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Sample records for all-atom md simulation

  1. Reorientation and Dimerization of the Membrane-Bound Antimicrobial Peptide PGLa from Microsecond All-Atom MD Simulations

    PubMed Central

    Ulmschneider, Jakob P.; Smith, Jeremy C.; Ulmschneider, Martin B.; Ulrich, Anne S.; Strandberg, Erik

    2012-01-01

    The membrane-active antimicrobial peptide PGLa from Xenopus laevis is known from solid-state 2H-, 15N-, and 19F-NMR spectroscopy to occupy two distinct α-helical surface adsorbed states in membranes: a surface-bound S-state with a tilt angle of ∼95° at low peptide/lipid molar ratio (P/L = 1:200), and an obliquely tilted T-state with a tilt angle of 127° at higher peptide concentration (P/L = 1:50). Using a rapid molecular-dynamics insertion protocol in combination with microsecond-scale simulation, we have characterized the structure of both states in detail. As expected, the amphiphilic peptide resides horizontally on the membrane surface in a monomeric form at a low P/L, whereas the T-state is seen in the simulations to be a symmetric antiparallel dimer, with close contacts between small glycine and alanine residues at the interface. The computed tilt angles and azimuthal rotations, as well as the quadrupolar splittings predicted from the simulations agree with the experimental NMR data. The simulations reveal many structural details previously inaccessible, such as the immersion depth of the peptide in the membrane and the packing of the dimerization interface. The study highlights the ability and limitations of current state-of-the-art multimicrosecond all-atom simulations of membrane-active peptides to complement experimental data from solid-state NMR. PMID:22947863

  2. All-atom Simulation of Amyloid Aggregates

    NASA Astrophysics Data System (ADS)

    Berhanu, Workalemahu M.; Alred, Erik J.; Bernhardt, Nathan A.; Hansmann, Ulrich H. E.

    Molecular simulations are now commonly used to complement experiments in the investigation of amyloid formation and their role in human diseases. While various simulations based on enhanced sampling techniques are used in amyloid formation simulations, this article will focus on those using standard atomistic simulations to evaluate the stability of fibril models. Such studies explore the limitations that arise from the choice of force field or polymorphism; and explore the stability of in vivo and in vitro forms of Aβ fibril aggregates, and the role of heterologous seeding as a link between different amyloid diseases.

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

    PubMed Central

    2016-01-01

    Molecular dynamics (MD) simulations of ions (K+, Na+, Ca2+ 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. PMID:27118886

  4. Benchmarking all-atom simulations using hydrogen exchange

    PubMed Central

    Skinner, John J.; Yu, Wookyung; Gichana, Elizabeth K.; Baxa, Michael C.; Hinshaw, James R.; Freed, Karl F.; Sosnick, Tobin R.

    2014-01-01

    Long-time molecular dynamics (MD) simulations 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]. These results indicate that modern force fields can reproduce the energy surface near the native structure. 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 and 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. Moreover, these comparisons provide a general protocol for validating the ability of simulations to accurately capture rare structural fluctuations. PMID:25349413

  5. All-atom simulations of crowding effects on ubiquitin dynamics

    NASA Astrophysics Data System (ADS)

    Abriata, Luciano A.; Spiga, Enrico; Dal Peraro, Matteo

    2013-08-01

    It is well-known that crowded environments affect the stability of proteins, with strong biological and biotechnological implications; however, beyond this, crowding is also expected to affect the dynamic properties of proteins, an idea that is hard to probe experimentally. Here we report on a simulation study aimed at evaluating the effects of crowding on internal protein dynamics, based on fully all-atom descriptions of the protein, the solvent and the crowder. Our model system consists of ubiquitin, a protein whose dynamic features are closely related to its ability to bind to multiple partners, in a 325 g L-1 solution of glucose in water, a condition widely employed in in vitro studies of crowding effects. We observe a slight reduction in loop flexibility accompanied by a dramatic restriction of the conformational space explored in the timescale of the simulations (˜0.5 µs), indicating that crowding slows down collective motions and the rate of exploration of the conformational space. This effect is attributed to the extensive and long-lasting interactions observed between protein residues and glucose molecules throughout the entire protein surface. Potential implications of the observed effects are discussed.

  6. All-atom Multiscale Simulation of Cowpea Chlorotic Mottle Virus Capsid Swelling

    PubMed Central

    Miao, Yinglong; Johnson, John E.; Ortoleva, Peter J.

    2010-01-01

    An all-atom multiscale computational modeling approach, Molecular Dynamics/Order Parameter eXtrapolation (MD/OPX), has recently been developed for simulating large bionanosystems. It accelerates MD simulations and addresses rapid atomistic fluctuations and slowly-varying nanoscale dynamics of bionanosystems simultaneously. With modules added to account for water molecules and ions, MD/OPX is applied to simulate the swelling of cowpea chlorotic mottle virus (CCMV) capsid solvated in a host medium in this study. Simulation results show that the N-terminal arms of capsid proteins undergo large deviations from the initial configurations with their length extended quickly during the early stage of capsid swelling. The capsid swelling is a symmetry-breaking process involving local initiation and front propagation. The capsid swelling rate is ~0.25 nm/ns (npn) during early stage of the simulation and propagation of the structural transition across the capsid is roughly 0.6npn. The system conditions that affect swelling of the capsid are analyzed. Prospects for creating a phase diagram for CCMV capsid swelling and using predictions to guide experiments are discussed. PMID:20695471

  7. All-atom crystal simulations of DNA and RNA duplexes

    PubMed Central

    Liu, Chunmei; Janowski, Pawel A.; Case, David A.

    2014-01-01

    Background Molecular dynamics simulations can complement experimental measures of structure and dynamics of biomolecules. The quality of such simulations can be tested by comparisons to models refined against experimental crystallographic data. Methods We report simulations of a DNA and RNA duplex in their crystalline environment. The calculations mimic the conditions for PDB entries 1D23 [d(CGATCGATCG)2] and 1RNA [(UUAUAUAUAUAUAA)2], and contain 8 unit cells, each with 4 copies of the Watson-Crick duplex; this yields in aggregate 64 µs of duplex sampling for DNA and 16 µs for RNA. Results The duplex structures conform much more closely to the average structure seen in the crystal than do structures extracted from a solution simulation with the same force field. Sequence-dependent variations in helical parameters, and in groove widths, are largely maintained in the crystal structure, but are smoothed out in solution. However, the integrity of the crystal lattice is slowly degraded in both simulations, with the result that the interfaces between chains become heterogeneous. This problem is more severe for the DNA crystal, which has fewer inter-chain hydrogen bond contacts than does the RNA crystal. Conclusions Crystal simulations using current force fields reproduce many features of observed crystal structures, but suffer from a gradual degradation of the integrity of the crystal lattice. General significance The results offer insights into force-field simulations that tests their ability to preserve weak interactions between chains, which will be of importance also in non-crystalline applications that involve binding and recognition. PMID:25255706

  8. All-atom and coarse-grained simulations of the forced unfolding pathways of the SNARE complex.

    PubMed

    Zheng, Wenjun

    2014-07-01

    The SNARE complex, consisting of three proteins (VAMP2, syntaxin, and SNAP-25), is thought to drive membrane fusion by assembling into a four-helix bundle through a zippering process. In support of the above zippering model, a recent single-molecule optical tweezers experiment by Gao et al. revealed a sequential unzipping of SNARE along VAMP2 in the order of the linker domain → the C-terminal domain → the N-terminal domain. To offer detailed structural insights to this unzipping process, we have performed all-atom and coarse-grained steered molecular dynamics (sMD) simulations of the forced unfolding pathways of SNARE using different models and force fields. Our findings are summarized as follows: First, the sMD simulations based on either an all-atom force field (with an implicit solvent model) or a coarse-grained Go model were unable to capture the forced unfolding pathway of SNARE as observed by Gao et al., which may be attributed to insufficient simulation time and inaccurate force fields. Second, the sMD simulations based on a reparameterized coarse-grained model (i.e., modified elastic network model) were able to predict a sequential unzipping of SNARE in good agreement with the findings by Gao et al. The key to this success is to reparameterize the intrahelix and interhelix nonbonded force constants against the pair-wise residue-residue distance fluctuations collected from all-atom MD simulations of SNARE. Therefore, our finding supports the importance of accurately describing the inherent dynamics/flexibility of SNARE (in the absence of force), in order to correctly simulate its unfolding behaviors under force. This study has established a useful computational framework for future studies of the zippering function of SNARE and its perturbations by point mutations with amino-acid level of details, and more generally the forced unfolding pathways of other helix bundle proteins. PMID:24403006

  9. On Using Atomistic Solvent Layers in Hybrid All-Atom/Coarse-Grained Molecular Dynamics Simulations.

    PubMed

    Kuhn, Alexander B; Gopal, Srinivasa M; Schäfer, Lars V

    2015-09-01

    Hybrid all-atom/coarse-grained (AA-CG) simulations in which AA solutes are embedded in a CG environment can provide a significant computational speed-up over conventional fully atomistic simulations and thus alleviate the current length and time scale limitations of molecular dynamics (MD) simulations of large biomolecular systems. On one hand, coarse graining the solvent is particularly appealing, since it typically constitutes the largest part of the simulation system and thus dominates computational cost. On the other hand, retaining atomic-level solvent layers around the solute is desirable for a realistic description of hydrogen bonds and other local solvation effects. Here, we devise and systematically validate fixed resolution AA-CG schemes, both with and without atomistic water layers. To quantify the accuracy and diagnose possible pitfalls, Gibbs free energies of solvation of amino acid side chain analogues were calculated, and the influence of the nature of the CG solvent surrounding (polarizable vs nonpolarizable CG water) and the size of the AA solvent region was investigated. We show that distance restraints to keep the AA solvent around the solute lead to too high of a density in the inner shell. Together with a long-ranged effect due to orientational ordering of water molecules at the AA-CG boundary, this affects solvation free energies. Shifting the onset of the distance restraints slightly away from the central solute significantly improves solvation free energies, down to mean unsigned errors with respect to experiment of 2.3 and 2.6 kJ/mol for the polarizable and nonpolarizable CG water surrounding, respectively. The speed-up of the nonpolarizable model renders it computationally more attractive. The present work thus highlights challenges, and outlines possible solutions, involved with modeling the boundary between different levels of resolution in hybrid AA-CG simulations. PMID:26575936

  10. 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

  11. Temperature-Dependent Conformational Properties of Human Neuronal Calcium Sensor-1 Protein Revealed by All-Atom Simulations.

