights into the thermal stability mechanism of Sto-RNase HI. Focused on Sulfolobus tokodaii RNase HI (Sto-RNase HI) and its derivative lacking the C-terminal tail (ΔC6 Sto-RNase HI) (PDB codes: 2EHG and 3ALY), we applied molecular dynamics (MD) simulations at four different temperatures (300, 375, 475, and 500 K) to examine the effect of the C-terminal tail on the hyperstabilization of Sto-RNase HI and to investigate the unfolding process of Sto-RNase HI and ΔC6 Sto-RNase HI. The simulations suggest that the C-terminal tail has significant impact in hyperstabilization of Sto-RNase HI and the unfolding of these two proteins evolves along dissimilar pathways. Essential dynamics analysis indicates that the essential subspaces of the two proteins at different temperatures are non-overlapping within the trajectories and they exhibit different directions of motion. Our work can give important information to understand the three-state folding mechanism of Sto-RNase HI and to offer alternative strategies to improve the protein stability.

An investigation of molecular dynamics simulation and molecular docking: interaction of citrus flavonoids and bovine β-lactoglobulin in focus.

PubMed

Sahihi, M; Ghayeb, Y

2014-08-01

Citrus flavonoids are natural compounds with important health benefits. The study of their interaction with a transport protein, such as bovine β-lactoglobulin (BLG), at the atomic level could be a valuable factor to control their transport to biological sites. In the present study, molecular docking and molecular dynamics simulation methods were used to investigate the interaction of hesperetin, naringenin, nobiletin and tangeretin as citrus flavonoids and BLG as transport protein. The molecular docking results revealed that these flavonoids bind in the internal cavity of BLG and the BLG affinity for binding the flavonoids follows naringenin>hesperetin>tangeretin>nobiletin. The docking results also indicated that the BLG-flavonoid complexes are stabilized through hydrophobic interactions, hydrogen bond interactions and π-π stacking interactions. The analysis of molecular dynamics (MD) simulation trajectories showed that the root mean square deviation (RMSD) of various systems reaches equilibrium and fluctuates around the mean value at various times. Time evolution of the radius of gyration, total solvent accessible surface of the protein and the second structure of protein showed as well that BLG and BLG-flavonoid complexes were stable around 2500ps, and there was not any conformational change as for BLG-flavonoid complexes. Further, the profiles of atomic fluctuations indicated the rigidity of the ligand binding site during the simulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Recursive Factorization of the Inverse Overlap Matrix in Linear-Scaling Quantum Molecular Dynamics Simulations.

PubMed

Negre, Christian F A; Mniszewski, Susan M; Cawkwell, Marc J; Bock, Nicolas; Wall, Michael E; Niklasson, Anders M N

2016-07-12

We present a reduced complexity algorithm to compute the inverse overlap factors required to solve the generalized eigenvalue problem in a quantum-based molecular dynamics (MD) simulation. Our method is based on the recursive, iterative refinement of an initial guess of Z (inverse square root of the overlap matrix S). The initial guess of Z is obtained beforehand by using either an approximate divide-and-conquer technique or dynamical methods, propagated within an extended Lagrangian dynamics from previous MD time steps. With this formulation, we achieve long-term stability and energy conservation even under the incomplete, approximate, iterative refinement of Z. Linear-scaling performance is obtained using numerically thresholded sparse matrix algebra based on the ELLPACK-R sparse matrix data format, which also enables efficient shared-memory parallelization. As we show in this article using self-consistent density-functional-based tight-binding MD, our approach is faster than conventional methods based on the diagonalization of overlap matrix S for systems as small as a few hundred atoms, substantially accelerating quantum-based simulations even for molecular structures of intermediate size. For a 4158-atom water-solvated polyalanine system, we find an average speedup factor of 122 for the computation of Z in each MD step.

Recursive Factorization of the Inverse Overlap Matrix in Linear Scaling Quantum Molecular Dynamics Simulations

DOE PAGES

Negre, Christian F. A; Mniszewski, Susan M.; Cawkwell, Marc Jon; ...

2016-06-06

We present a reduced complexity algorithm to compute the inverse overlap factors required to solve the generalized eigenvalue problem in a quantum-based molecular dynamics (MD) simulation. Our method is based on the recursive iterative re nement of an initial guess Z of the inverse overlap matrix S. The initial guess of Z is obtained beforehand either by using an approximate divide and conquer technique or dynamically, propagated within an extended Lagrangian dynamics from previous MD time steps. With this formulation, we achieve long-term stability and energy conservation even under incomplete approximate iterative re nement of Z. Linear scaling performance ismore » obtained using numerically thresholded sparse matrix algebra based on the ELLPACK-R sparse matrix data format, which also enables e cient shared memory parallelization. As we show in this article using selfconsistent density functional based tight-binding MD, our approach is faster than conventional methods based on the direct diagonalization of the overlap matrix S for systems as small as a few hundred atoms, substantially accelerating quantum-based simulations even for molecular structures of intermediate size. For a 4,158 atom water-solvated polyalanine system we nd an average speedup factor of 122 for the computation of Z in each MD step.« less

Substructured multibody molecular dynamics.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grest, Gary Stephen; Stevens, Mark Jackson; Plimpton, Steven James

2006-11-01

We have enhanced our parallel molecular dynamics (MD) simulation software LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator, lammps.sandia.gov) to include many new features for accelerated simulation including articulated rigid body dynamics via coupling to the Rensselaer Polytechnic Institute code POEMS (Parallelizable Open-source Efficient Multibody Software). We use new features of the LAMMPS software package to investigate rhodopsin photoisomerization, and water model surface tension and capillary waves at the vapor-liquid interface. Finally, we motivate the recipes of MD for practitioners and researchers in numerical analysis and computational mechanics.

Dielectric Relaxation of the Ionic Liquid 1-Ethyl-3-methylimidazolium Ethyl Sulfate: Microwave and Far-IR Properties.

PubMed

Dhumal, Nilesh R; Kiefer, Johannes; Turton, David; Wynne, Klaas; Kim, Hyung J

2017-05-11

Dielectric relaxation of the ionic liquid, 1-ethyl-3-methylimidazolium ethyl sulfate (EMI + ETS - ), is studied using molecular dynamics (MD) simulations. The collective dynamics of polarization arising from cations and anions are examined. Characteristics of the rovibrational and translational components of polarization dynamics are analyzed to understand their respective roles in the microwave and terahertz regions of dielectric relaxation. The MD results are compared with the experimental low-frequency spectrum of EMI + ETS - , obtained via ultrafast optical Kerr effect (OKE) measurements.