    PubMed

    Zhu, Yuzhen; Ma, Buyong; Qi, Ruxi; Nussinov, Ruth; Zhang, Qingwen

    2016-04-14

    Neuronal calcium sensor-1 (NCS-1) protein has orthologues from Saccharomyces cerevisiae to human with highly conserved amino acid sequences. NCS-1 is an important factor controlling the animal's response to temperature change. This leads us to investigate the temperature effects on the conformational dynamics of human NCS-1 at 310 and 316 K by all-atom molecular dynamics (MD) simulations and dynamic community network analysis. Four independent 500 ns MD simulations show that secondary structure content at 316 K is similar to that at 310 K, whereas the global protein structure is expanded. Loop 3 (L3) adopts an extended state occuping the hydrophobic crevice, and the number of suboptimal communication paths between residue D176 and V190 is reduced at 316 K. The dynamic community network analysis suggests that the interdomain correlation is weakened, and the intradomain coupling is strengthened at 316 K. The elevated temperature reduces the number of the salt bridges, especially in C-domain. This study suggests that the elevated temperature affects the conformational dynamics of human NCS-1 protein. Comparison of the structural dynamics of R102Q mutant and Δ176-190 truncated NCS-1 suggests that the structural and dynamical response of NCS-1 protein to elevated temperature may be one of its intrinsic functional properties. PMID:27007011

  12. 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.

  13. Picosecond infrared laser-induced all-atom nonequilibrium molecular dynamics simulation of dissociation of viruses.

    PubMed

    Hoang Man, Viet; Van-Oanh, Nguyen-Thi; Derreumaux, Philippe; Li, Mai Suan; Roland, Christopher; Sagui, Celeste; Nguyen, Phuong H

    2016-04-28

    Since the discovery of the plant pathogen tobacco mosaic virus as the first viral entity in the late 1800s, viruses traditionally have been mainly thought of as pathogens for disease-resistances. However, viruses have recently been exploited as nanoplatforms with applications in biomedicine and materials science. To this aim, a large majority of current methods and tools have been developed to improve the physical stability of viral particles, which may be critical to the extreme physical or chemical conditions that viruses may encounter during purification, fabrication processes, storage and use. However, considerably fewer studies are devoted to developing efficient methods to degrade or recycle such enhanced stability biomaterials. With this in mind, we carry out all-atom nonequilibrium molecular dynamics simulation, inspired by the recently developed mid-infrared free-electron laser pulse technology, to dissociate viruses. Adopting the poliovirus as a representative example, we find that the primary step in the dissociation process is due to the strong resonance between the amide I vibrational modes of the virus and the tuned laser frequencies. This process is determined by a balance between the formation and dissociation of the protein shell, reflecting the highly plasticity of the virus. Furthermore, our method should provide a feasible approach to simulate viruses, which is otherwise too expensive for conventional equilibrium all-atom simulations of such very large systems. Our work shows a proof of concept which may open a new, efficient way to cleave or to recycle virus-based materials, provide an extremely valuable tool for elucidating mechanical aspects of viruses, and may well play an important role in future fighting against virus-related diseases. PMID:27071540

  14. A combined coarse-grained and all-atom simulation of TRPV1 channel gating and heat activation

    PubMed Central

    Qin, Feng

    2015-01-01

    The transient receptor potential (TRP) channels act as key sensors of various chemical and physical stimuli in eukaryotic cells. Despite years of study, the molecular mechanisms of TRP channel activation remain unclear. To elucidate the structural, dynamic, and energetic basis of gating in TRPV1 (a founding member of the TRPV subfamily), we performed coarse-grained modeling and all-atom molecular dynamics (MD) simulation based on the recently solved high resolution structures of the open and closed form of TRPV1. Our coarse-grained normal mode analysis captures two key modes of collective motions involved in the TRPV1 gating transition, featuring a quaternary twist motion of the transmembrane domains (TMDs) relative to the intracellular domains (ICDs). Our transition pathway modeling predicts a sequence of structural movements that propagate from the ICDs to the TMDs via key interface domains (including the membrane proximal domain and the C-terminal domain), leading to sequential opening of the selectivity filter followed by the lower gate in the channel pore (confirmed by modeling conformational changes induced by the activation of ICDs). The above findings of coarse-grained modeling are robust to perturbation by lipids. Finally, our MD simulation of the ICD identifies key residues that contribute differently to the nonpolar energy of the open and closed state, and these residues are predicted to control the temperature sensitivity of TRPV1 gating. These computational predictions offer new insights to the mechanism for heat activation of TRPV1 gating, and will guide our future electrophysiology and mutagenesis studies. PMID:25918362

  15. All-atom molecular dynamics simulation studies of fully hydrated gel phase DPPG and DPPE bilayers

    NASA Astrophysics Data System (ADS)

    Pimthon, Jutarat; Willumeit, Regine; Lendlein, Andreas; Hofmann, Dieter

    2009-03-01

    Here in silico lipid membranes are described providing a structural background of the organization of the lipid components of membranes and aiding further biological or biophysical studies. An all-atom molecular dynamics simulations has been performed to investigate structural and dynamical properties of two fully hydrated gel-phase bilayers of 1,2-dipalmitoyl- sn-glycero-3-phosphoglycerol (DPPG) and 1,2-dipalmitoyl- sn-glycero-3-phospho-ethanolamine (DPPE) bilayers at 303 K. The respective starting configuration of lipids in the simulation bilayer unit cells were taken on the basis of scattering data. In both simulations, we found overall reasonably good agreement with the available experimental data (area per lipid, phosphorus-phosphorus distance). The distribution of the water/counterions at the membrane interface, interactions/orientations of lipid headgroups, and hydrocarbon chain organization were extensively studied in terms of pair distribution functions between main structural components of the system. Intra/intermolecular hydrogen bond formation was discussed in detail. The water orientation at the lipid membrane interface was explored thoroughly in terms of dipole moment as a function of the water molecule positions along the membrane, where we found that the counterions changed the orientation of the water at the interface. Special attention has been devoted to the distribution of the sodium counterions around the DPPG headgroup. We found preferential binding of Na + ions to the phosphate oxygen species.

  16. ALMOST: an all atom molecular simulation toolkit for protein structure determination.

    PubMed

    Fu, Biao; Sahakyan, Aleksandr B; Camilloni, Carlo; Tartaglia, Gian Gaetano; Paci, Emanuele; Caflisch, Amedeo; Vendruscolo, Michele; Cavalli, Andrea

    2014-05-30

    Almost (all atom molecular simulation toolkit) is an open source computational package for structure determination and analysis of complex molecular systems including proteins, and nucleic acids. Almost has been designed with two primary goals: to provide tools for molecular structure determination using various types of experimental measurements as conformational restraints, and to provide methods for the analysis and assessment of structural and dynamical properties of complex molecular systems. The methods incorporated in Almost include the determination of structural and dynamical features of proteins using distance restraints derived from nuclear Overhauser effect measurements, orientational restraints obtained from residual dipolar couplings and the structural restraints from chemical shifts. Here, we present the first public release of Almost, highlight the key aspects of its computational design and discuss the main features currently implemented. Almost is available for the most common Unix-based operating systems, including Linux and Mac OS X. Almost is distributed free of charge under the GNU Public License, and is available both as a source code and as a binary executable from the project web site at http://www.open-almost.org. Interested users can follow and contribute to the further development of Almost on http://sourceforge.net/projects/almost. PMID:24676684

  17. Molecular jamming—The cystine slipknot mechanical clamp in all-atom simulations

    NASA Astrophysics Data System (ADS)

    Pepłowski, Łukasz; Sikora, Mateusz; Nowak, Wiesław; Cieplak, Marek

    2011-02-01

    A recent survey of 17 134 proteins has identified a new class of proteins which are expected to yield stretching induced force peaks in the range of 1 nN. Such high force peaks should be due to forcing of a slip-loop through a cystine ring, i.e., by generating a cystine slipknot. The survey has been performed in a simple coarse grained model. Here, we perform all-atom steered molecular dynamics simulations on 15 cystine knot proteins and determine their resistance to stretching. In agreement with previous studies within a coarse grained structure based model, the level of resistance is found to be substantially higher than in proteins in which the mechanical clamp operates through shear. The large stretching forces arise through formation of the cystine slipknot mechanical clamp and the resulting steric jamming. We elucidate the workings of such a clamp in an atomic detail. We also study the behavior of five top strength proteins with the shear-based mechanostability in which no jamming is involved. We show that in the atomic model, the jamming state is relieved by moving one amino acid at a time and there is a choice in the selection of the amino acid that advances the first. In contrast, the coarse grained model also allows for a simultaneous passage of two amino acids.

  18. Molecular jamming--the cystine slipknot mechanical clamp in all-atom simulations.

    PubMed

    Pepłowski, Lukasz; Sikora, Mateusz; Nowak, Wiesław; Cieplak, Marek

    2011-02-28

    A recent survey of 17 134 proteins has identified a new class of proteins which are expected to yield stretching induced force peaks in the range of 1 nN. Such high force peaks should be due to forcing of a slip-loop through a cystine ring, i.e., by generating a cystine slipknot. The survey has been performed in a simple coarse grained model. Here, we perform all-atom steered molecular dynamics simulations on 15 cystine knot proteins and determine their resistance to stretching. In agreement with previous studies within a coarse grained structure based model, the level of resistance is found to be substantially higher than in proteins in which the mechanical clamp operates through shear. The large stretching forces arise through formation of the cystine slipknot mechanical clamp and the resulting steric jamming. We elucidate the workings of such a clamp in an atomic detail. We also study the behavior of five top strength proteins with the shear-based mechanostability in which no jamming is involved. We show that in the atomic model, the jamming state is relieved by moving one amino acid at a time and there is a choice in the selection of the amino acid that advances the first. In contrast, the coarse grained model also allows for a simultaneous passage of two amino acids. PMID:21361557

  19. Local elasticity of strained DNA studied by all-atom simulations

    NASA Astrophysics Data System (ADS)

    Mazur, Alexey K.

    2011-08-01

    Genomic DNA is constantly subjected to various mechanical stresses arising from its biological functions and cell packaging. If the local mechanical properties of DNA change under torsional and tensional stress, the activity of DNA-modifying proteins and transcription factors can be affected and regulated allosterically. To check this possibility, appropriate steady forces and torques were applied in the course of all-atom molecular dynamics simulations of DNA with AT- and GC-alternating sequences. It is found that the stretching rigidity grows with tension as well as twisting. The torsional rigidity is not affected by stretching, but it varies with twisting very strongly, and differently for the two sequences. Surprisingly, for AT-alternating DNA it passes through a minimum with the average twist close to the experimental value in solution. For this fragment, but not for the GC-alternating sequence, the bending rigidity noticeably changes with both twisting and stretching. The results have important biological implications and shed light on earlier experimental observations.

  20. Human Inducible Hsp70: Structures, Dynamics, and Interdomain Communication from All-Atom Molecular Dynamics Simulations.

    PubMed

    Nicolaï, Adrien; Senet, Patrick; Delarue, Patrice; Ripoll, Daniel R

    2010-08-10

    The 70 kDa human heat shock protein is a major molecular chaperone involved in de novo folding of proteins in vivo and refolding of proteins under stress conditions. Hsp70 is related to several "misfolding diseases" and other major pathologies, such as cancer, and is a target for new therapies. Hsp70 is comprised of two main domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal substrate protein binding domain (SBD). The chaperone function of Hsp70 is based on an allosteric mechanism. Binding of ATP in NBD decreases the affinity of the substrate for SBD, and hydrolysis of ATP is promoted by binding of polypeptide segments in the SBD. No complete structure of human Hsp70 is known. Here, we report two models of human Hsp70, constructed by homology with Saccharomyces cerevisiae cochaperone protein Hsp110 (open model) and with Escherichia coli 70 kDa DnaK (closed model) and relaxed for several tens to hundreds of nanoseconds by using all-atom molecular dynamics simulations in explicit solvent. We obtain two stable states, Hsp70 with SBD open and SBD closed, which agree with experimental and structural information for ATP-Hsp70 and ADP-Hsp70, respectively. The dynamics of the transition from the open to closed states is investigated with a coarse-grained model and normal-mode analysis. The results show that the conformational change between the two states can be represented by a relatively small number of collective modes which involved major conformational changes in the two domains. These modes provide a mechanistic representation of the communication between NBD and SBD and allow us to identify subdomains and residues that appear to have a critical role in the conformational change mechanism that guides the chaperoning cycle of Hsp70. PMID:26613502

  1. Lipid receptor S1P₁ activation scheme concluded from microsecond all-atom molecular dynamics simulations.

    PubMed

    Yuan, Shuguang; Wu, Rongliang; Latek, Dorota; Trzaskowski, Bartosz; Filipek, Slawomir

    2013-01-01

    Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator which activates G protein-coupled sphingosine 1-phosphate receptors and thus evokes a variety of cell and tissue responses including lymphocyte trafficking, endothelial development, integrity, and maturation. We performed five all-atom 700 ns molecular dynamics simulations of the sphingosine 1-phosphate receptor 1 (S1P₁) based on recently released crystal structure of that receptor with an antagonist. We found that the initial movements of amino acid residues occurred in the area of highly conserved W269⁶·⁴⁸ in TM6 which is close to the ligand binding location. Those residues located in the central part of the receptor and adjacent to kinks of TM helices comprise of a transmission switch. Side chains movements of those residues were coupled to the movements of water molecules inside the receptor which helped in the gradual opening of intracellular part of the receptor. The most stable parts of the protein were helices TM1 and TM2, while the largest movement was observed for TM7, possibly due to the short intracellular part starting with a helix kink at P⁷·⁵⁰, which might be the first helix to move at the intracellular side. We show for the first time the detailed view of the concerted action of the transmission switch and Trp (W⁶·⁴⁸) rotamer toggle switch leading to redirection of water molecules flow in the central part of the receptor. That event is a prerequisite for subsequent changes in intracellular part of the receptor involving water influx and opening of the receptor structure. PMID:24098103

  2. Dissociation of a Dynamic Protein Complex Studied by All-Atom Molecular Simulations.

    PubMed

    Zhang, Liqun; Borthakur, Susmita; Buck, Matthias

    2016-02-23

    The process of protein complex dissociation remains to be understood at the atomic level of detail. Computers now allow microsecond timescale molecular-dynamics simulations, which make the visualization of such processes possible. Here, we investigated the dissociation process of the EphA2-SHIP2 SAM-SAM domain heterodimer complex using unrestrained all-atom molecular-dynamics simulations. Previous studies on this system have shown that alternate configurations are sampled, that their interconversion can be fast, and that the complex is dynamic by nature. Starting from different NMR-derived structures, mutants were designed to stabilize a subset of configurations by swapping ion pairs across the protein-protein interface. We focused on two mutants, K956D/D1235K and R957D/D1223R, with attenuated binding affinity compared with the wild-type proteins. In contrast to calculations on the wild-type complexes, the majority of simulations of these mutants showed protein dissociation within 2.4 μs. During the separation process, we observed domain rotation and pivoting as well as a translation and simultaneous rolling, typically to alternate and weaker binding interfaces. Several unsuccessful recapturing attempts occurred once the domains were moderately separated. An analysis of protein solvation suggests that the dissociation process correlates with a progressive loss of protein-protein contacts. Furthermore, an evaluation of internal protein dynamics using quasi-harmonic and order parameter analyses indicates that changes in protein internal motions are expected to contribute significantly to the thermodynamics of protein dissociation. Considering protein association as the reverse of the separation process, the initial role of charged/polar interactions is emphasized, followed by changes in protein and solvent dynamics. The trajectories show that protein separation does not follow a single distinct pathway, but suggest that the mechanism of dissociation is common in

  3. Simplified protein models can rival all atom simulations in predicting folding pathways and structure

    PubMed Central

    Adhikari, Aashish N.; Freed, Karl F.; Sosnick, Tobin R.

    2014-01-01

    We demonstrate the ability of simultaneously determining a protein’s folding pathway and structure using a properly formulated model without prior knowledge of the native structure. Our model employs a natural coordinate system for describing proteins and a search strategy inspired by the observation that real proteins fold in a sequential fashion by incrementally stabilizing native-like substructures or "foldons". Comparable folding pathways and structures are obtained for the twelve proteins recently studied using atomistic molecular dynamics simulations [K. Lindorff-Larsen, S. Piana, R.O. Dror, D. E. Shaw, Science 334, 517 (2011)], with our calculations running several orders of magnitude faster. We find that native-like propensities in the unfolded state do not necessarily determine the order of structure formation, a departure from a major conclusion of the MD study. Instead, our results support a more expansive view wherein intrinsic local structural propensities may be enhanced or overridden in the folding process by environmental context. The success of our search strategy validates it as an expedient mechanism for folding both in silico and in vivo. PMID:23889448

  4. Harvesting graphics power for MD simulations

    NASA Astrophysics Data System (ADS)

    van Meel, J.; Arnold, A.; Frenkel, D.; Portegies Zwart, S. F.; Belleman, R.

    2008-05-01

    We discuss an implementation of molecular dynamics (MD) simulations on a graphic processing unit (GPU) in the NVIDIA CUDA language. We tested our code on a modern GPU, the NVIDIA GeForce 8800 GTX. Results for two MD algorithms suitable for short-ranged and long-ranged interactions, and a congruential shift random number generator are presented. The performance of the GPU's is compared to their main processor counterpart. We achieve speedups of up to 40, 80 and 150 fold, respectively. With the latest generation of GPU's one can run standard MD simulations at 107 flops/s.

  5. Insight into the Properties of Cardiolipin Containing Bilayers from Molecular Dynamics Simulations, Using a Hybrid All-Atom/United-Atom Force Field.

    PubMed

    Aguayo, Daniel; González-Nilo, Fernando D; Chipot, Christophe

    2012-05-01

    Simulation of three models of cardiolipin (CL) containing membranes using a new set of parameters for tetramyristoyl and tetraoleoyl CLs has been developed in the framework of the united-atom CHARMM27-UA and the all-atom CHARMM36 force fields with the aim of performing molecular dynamics (MD) simulations of cardiolipin-containing mixed-lipid membranes. The new parameters use a hybrid representation of all-atom head groups in conjunction with implicit-hydrogen united-atom (UA) to describe the oleoyl and myristoyl chains of the CLs, in lieu of the fully atomistic description, thereby allowing longer simulations to be undertaken. The physicochemical properties of the bilayers were determined and compared with previously reported data. Furthermore, using tetramyristoyl CL mixed with POPG and POPE lipids, a mitochondrial membrane was simulated. The results presented here show the different behavior of the bilayers as a result of the lipid composition, where the length of the acyl chain and the conformation of the headgroup can be associated with the mitochondrial membrane properties. The new hybrid CL parameters prove to be well suited for the simulation of the molecular structure of CL-containing bilayers and can be extended to other lipid bilayers composed of CLs with different acyl chains or alternate head groups. PMID:26593668

  6. All-atom simulation study of protein PTH(1-34) by using the Wang-Landau sampling method

    NASA Astrophysics Data System (ADS)

    Kim, Seung-Yeon; Kwak, Wooseop

    2014-12-01

    We perform simulations of the N-terminal 34-residue protein fragment PTH(1-34), consisting of 581 atoms, of the 84-residue human parathyroid hormone by using the all-atom ECEPP/3 force field and the Wang-Landau sampling method. Through a massive high-performance computation, the density of states and the partition function Z( T), as a continuous function of T, are obtained for PTH(1-34). From the continuous partition function Z( T), the partition function zeros of PTH(1-34) are evaluated for the first time. From both the specific heat and the partition function zeros, two characteristic transition temperatures are obtained for the all-atom protein PTH(1-34). The higher transition temperature T 1 and the lower transition temperature T 2 of PTH(1-34) can be interpreted as the collapse temperature T θ and the folding temperature T f , respectively.

  7. Theory and MD Simulation of Polyolefin Blends

    NASA Astrophysics Data System (ADS)

    Curro, John G.; Grest, Gary S.; Jaramillo, Eugenio; Wu, David T.; Li, Huimin

    2004-03-01

    Molecular dynamics (MD) simulations and PRISM theory calculations were carried out on various polyolefin homopolymer and copolymer blends. These polyolefins were modeled at the united atom level at 453K using the TRaPPE potential between pairs of sites. The chi parameters from the simulations were estimated from the structure factors using the random phase approximation (RPA) in analogy with neutron scattering (SANS) experiments. The heats of mixing were computed from both simulation and PRISM theory. The MD simulations predicted temperature dependent chi parameters in good agreement with SANS measurements previously reported on hhPP/PIB, hhPP/PP, and hhPP/PE. PRISM theory calculations on the PE(x)PEE(1-x)/PP blend suggest a miscibility window for a range of copolymer compositions x in agreement with SANS experiments.

  8. Gordon Fullerton in PCA (MD-11) Simulator

    NASA Technical Reports Server (NTRS)

    1998-01-01

    NASA research pilot Gordon Fullerton 'flying' in the MD-11 simulator during the Propulsion Controlled Aircraft (PCA) project. This investigation grew out of the crash of a DC-10 airliner on July 19, 1989, following an explosion in the rear engine which caused the loss of all manual flight controls. The flight crew attempted to control the airliner using only the thrust from the two remaining engines. Although the DC-10 crashed during the landing attempt, 184 of the 296 passengers and crew aboard survived. The PCA effort at the Dryden Flight Research Center grew out of the crash, and attempted to develop a means to successfully land an aircraft using only engine thrust. After more than five years of work, on August 29, 1995, Gordon Fullerton made the first PCA touchdown aboard an MD-11 airliner (a later version of the DC-10). The concept was further refined over the years that followed this first landing. Simulators were essential ingredients of the PCA development process. The feasibility of the concept was first tested with an F-15 simulator, then the results of actual flight tests in an F-15 were incorporated back into the simulator. Additional simulations were run on the Boeing 720 airliner simulator used in the Controlled Impact Demonstration project. After the MD-11 test landings, Boeing 747 and 757 simulators tested a wide range of possible situations. Simulations even helped develop a method of landing an airliner if it lost its complete hydraulic system as well as a wing engine, by transferring fuel to shift the center of gravity toward the working engine. The most extreme procedure was undertaken in a 747 simulator. The aircraft simulated the loss of the hydraulic system at 35,000 feet and rolled upside down. Then, the PCA mode was engaged, the airliner righted itself, leveled its wings, and made an approach nearly identical to that of a normal auto landing.

  9. Molecular insights into diphenylalanine nanotube assembly: all-atom simulations of oligomerization.

    PubMed

    Jeon, Joohyun; Mills, Carolyn E; Shell, M Scott

    2013-04-18

    Self-assembling peptides represent a growing class of inexpensive, environmentally benign, nanostructured materials. In particular, diphenylalanine (FF) self-assembles into nanotubes with remarkable strength and thermal stability that have found use in a wide variety of applications, including as sacrificial templates and scaffolds for structuring inorganic materials and as interfacial "nanoforests" for superhydrophobic surfaces and high-performance supercapacitors and biosensors. However, little is known about the assembly mechanisms of FF nanotubes or the forces underlying their stability. Here, we perform a variety of molecular dynamics simulations on both zwitterionic and capped (uncharged) versions of the FF peptide to understand the early stages of self-assembly. We compare these results to simulations of the proposed nanotube X-ray crystal structure. When comparing the zwitterionic and uncharged FF peptides, we find that, while electrostatic interactions steer the former into more ordered dimers and trimers, the hydrophobic side chain interactions play a strong role in determining the structures of larger oligomers. Simulations of the crystal structure fragment also suggest that the strongest interactions occur between side chains, not between the charged termini that form salt bridges. We conclude that the amphiphilic nature of FF is key to understanding its self-assembly, and that the early precursors to nanotube structures are likely to involve substantial hydrophobic clustering, rather than hexamer ring motifs as has been previously suggested. PMID:23521630

  10. Molecular Dynamics/Order Parameter eXtrapolation (MD/OPX) for Bionanosystem Simulations

    PubMed Central

    Miao, Yinglong; Ortoleva, Peter J.

    2012-01-01

    A multiscale approach, Molecular Dynamics/Order Parameter eXtrapolation (MD/OPX), to the all-atom simulation of large bionanosystems is presented. The approach starts with the introduction of a set of order parameters (OPs) automatically generated with orthogonal polynomials to characterize the nanoscale features of bionanosystems. The OPs are shown to evolve slowly via Newton’s equations and the all-atom multiscale analysis (AMA) developed earlier1 demonstrates the existence of their stochastic dynamics, which serve as the justification for our MD/OPX approach. In MD/OPX, a short MD run estimates the rate of change of the OPs, which is then used to extrapolate the state of the system over time that is much longer than the 10−14 second timescale of fast atomic vibrations and collisions. The approach is implemented in NAMD and demonstrated on cowpea chlorotic mottle virus (CCMV) capsid structural transitions (STs). It greatly accelerates the MD code and its underlying all-atom description of the nanosystems enables the use of a universal inter-atomic force field, avoiding recalibration with each new application as needed for coarse-grained models. PMID:18636559

  11. Elastic properties of dynein motor domain obtained from all-atom molecular dynamics simulations

    PubMed Central

    Kamiya, Narutoshi; Mashimo, Tadaaki; Takano, Yu; Kon, Takahide; Kurisu, Genji; Nakamura, Haruki

    2016-01-01

    Dyneins are large microtubule motor proteins that convert ATP energy to mechanical power. High-resolution crystal structures of ADP-bound cytoplasmic dynein have revealed the organization of the motor domain, comprising the AAA+ ring, the linker, the stalk/strut and the C sequence. Recently, the ADP.vanadate-bound structure, which is similar to the ATP hydrolysis transition state, revealed how the structure of dynein changes upon ATP binding. Although both the ADP- and ATP-bound state structures have been resolved, the dynamic properties at the atomic level remain unclear. In this work, we built two models named ‘the ADP model’ and ‘the ATP model’, where ADP and ATP are bound to AAA1 in the AAA+ ring, respectively, to observe the initial procedure of the structural change from the unprimed to the primed state. We performed 200-ns molecular dynamics simulations for both models and compared their structures and dynamics. The motions of the stalk, consisting of a long coiled coil with a microtubule-binding domain, significantly differed between the two models. The elastic properties of the stalk were analyzed and compared with the experimental results. PMID:27334455

  12. Elastic properties of dynein motor domain obtained from all-atom molecular dynamics simulations.

    PubMed

    Kamiya, Narutoshi; Mashimo, Tadaaki; Takano, Yu; Kon, Takahide; Kurisu, Genji; Nakamura, Haruki

    2016-08-01

    Dyneins are large microtubule motor proteins that convert ATP energy to mechanical power. High-resolution crystal structures of ADP-bound cytoplasmic dynein have revealed the organization of the motor domain, comprising the AAA(+) ring, the linker, the stalk/strut and the C sequence. Recently, the ADP.vanadate-bound structure, which is similar to the ATP hydrolysis transition state, revealed how the structure of dynein changes upon ATP binding. Although both the ADP- and ATP-bound state structures have been resolved, the dynamic properties at the atomic level remain unclear. In this work, we built two models named 'the ADP model' and 'the ATP model', where ADP and ATP are bound to AAA1 in the AAA(+) ring, respectively, to observe the initial procedure of the structural change from the unprimed to the primed state. We performed 200-ns molecular dynamics simulations for both models and compared their structures and dynamics. The motions of the stalk, consisting of a long coiled coil with a microtubule-binding domain, significantly differed between the two models. The elastic properties of the stalk were analyzed and compared with the experimental results. PMID:27334455

  13. Analysis of Ligand-Receptor Association and Intermediate Transfer Rates in Multienzyme Nanostructures with All-Atom Brownian Dynamics Simulations.

    PubMed

    Roberts, Christopher C; Chang, Chia-En A

    2016-08-25

    We present the second-generation GeomBD Brownian dynamics software for determining interenzyme intermediate transfer rates and substrate association rates in biomolecular complexes. Substrate and intermediate association rates for a series of enzymes or biomolecules can be compared between the freely diffusing disorganized configuration and various colocalized or complexed arrangements for kinetic investigation of enhanced intermediate transfer. In addition, enzyme engineering techniques, such as synthetic protein conjugation, can be computationally modeled and analyzed to better understand changes in substrate association relative to native enzymes. Tools are provided to determine nonspecific ligand-receptor association residence times, and to visualize common sites of nonspecific association of substrates on receptor surfaces. To demonstrate features of the software, interenzyme intermediate substrate transfer rate constants are calculated and compared for all-atom models of DNA origami scaffold-bound bienzyme systems of glucose oxidase and horseradish peroxidase. Also, a DNA conjugated horseradish peroxidase enzyme was analyzed for its propensity to increase substrate association rates and substrate local residence times relative to the unmodified enzyme. We also demonstrate the rapid determination and visualization of common sites of nonspecific ligand-receptor association by using HIV-1 protease and an inhibitor, XK263. GeomBD2 accelerates simulations by precomputing van der Waals potential energy grids and electrostatic potential grid maps, and has a flexible and extensible support for all-atom and coarse-grained force fields. Simulation software is written in C++ and utilizes modern parallelization techniques for potential grid preparation and Brownian dynamics simulation processes. Analysis scripts, written in the Python scripting language, are provided for quantitative simulation analysis. GeomBD2 is applicable to the fields of biophysics, bioengineering

  14. Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations.

    PubMed

    Lei, Dongsheng; Rames, Matthew; Zhang, Xing; Zhang, Lei; Zhang, Shengli; Ren, Gang

    2016-07-01

    Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases. PMID:27143480

  15. Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations*

    PubMed Central

    Lei, Dongsheng; Rames, Matthew; Zhang, Xing; Zhang, Lei; Zhang, Shengli; Ren, Gang

    2016-01-01

    Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases. PMID:27143480

  16. Insights into activation and RNA binding of trp RNA-binding attenuation protein (TRAP) through all-atom simulations.

    PubMed

    Murtola, Teemu; Vattulainen, Ilpo; Falck, Emma

    2008-06-01

    Tryptophan biosynthesis in Bacillus stearothermophilus is regulated by a trp RNA binding attenuation protein (TRAP). It is a ring-shaped 11-mer of identical 74 residue subunits. Tryptophan binding pockets are located between adjacent subunits, and tryptophan binding activates TRAP to bind RNA. Here, we report results from all-atom molecular dynamics simulations of the system, complementing existing extensive experimental studies. We focus on two questions. First, we look at the activation mechanism, of which relatively little is known experimentally. We find that the absence of tryptophan allows larger motions close to the tryptophan binding site, and we see indication of a conformational change in the BC loop. However, complete deactivation seems to occur on much longer time scales than the 40 ns studied here. Second, we study the TRAP-RNA interactions. We look at the relative flexibilities of the different bases in the complex and analyze the hydrogen bonds between the protein and RNA. We also study the role of Lys37, Lys56, and Arg58, which have been experimentally identified as essential for RNA binding. Hydrophobic stacking of Lys37 with the nearby RNA base is confirmed, but we do not see direct hydrogen bonding between RNA and the other two residues, in contrast to the crystal structure. Rather, these residues seem to stabilize the RNA-binding surface, and their positive charge may also play a role in RNA binding. Simulations also indicate that TRAP is able to attract RNA nonspecifically, and the interactions are quantified in more detail using binding energy calculations. The formation of the final binding complex is a very slow process: within the simulation time scale of 40 ns, only two guanine bases become bound (and no others), indicating that the binding initiates at these positions. In general, our results are in good agreement with experimental studies, and provide atomic-scale insights into the processes. PMID:18186477

  17. Non-equilibrium all-atom molecular dynamics simulations of free and tethered DNA molecules in nanochannel shear flows

    NASA Astrophysics Data System (ADS)

    Wang, Guan M.; Sandberg, William C.

    2007-04-01

    In order to gain insight into the mechanical and dynamical behaviour of free and tethered short chains of ss/ds DNA molecules in flow, and in parallel to investigate the properties of long chain molecules in flow fields, we have developed a series of quantum and molecular methods to extend the well developed equilibrium software CHARMM to handle non-equilibrium dynamics. These methods have been applied to cases of DNA molecules in shear flows in nanochannels. Biomolecules, both free and wall-tethered, have been simulated in the all-atom style in solvent-filled nanochannels. The new methods were demonstrated by carrying out NEMD simulations of free single-stranded DNA (ssDNA) molecules of 21 bases as well as double-stranded DNA (dsDNA) molecules of 21 base pairs tethered on gold surfaces in an ionic water shear flow. The tethering of the linker molecule (6-mercapto-1-hexanol) to perfect Au(111) surfaces was parametrized based on density functional theory (DFT) calculations. Force field parameters were incorporated into the CHARMM database. Gold surfaces are simulated in a Lennard-Jones style model that was fitted to the Morse potential model of bulk gold. The bonding force of attachment of the DNA molecules to the gold substrate linker molecule was computed to be up to a few nN when the DNA molecules are fully stretched at high shear rates. For the first time, we calculated the relaxation time of DNA molecules in picoseconds (ps) and the hydrodynamic force up to a few nanoNewtons (nN) per base pair in a nanochannel flow. The velocity profiles in the solvent due to the presence of the tethered DNA molecules were found to be nonlinear only at high shear flow rates. Free ssDNA molecules in a shear flow were observed to behave differently from each other depending upon their initial orientation in the flow field. Both free and tethered DNA molecules are clearly observed to be stretching, rotating and relaxing. Methods developed in this initial work can be incorporated

  18. Probing the Huntingtin 1-17 Membrane Anchor on a Phospholipid Bilayer by Using All-Atom Simulations

    PubMed Central

    Côté, Sébastien; Binette, Vincent; Salnikov, Evgeniy S.; Bechinger, Burkhard; Mousseau, Normand

    2015-01-01

    Mislocalization and aggregation of the huntingtin protein are related to Huntington’s disease. Its first exon—more specifically the first 17 amino acids (Htt17)—is crucial for the physiological and pathological functions of huntingtin. It regulates huntingtin’s activity through posttranslational modifications and serves as an anchor to membrane-containing organelles of the cell. Recently, structure and orientation of the Htt17 membrane anchor were determined using a combined solution and solid-state NMR approach. This prompted us to refine this model by investigating the dynamics and thermodynamics of this membrane anchor on a POPC bilayer using all-atom, explicit solvent molecular dynamics and Hamiltonian replica exchange. Our simulations are combined with various experimental measurements to generate a high-resolution atomistic model for the huntingtin Htt17 membrane anchor on a POPC bilayer. More precisely, we observe that the single α-helix structure is more stable in the phospholipid membrane than the NMR model obtained in the presence of dodecylphosphocholine detergent micelles. The resulting Htt17 monomer has its hydrophobic plane oriented parallel to the bilayer surface. Our results further unveil the key residues interacting with the membrane in terms of hydrogen bonds, salt-bridges, and nonpolar contributions. We also observe that Htt17 equilibrates at a well-defined insertion depth and that it perturbs the physical properties—order parameter, thickness, and area per lipid—of the bilayer in a manner that could favor its dimerization. Overall, our observations reinforce and refine the NMR measurements on the Htt17 membrane anchor segment of huntingtin that is of fundamental importance to its biological functions. PMID:25762330

  19. DFT-MD simulations of shocked Xenon

    NASA Astrophysics Data System (ADS)

    Magyar, Rudolph J.; Mattsson, Thomas R.

    2009-03-01

    Xenon is not only a technologically important element used in laser technologies, jet propulsion and dental anesthesia, but it is also arguably the simplest material in which to study the metal-insulator transition at high pressure. Because of its closed shell electronic configuration, Xenon is often assumed to be chemically inert, interacting almost entirely through the van der Waals interaction, and at liquid density, is typically modeled well using Leonard-Jones potentials. However, such modeling has a limited range of validity as Xenon is known to form compounds at normal conditions and likely exhibits considerably more chemistry at higher densities when hybridization of occupied orbitals becomes significant. In this talk, we present DFT-MD simulations of shocked liquid Xenon with the goal of developing an improved equation of state. The relative importance of the van der Waals interaction compared to other Coulomb interactions is considered, and estimates of the relative accuracy of various density functionals are quantified. Sandia is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

  20. A coarse-graining approach for molecular simulation that retains the dynamics of the all-atom reference system by implementing hydrodynamic interactions

    SciTech Connect

    Markutsya, Sergiy; Lamm, Monica H

    2014-11-07

    We report on a new approach for deriving coarse-grained intermolecular forces that retains the frictional contribution that is often discarded by conventional coarse-graining methods. The approach is tested for water and an aqueous glucose solution, and the results from the new implementation for coarse-grained molecular dynamics simulation show remarkable agreement with the dynamics obtained from reference all-atom simulations. The agreement between the structural properties observed in the coarse-grained and all-atom simulations is also preserved. We discuss how this approach may be applied broadly to any existing coarse-graining method where the coarse-grained models are rigorously derived from all-atom reference systems.

  1. Parameterization of backbone flexibility in a coarse-grained force field for proteins (COFFDROP) derived from all-atom explicit-solvent molecular dynamics simulations of all possible two-residue peptides

    PubMed Central

    Frembgen-Kesner, Tamara; Andrews, Casey T.; Li, Shuxiang; Ngo, Nguyet Anh; Shubert, Scott A.; Jain, Aakash; Olayiwola, Oluwatoni; Weishaar, Mitch R.; Elcock, Adrian H.

    2015-01-01

    Recently, we reported the parameterization of a set of coarse-grained (CG) nonbonded potential functions, derived from all-atom explicit-solvent molecular dynamics (MD) simulations of amino acid pairs, and designed for use in (implicit-solvent) Brownian dynamics (BD) simulations of proteins; this force field was named COFFDROP (COarse-grained Force Field for Dynamic Representations Of Proteins). Here, we describe the extension of COFFDROP to include bonded backbone terms derived from fitting to results of explicit-solvent MD simulations of all possible two-residue peptides containing the 20 standard amino acids, with histidine modeled in both its protonated and neutral forms. The iterative Boltzmann inversion (IBI) method was used to optimize new CG potential functions for backbone-related terms by attempting to reproduce angle, dihedral and distance probability distributions generated by the MD simulations. In a simple test of the transferability of the extended force field, the angle, dihedral and distance probability distributions obtained from BD simulations of 56 three-residue peptides were compared to results from corresponding explicit-solvent MD simulations. In a more challenging test of the COFFDROP force field, it was used to simulate eight intrinsically disordered proteins and was shown to quite accurately reproduce the experimental hydrodynamic radii (Rhydro), provided that the favorable nonbonded interactions of the force field were uniformly scaled downwards in magnitude. Overall, the results indicate that the COFFDROP force field is likely to find use in modeling the conformational behavior of intrinsically disordered proteins and multi-domain proteins connected by flexible linkers. PMID:26574429

  2. Direct NOE simulation from long MD trajectories

    NASA Astrophysics Data System (ADS)

    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.

  3. Probing the folded state and mechanical unfolding pathways of T4 lysozyme using all-atom and coarse-grained molecular simulation

    NASA Astrophysics Data System (ADS)

    Zheng, Wenjun; Glenn, Paul

    2015-01-01

    The Bacteriophage T4 Lysozyme (T4L) is a prototype modular protein comprised of an N-terminal and a C-domain domain, which was extensively studied to understand the folding/unfolding mechanism of modular proteins. To offer detailed structural and dynamic insights to the folded-state stability and the mechanical unfolding behaviors of T4L, we have performed extensive equilibrium and steered molecular dynamics simulations of both the wild-type (WT) and a circular permutation (CP) variant of T4L using all-atom and coarse-grained force fields. Our all-atom and coarse-grained simulations of the folded state have consistently found greater stability of the C-domain than the N-domain in isolation, which is in agreement with past thermostatic studies of T4L. While the all-atom simulation cannot fully explain the mechanical unfolding behaviors of the WT and the CP variant observed in an optical tweezers study, the coarse-grained simulations based on the Go model or a modified elastic network model (mENM) are in qualitative agreement with the experimental finding of greater unfolding cooperativity in the WT than the CP variant. Interestingly, the two coarse-grained models predict different structural mechanisms for the observed change in cooperativity between the WT and the CP variant—while the Go model predicts minor modification of the unfolding pathways by circular permutation (i.e., preserving the general order that the N-domain unfolds before the C-domain), the mENM predicts a dramatic change in unfolding pathways (e.g., different order of N/C-domain unfolding in the WT and the CP variant). Based on our simulations, we have analyzed the limitations of and the key differences between these models and offered testable predictions for future experiments to resolve the structural mechanism for cooperative folding/unfolding of T4L.

  4. Probing the folded state and mechanical unfolding pathways of T4 lysozyme using all-atom and coarse-grained molecular simulation

    SciTech Connect

    Zheng, Wenjun Glenn, Paul

    2015-01-21

    The Bacteriophage T4 Lysozyme (T4L) is a prototype modular protein comprised of an N-terminal and a C-domain domain, which was extensively studied to understand the folding/unfolding mechanism of modular proteins. To offer detailed structural and dynamic insights to the folded-state stability and the mechanical unfolding behaviors of T4L, we have performed extensive equilibrium and steered molecular dynamics simulations of both the wild-type (WT) and a circular permutation (CP) variant of T4L using all-atom and coarse-grained force fields. Our all-atom and coarse-grained simulations of the folded state have consistently found greater stability of the C-domain than the N-domain in isolation, which is in agreement with past thermostatic studies of T4L. While the all-atom simulation cannot fully explain the mechanical unfolding behaviors of the WT and the CP variant observed in an optical tweezers study, the coarse-grained simulations based on the Go model or a modified elastic network model (mENM) are in qualitative agreement with the experimental finding of greater unfolding cooperativity in the WT than the CP variant. Interestingly, the two coarse-grained models predict different structural mechanisms for the observed change in cooperativity between the WT and the CP variant—while the Go model predicts minor modification of the unfolding pathways by circular permutation (i.e., preserving the general order that the N-domain unfolds before the C-domain), the mENM predicts a dramatic change in unfolding pathways (e.g., different order of N/C-domain unfolding in the WT and the CP variant). Based on our simulations, we have analyzed the limitations of and the key differences between these models and offered testable predictions for future experiments to resolve the structural mechanism for cooperative folding/unfolding of T4L.

  5. Poly(Ethylene Glycol) in Drug Delivery, Why Does it Work, and Can We do Better? All Atom Molecular Dynamics Simulation Provides Some Answers

    NASA Astrophysics Data System (ADS)

    Bunker, Alex

    We summarize our recent work, using all atom molecular dynamics simulation to study the role of poly(ethylene glycol) (PEG) in drug delivery. We have simulated the drug delivery liposome membrane, in both the Gel and Liquid crystalline states. The simulations of the PEGylated membrane have been carried out in the presence of a physiological concentration of NaCl, and two other salts encountered in physiological conditions, KCL and CaCl2. We also simulated targeting moieties on the PEGylated membrane, comparing the behavior of two targeting moieties. We also simulated PEG with three drug molecules for which it is used as a delivery aid: paclitaxel, piroxicam, and hematoporphyrin. We found that the specific properties of PEG, its solubility in both polar and non-polar solvents, and its acting as a polymer electrolyte, have a significant e_ect on its behavior when used in drug delivery.

  6. Evaluating rotational diffusion from protein MD simulations.

    PubMed

    Wong, Vance; Case, David A

    2008-05-15

    It is now feasible to carry out molecular dynamics simulations of proteins in water that are long compared to the overall tumbling of the molecule. Here, we examine rotational diffusion in four small, globular proteins (ubiquitin, binase, lysozyme, and fragment B3 of protein G) with the TIP3P, TIP4P/EW, and SPC/E water models, in simulations that are 6 to 60 times as long as the mean rotational tumbling time. We describe a method for extracting diffusion tensors from such simulations and compare the results to experimental values extracted from NMR relaxation measurements. The simulation results accurately follow a diffusion equation, even for spherical harmonic correlation functions with l as large as 8. However, the best-fit tensors are significantly different from experiment, especially for the commonly used TIP3P water model. Simulations that are 20 to 100 times longer than the rotational tumbling times are needed for good statistics. A number of residues exhibit internal motions on the nanosecond time scale, but in all cases examined here, a product of internal and overall time-correlation functions matches the total time-correlation function well. PMID:18052365

  7. Variational Optimization of an All-Atom Implicit Solvent Force Field to Match Explicit Solvent Simulation Data.

    PubMed

    Bottaro, Sandro; Lindorff-Larsen, Kresten; Best, Robert B

    2013-12-10

    The development of accurate implicit solvation models with low computational cost is essential for addressing many large-scale biophysical problems. Here, we present an efficient solvation term based on a Gaussian solvent-exclusion model (EEF1) for simulations of proteins in aqueous environment, with the primary aim of having a good overlap with explicit solvent simulations, particularly for unfolded and disordered states - as would be needed for multiscale applications. In order to achieve this, we have used a recently proposed coarse-graining procedure based on minimization of an entropy-related objective function to train the model to reproduce the equilibrium distribution obtained from explicit water simulations. Via this methodology, we have optimized both a charge screening parameter and a backbone torsion term against explicit solvent simulations of an α-helical and a β-stranded peptide. The performance of the resulting effective energy function, termed EEF1-SB, is tested with respect to the properties of folded proteins, the folding of small peptides or fast-folding proteins, and NMR data for intrinsically disordered proteins. The results show that EEF1-SB provides a reasonable description of a wide range of systems, but its key advantage over other methods tested is that it captures very well the structure and dimension of disordered or weakly structured peptides. EEF1-SB is thus a computationally inexpensive (~ 10 times faster than Generalized-Born methods) and transferable approximation for treating solvent effects. PMID:24748852

  8. Isotropic MD simulations of dynamic brittle fracture

    SciTech Connect

    Espanol, P.; Rubio, M.A.; Zuniga, I.

    1996-12-01

    The authors present results obtained by molecular dynamics simulations on the propagation of fast cracks in triangular 2D lattices. Their aim is to simulate Mode 1 fracture of brittle isotropic materials. They propose a force law that respects the isotropy of the material. The code yields the correct imposed sound c{sub {parallel}}, shear c{sub {perpendicular}} and surface V{sub R} wave speeds. Different notch lengths are systematically studied. They observed that initially the cracks are linear and always branch at a particular critical velocity c* {approx} 0.8V{sub R} and that this occurs when the crack tip reaches the position of a front emitted from the initial crack tip and propagating at a speed c = 0.68V{sub R}.

  9. Free-energy analysis of lysozyme-triNAG binding modes with all-atom molecular dynamics simulation combined with the solution theory in the energy representation

    NASA Astrophysics Data System (ADS)

    Takemura, Kazuhiro; Burri, Raghunadha Reddy; Ishikawa, Takeshi; Ishikura, Takakazu; Sakuraba, Shun; Matubayasi, Nobuyuki; Kuwata, Kazuo; Kitao, Akio

    2013-02-01

    We propose a method for calculating the binding free energy of protein-ligand complexes using all-atom molecular dynamics simulation combined with the solution theory in the energy representation. Four distinct modes for the binding of tri-N-acetyl-D-glucosamine (triNAG) to hen egg-white lysozyme were investigated, one from the crystal structure and three generated by docking predictions. The proposed method was demonstrated to be used to distinguish the most plausible binding mode (crystal model) as the lowest binding energy mode.

  10. Evaluation of protein-protein docking model structures using all-atom molecular dynamics simulations combined with the solution theory in the energy representation

    NASA Astrophysics Data System (ADS)

    Takemura, Kazuhiro; Guo, Hao; Sakuraba, Shun; Matubayasi, Nobuyuki; Kitao, Akio

    2012-12-01

    We propose a method to evaluate binding free energy differences among distinct protein-protein complex model structures through all-atom molecular dynamics simulations in explicit water using the solution theory in the energy representation. Complex model structures are generated from a pair of monomeric structures using the rigid-body docking program ZDOCK. After structure refinement by side chain optimization and all-atom molecular dynamics simulations in explicit water, complex models are evaluated based on the sum of their conformational and solvation free energies, the latter calculated from the energy distribution functions obtained from relatively short molecular dynamics simulations of the complex in water and of pure water based on the solution theory in the energy representation. We examined protein-protein complex model structures of two protein-protein complex systems, bovine trypsin/CMTI-1 squash inhibitor (PDB ID: 1PPE) and RNase SA/barstar (PDB ID: 1AY7), for which both complex and monomer structures were determined experimentally. For each system, we calculated the energies for the crystal complex structure and twelve generated model structures including the model most similar to the crystal structure and very different from it. In both systems, the sum of the conformational and solvation free energies tended to be lower for the structure similar to the crystal. We concluded that our energy calculation method is useful for selecting low energy complex models similar to the crystal structure from among a set of generated models.

  11. Density relaxation and particle motion characteristics in a non-ionic deep eutectic solvent (acetamide + urea): time-resolved fluorescence measurements and all-atom molecular dynamics simulations.

    PubMed

    Das, Anuradha; Das, Suman; Biswas, Ranjit

    2015-01-21

    Temperature dependent relaxation dynamics, particle motion characteristics, and heterogeneity aspects of deep eutectic solvents (DESs) made of acetamide (CH3CONH2) and urea (NH2CONH2) have been investigated by employing time-resolved fluorescence measurements and all-atom molecular dynamics simulations. Three different compositions (f) for the mixture [fCH3CONH2 + (1 - f)NH2CONH2] have been studied in a temperature range of 328-353 K which is ∼120-145 K above the measured glass transition temperatures (∼207 K) of these DESs but much lower than the individual melting temperature of either of the constituents. Steady state fluorescence emission measurements using probe solutes with sharply different lifetimes do not indicate any dependence on excitation wavelength in these metastable molten systems. Time-resolved fluorescence anisotropy measurements reveal near-hydrodynamic coupling between medium viscosity and rotation of a dissolved dipolar solute. Stokes shift dynamics have been found to be too fast to be detected by the time-resolution (∼70 ps) employed, suggesting extremely rapid medium polarization relaxation. All-atom simulations reveal Gaussian distribution for particle displacements and van Hove correlations, and significant overlap between non-Gaussian (α2) and new non-Gaussian (γ) heterogeneity parameters. In addition, no stretched exponential relaxations have been detected in the simulated wavenumber dependent acetamide dynamic structure factors. All these results are in sharp contrast to earlier observations for ionic deep eutectics with acetamide [Guchhait et al., J. Chem. Phys. 140, 104514 (2014)] and suggest a fundamental difference in interaction and dynamics between ionic and non-ionic deep eutectic solvent systems. PMID:25612718

  12. Density relaxation and particle motion characteristics in a non-ionic deep eutectic solvent (acetamide + urea): Time-resolved fluorescence measurements and all-atom molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Das, Anuradha; Das, Suman; Biswas, Ranjit

    2015-01-01

    Temperature dependent relaxation dynamics, particle motion characteristics, and heterogeneity aspects of deep eutectic solvents (DESs) made of acetamide (CH3CONH2) and urea (NH2CONH2) have been investigated by employing time-resolved fluorescence measurements and all-atom molecular dynamics simulations. Three different compositions (f) for the mixture [fCH3CONH2 + (1 - f)NH2CONH2] have been studied in a temperature range of 328-353 K which is ˜120-145 K above the measured glass transition temperatures (˜207 K) of these DESs but much lower than the individual melting temperature of either of the constituents. Steady state fluorescence emission measurements using probe solutes with sharply different lifetimes do not indicate any dependence on excitation wavelength in these metastable molten systems. Time-resolved fluorescence anisotropy measurements reveal near-hydrodynamic coupling between medium viscosity and rotation of a dissolved dipolar solute. Stokes shift dynamics have been found to be too fast to be detected by the time-resolution (˜70 ps) employed, suggesting extremely rapid medium polarization relaxation. All-atom simulations reveal Gaussian distribution for particle displacements and van Hove correlations, and significant overlap between non-Gaussian (α2) and new non-Gaussian (γ) heterogeneity parameters. In addition, no stretched exponential relaxations have been detected in the simulated wavenumber dependent acetamide dynamic structure factors. All these results are in sharp contrast to earlier observations for ionic deep eutectics with acetamide [Guchhait et al., J. Chem. Phys. 140, 104514 (2014)] and suggest a fundamental difference in interaction and dynamics between ionic and non-ionic deep eutectic solvent systems.

  13. Density relaxation and particle motion characteristics in a non-ionic deep eutectic solvent (acetamide + urea): Time-resolved fluorescence measurements and all-atom molecular dynamics simulations

    SciTech Connect

    Das, Anuradha; Das, Suman; Biswas, Ranjit

    2015-01-21

    Temperature dependent relaxation dynamics, particle motion characteristics, and heterogeneity aspects of deep eutectic solvents (DESs) made of acetamide (CH{sub 3}CONH{sub 2}) and urea (NH{sub 2}CONH{sub 2}) have been investigated by employing time-resolved fluorescence measurements and all-atom molecular dynamics simulations. Three different compositions (f) for the mixture [fCH{sub 3}CONH{sub 2} + (1 − f)NH{sub 2}CONH{sub 2}] have been studied in a temperature range of 328-353 K which is ∼120-145 K above the measured glass transition temperatures (∼207 K) of these DESs but much lower than the individual melting temperature of either of the constituents. Steady state fluorescence emission measurements using probe solutes with sharply different lifetimes do not indicate any dependence on excitation wavelength in these metastable molten systems. Time-resolved fluorescence anisotropy measurements reveal near-hydrodynamic coupling between medium viscosity and rotation of a dissolved dipolar solute. Stokes shift dynamics have been found to be too fast to be detected by the time-resolution (∼70 ps) employed, suggesting extremely rapid medium polarization relaxation. All-atom simulations reveal Gaussian distribution for particle displacements and van Hove correlations, and significant overlap between non-Gaussian (α{sub 2}) and new non-Gaussian (γ) heterogeneity parameters. In addition, no stretched exponential relaxations have been detected in the simulated wavenumber dependent acetamide dynamic structure factors. All these results are in sharp contrast to earlier observations for ionic deep eutectics with acetamide [Guchhait et al., J. Chem. Phys. 140, 104514 (2014)] and suggest a fundamental difference in interaction and dynamics between ionic and non-ionic deep eutectic solvent systems.

  14. Enhancing MD simulations of proteins using vague and combinatorics information

    NASA Astrophysics Data System (ADS)

    Dill, Ken

    We have developed MELD, a method that `melds' together replica-exchange molecular dynamics simulations with external information. Traditionally, accelerating MD simulations has only been possible by using information that is precise and correct. In contrast, MELD allows us to leverage information that is vague or corrupted. For example, we give generic instructives, such as `make a hydrophobic core', `make good secondary structures', or `search only compact structures'. Normally, such information implies a loss of ability to compute free energies and populations. But, MELD satisfies detailed balance. We show that it can fold small proteins much faster than brute-force MD can, that it gives reasonable populations, and that it can succeed in CASP, the blind protein-structure prediction event.

  15. Structure and Properties of HELICAL CARBON NANOTUBES through MD Simulations

    NASA Astrophysics Data System (ADS)

    Dahiya, Akshay; Verma, Deepti; Gupta, Shakti S.

    Helical Carbon Nanotubes (HCNTs) are coiled 3-valent carbon networks which represent pure carbon helix. Here we study the geometries of two classes: hexagonal helix containing purely polyhex networks and the second class with 5-and 7-membered rings besides hexagons. We followed a model of hexagonal, single wall HCNTs, and determined their relaxed configuration using MD simulations based on Tersoff potential. A race-track like structure is observed in the cross-section of HCNTs upon minimization. For generating class two helix, the adjacency matrix eigenvector's (AME) method is applied which utilizes 3-coordinated tiling of the plane by 5-,6-,and 7-membered ring for the construction of helical structures. The application of the AME method to torusenes is crucial for class two helix generation as it is based on an appropriate choice of bi-lobial eigenvectors triplet which can be selected on the basis of their nodal properties as verified here. After 3-D transformations the final structure was obtained with the help of MM3-potential based MD simulations on Tinker commercial code. The spring constants of HCNTs are computed through MD simulations.

  16. Understanding the mechanism of LCST phase separation of mixed ionic liquids in water by MD simulations.

    PubMed

    Zhao, Yuling; Wang, Huiyong; Pei, Yuanchao; Liu, Zhiping; Wang, Jianji

    2016-08-17

    Recently, it has been found experimentally that two different amino acid ionic liquids (ILs) can be mixed to show unique lowest critical solution temperature (LCST) phase separation in water. However, little is known about the mechanism of phase separation in these IL/water mixtures at the molecular level. In this work, five kinds of amino acid ILs were chosen to study the mechanism of LCST-type phase separation by molecular dynamics (MD) simulations. Toward this end, a series of all-atom MD simulations were carried out on the ternary mixtures consisting of two different ILs and water at different temperatures. The various interaction energies and radial distribution functions (RDFs) were calculated and analyzed for these mixed systems. It was found that for amino acid ILs, the -NH2 or -COOH group of one anion could have a hydrogen bonding interaction with the -COO(-) group of another anion. With the increase of temperature, this kind of hydrogen bonding interaction between anions was strengthened and then the anion-H2O electrostatic interaction was weakened, which led to the LCST-type phase separation of the mixed ILs in water. In addition, a series of MD simulations for [P6668]1[Lys]n[Asp]1-n/H2O systems were also performed to study the effect of the mixing ratio of ILs on phase separation. It was also noted that the experimental critical composition corresponding to the lowest critical solution temperature was well predicted from the total electrostatic interaction energies as a function of mole fraction of [P6668][Lys] in these systems. The conclusions drawn from this study may provide new insight into the LCST-type phase behavior of ILs in water, and motivate further studies on practical applications. PMID:27498928

  17. Improving an all-atom force field.

    PubMed

    Mohanty, Sandipan; Hansmann, U H E

    2007-07-01

    Experimentally well-characterized proteins that are small enough to be computationally tractable provide useful information for refining existing all-atom force fields. This is used by us for reparametrizing a recently developed all-atom force field. Relying on high statistics parallel tempering simulations of a designed 20 residue beta-sheet peptide, we propose incremental changes that improve the force field's range of applicability. PMID:17677516

  18. All-atom simulations and free-energy calculations of coiled-coil peptides with lipid bilayers: binding strength, structural transition, and effect on lipid dynamics.

    PubMed

    Woo, Sun Young; Lee, Hwankyu

    2016-01-01

    Peptides E and K, which are synthetic coiled-coil peptides for membrane fusion, were simulated with lipid bilayers composed of lipids and cholesterols at different ratios using all-atom models. We first calculated free energies of binding from umbrella sampling simulations, showing that both E and K peptides tend to adsorb onto the bilayer surface, which occurs more strongly in the bilayer composed of smaller lipid headgroups. Then, unrestrained simulations show that K peptides more deeply insert into the bilayer with partially retaining the helical structure, while E peptides less insert and predominantly become random coils, indicating the structural transition from helices to random coils, in quantitative agreement with experiments. This is because K peptides electrostatically interact with lipid phosphates, as well as because hydrocarbons of lysines of K peptide are longer than those of glutamic acids of E peptide and thus form stronger hydrophobic interactions with lipid tails. This deeper insertion of K peptide increases the bilayer dynamics and a vacancy below the peptide, leading to the rearrangement of smaller lipids. These findings help explain the experimentally observed or proposed differences in the insertion depth, binding strength, and structural transition of E and K peptides, and support the snorkeling effect. PMID:26926570

  19. All-atom simulations and free-energy calculations of coiled-coil peptides with lipid bilayers: binding strength, structural transition, and effect on lipid dynamics

    PubMed Central

    Woo, Sun Young; Lee, Hwankyu

    2016-01-01

    Peptides E and K, which are synthetic coiled-coil peptides for membrane fusion, were simulated with lipid bilayers composed of lipids and cholesterols at different ratios using all-atom models. We first calculated free energies of binding from umbrella sampling simulations, showing that both E and K peptides tend to adsorb onto the bilayer surface, which occurs more strongly in the bilayer composed of smaller lipid headgroups. Then, unrestrained simulations show that K peptides more deeply insert into the bilayer with partially retaining the helical structure, while E peptides less insert and predominantly become random coils, indicating the structural transition from helices to random coils, in quantitative agreement with experiments. This is because K peptides electrostatically interact with lipid phosphates, as well as because hydrocarbons of lysines of K peptide are longer than those of glutamic acids of E peptide and thus form stronger hydrophobic interactions with lipid tails. This deeper insertion of K peptide increases the bilayer dynamics and a vacancy below the peptide, leading to the rearrangement of smaller lipids. These findings help explain the experimentally observed or proposed differences in the insertion depth, binding strength, and structural transition of E and K peptides, and support the snorkeling effect. PMID:26926570

  20. The Ensemble Folding Kinetics of the FBP28 WW Domain Revealed by an All-atom Monte Carlo Simulation in a Knowledge-based Potential

    PubMed Central

    Xu, Jiabin; Huang, Lei; Shakhnovich, Eugene I.

    2011-01-01

    In this work, we apply a detailed all-atom model with a transferable knowledge-based potential to study the folding kinetics of Formin-Binding protein, FBP28, which is a canonical three-stranded β-sheet WW domain. Replica exchange Monte Carlo (REMC) simulations starting from random coils find native-like (C α RMSD of 2.68Å) lowest energy structure. We also study the folding kinetics of FBP28 WW domain by performing a large number of ab initio Monte Carlo folding simulations. Using these trajectories, we examine the order of formation of two β –hairpins, the folding mechanism of each individual β– hairpin, and transition state ensemble (TSE) of FBP28 WW domain and compare our results with experimental data and previous computational studies. To obtain detailed structural information on the folding dynamics viewed as an ensemble process, we perform a clustering analysis procedure based on graph theory. Further, a rigorous Pfold analysis is used to obtain representative samples of the TSEs showing good quantitative agreement between experimental and simulated Φ values. Our analysis shows that the turn structure between first and second β strands is a partially stable structural motif that gets formed before entering the TSE in FBP28 WW domain and there exist two major pathways for the folding of FBP28 WW domain, which differ in the order and mechanism of hairpin formation. PMID:21365688

  1. All-atom simulations and free-energy calculations of coiled-coil peptides with lipid bilayers: binding strength, structural transition, and effect on lipid dynamics

    NASA Astrophysics Data System (ADS)

    Woo, Sun Young; Lee, Hwankyu

    2016-03-01

    Peptides E and K, which are synthetic coiled-coil peptides for membrane fusion, were simulated with lipid bilayers composed of lipids and cholesterols at different ratios using all-atom models. We first calculated free energies of binding from umbrella sampling simulations, showing that both E and K peptides tend to adsorb onto the bilayer surface, which occurs more strongly in the bilayer composed of smaller lipid headgroups. Then, unrestrained simulations show that K peptides more deeply insert into the bilayer with partially retaining the helical structure, while E peptides less insert and predominantly become random coils, indicating the structural transition from helices to random coils, in quantitative agreement with experiments. This is because K peptides electrostatically interact with lipid phosphates, as well as because hydrocarbons of lysines of K peptide are longer than those of glutamic acids of E peptide and thus form stronger hydrophobic interactions with lipid tails. This deeper insertion of K peptide increases the bilayer dynamics and a vacancy below the peptide, leading to the rearrangement of smaller lipids. These findings help explain the experimentally observed or proposed differences in the insertion depth, binding strength, and structural transition of E and K peptides, and support the snorkeling effect.

  2. Energetics of nonpolar and polar compounds in cationic, anionic, and nonionic micelles studied by all-atom molecular dynamics simulation combined with a theory of solutions.

    PubMed

    Date, Atsushi; Ishizuka, Ryosuke; Matubayasi, Nobuyuki

    2016-05-21

    Energetic analysis was conducted for nonpolar and polar solutes bound in a cationic micelle of dodecyl trimethyl ammonium bromide (DTAB), an anionic micelle of sodium dodecyl sulfate (SDS), and a nonionic micelle of tetraethylene glycol monododecyl ether (Brij30). All-atom molecular dynamics simulation was performed, and the free energies of binding the solutes in the hydrophobic-core and headgroup regions of the micelles were computed using the energy-representation method. It was found in all the micelles examined that aromatic naphthalene is preferably located more outward than aliphatic propane and that the polar solutes are localized at the interface of the hydrophobic and hydrophilic regions. The roles of the surfactant and water were then elucidated by decomposing the free energy into the contributions from the respective species. Water was observed to play a decisive role in determining the binding location of the solute, while the surfactant was found to be more important for the overall stabilization of the solute within the micelle. The effects of attractive and repulsive interactions of the solute with the surfactant and water were further examined, and their competition was analyzed in connection with the preferable location of the solute in the micellar system. PMID:27117093

  3. Effects of Water Models on Binding Affinity: Evidence from All-Atom Simulation of Binding of Tamiflu to A/H5N1 Neuraminidase

    PubMed Central

    Nguyen, Trang Truc; Viet, Man Hoang

    2014-01-01

    The influence of water models SPC, SPC/E, TIP3P, and TIP4P on ligand binding affinity is examined by calculating the binding free energy ΔGbind of oseltamivir carboxylate (Tamiflu) to the wild type of glycoprotein neuraminidase from the pandemic A/H5N1 virus. ΔGbind is estimated by the Molecular Mechanic-Poisson Boltzmann Surface Area method and all-atom simulations with different combinations of these aqueous models and four force fields AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L. It is shown that there is no correlation between the binding free energy and the water density in the binding pocket in CHARMM. However, for three remaining force fields ΔGbind decays with increase of water density. SPC/E provides the lowest binding free energy for any force field, while the water effect is the most pronounced in CHARMM. In agreement with the popular GROMACS recommendation, the binding score obtained by combinations of AMBER-TIP3P, OPLS-TIP4P, and GROMOS-SPC is the most relevant to the experiments. For wild-type neuraminidase we have found that SPC is more suitable for CHARMM than TIP3P recommended by GROMACS for studying ligand binding. However, our study for three of its mutants reveals that TIP3P is presumably the best choice for CHARMM. PMID:24672329

  4. Effect of water on structure and dynamics of [BMIM][PF6] ionic liquid: An all-atom molecular dynamics simulation investigation

    NASA Astrophysics Data System (ADS)

    Sharma, Anirban; Ghorai, Pradip Kr.

    2016-03-01

    Composition dependent structural and dynamical properties of aqueous hydrophobic 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) ionic liquid (IL) have been investigated by using all-atom molecular dynamics simulation. We observe that addition of water does not increase significant number of dissociated ions in the solution over the pure state. As a consequence, self-diffusion coefficient of the cation and anion is comparable to each other at all water concentration similar to that is observed for the pure state. Voronoi polyhedra analysis exhibits strong dependence on the local environment of IL concentration. Void and neck distributions in Voronoi tessellation are approximately Gaussian for pure IL but upon subsequent addition of water, we observe deviation from the Gaussian behaviour with an asymmetric broadening with long tail of exponential decay at large void radius, particularly at higher water concentrations. The increase in void space and neck size at higher water concentration facilitates ionic motion, thus, decreasing dynamical heterogeneity and IL reorientation time and increases self-diffusion coefficient significantly.

  5. Free energetics of carbon nanotube association in aqueous inorganic NaI salt solutions: Temperature effects using all-atom molecular dynamics simulations.

    PubMed

    Ou, Shu-Ching; Cui, Di; Wezowicz, Matthew; Taufer, Michela; Patel, Sandeep

    2015-06-15

    In this study, we examine the temperature dependence of free energetics of nanotube association using graphical processing unit-enabled all-atom molecular dynamics simulations (FEN ZI) with two (10,10) single-walled carbon nanotubes in 3 m NaI aqueous salt solution. Results suggest that the free energy, enthalpy and entropy changes for the association process are all reduced at the high temperature, in agreement with previous investigations using other hydrophobes. Via the decomposition of free energy into individual components, we found that solvent contribution (including water, anion, and cation contributions) is correlated with the spatial distribution of the corresponding species and is influenced distinctly by the temperature. We studied the spatial distribution and the structure of the solvent in different regions: intertube, intratube and the bulk solvent. By calculating the fluctuation of coarse-grained tube-solvent surfaces, we found that tube-water interfacial fluctuation exhibits the strongest temperature dependence. By taking ions to be a solvent-like medium in the absence of water, tube-anion interfacial fluctuation shows similar but weaker dependence on temperature, while tube-cation interfacial fluctuation shows no dependence in general. These characteristics are discussed via the malleability of their corresponding solvation shells relative to the nanotube surface. Hydrogen bonding profiles and tetrahedrality of water arrangement are also computed to compare the structure of solvent in the solvent bulk and intertube region. The hydrophobic confinement induces a relatively lower concentration environment in the intertube region, therefore causing different intertube solvent structures which depend on the tube separation. This study is relevant in the continuing discourse on hydrophobic interactions (as they impact generally a broad class of phenomena in biology, biochemistry, and materials science and soft condensed matter research), and

  6. Free Energetics of Carbon Nanotube Association in Aqueous Inorganic NaI Salt Solutions: Temperature Effects using All-Atom Molecular Dynamics Simulations

    PubMed Central

    Ou, Shu-Ching; Cui, Di; Wezowicz, Matthew; Taufer, Michela; Patel, Sandeep

    2015-01-01

    In this study we examine the temperature dependence of free energetics of nanotube association by using GPU-enabled all-atom molecular dynamics simulations (FEN ZI) with two (10,10) single-walled carbon nanotubes in 3 m NaI aqueous salt solution. Results suggest that the free energy, enthalpy and entropy changes for the association process are all reduced at the high temperature, in agreement with previous investigations using other hydrophobes. Via the decomposition of free energy into individual components, we found that solvent contribution (including water, anion and cation contributions) is correlated with the spatial distribution of the corresponding species and is influenced distinctly by the temperature. We studied the spatial distribution and the structure of the solvent in different regions: intertube, intra-tube and the bulk solvent. By calculating the fluctuation of coarse-grained tube-solvent surfaces, we found that tube-water interfacial fluctuation exhibits the strongest temperature dependence. By taking ions to be a solvent-like medium in the absence of water, tube-anion interfacial fluctuation also shows similar but weaker dependence on temperature, while tube-cation interfacial fluctuation shows no dependence in general. These characteristics are discussed via the malleability of their corresponding solvation shells relative to the nanotube surface. Hydrogen bonding profiles and tetrahedrality of water arrangement are also computed to compare the structure of solvent in the solvent bulk and intertube region. The hydrophobic confinement induces a relatively lower concentration environment in the intertube region, therefore causing different intertube solvent structures which depend on the tube separation. This study is relevant in the continuing discourse on hydrophobic interactions (as they impact generally a broad class of phenomena in biology, biochemistry, and materials science and soft condensed matter research), and interpretations of

  7. Plasticity and Failure in Nanocrystalline BCC Metals via MD Simulation

    SciTech Connect

    Rudd, R E

    2010-02-12

    Advances in the ability to generate extremely high pressures in dynamic experiments such as at the National Ignition Facility has motivated the need for special materials optimized for those conditions as well as ways to probe the response of these materials as they are deformed. We need to develop a much deeper understanding of the behavior of materials subjected to high pressure, especially the effect of rate at the extremely high rates encountered in those experiments. Here we use large-scale molecular dynamics (MD) simulations of the high-rate deformation of nanocrystalline tantalum at pressures less than 100 GPa to investigate the processes associated with plastic deformation for strains up to 100%. We focus on 3D polycrystalline systems with typical grain sizes of 10-20 nm. We also study a rapidly quenched liquid (amorphous solid) tantalum. We apply a constant volume (isochoric), constant temperature (isothermal) shear deformation over a range of strain rates, and compute the resulting stress-strain curves to large strains for both uniaxial and biaxial compression. We study the rate dependence and identify plastic deformation mechanisms. The identification of the mechanisms is facilitated through a novel technique that computes the local grain orientation, returning it as a quaternion for each atom. This analysis technique is robust and fast, and has been used to compute the orientations on the fly during our parallel MD simulations on supercomputers. We find both dislocation and twinning processes are important, and they interact in the weak strain hardening in these extremely fine-grained microstructures. We also present some results on void growth in nanocrystalline BCC metals under tension.

  8. Using MD Simulations To Calculate How Solvents Modulate Solubility.

    PubMed

    Liu, Shuai; Cao, Shannon; Hoang, Kevin; Young, Kayla L; Paluch, Andrew S; Mobley, David L

    2016-04-12

    Here, our interest is in predicting solubility in general, and we focus particularly on predicting how the solubility of particular solutes is modulated by the solvent environment. Solubility in general is extremely important, both for theoretical reasons - it provides an important probe of the balance between solute-solute and solute-solvent interactions - and for more practical reasons, such as how to control the solubility of a given solute via modulation of its environment, as in process chemistry and separations. Here, we study how the change of solvent affects the solubility of a given compound. That is, we calculate relative solubilities. We use MD simulations to calculate relative solubility and compare our calculated values with experiment as well as with results from several other methods, SMD and UNIFAC, the latter of which is commonly used in chemical engineering design. We find that straightforward solubility calculations based on molecular simulations using a general small-molecule force field outperform SMD and UNIFAC both in terms of accuracy and coverage of the relevant chemical space. PMID:26878198

  9. Multiscale MD Simulations of Folding Dynamics and Mobility of Beta-Amyloid Peptide on Lipid Bilayer Surfaces

    NASA Astrophysics Data System (ADS)

    van Tilburg, Scott; Cheng, Kelvin

    2013-03-01

    Early interaction events of beta-amyloid peptides with the neuronal membranes play a key role in the pathogenesis of Alzheimer's disease. We have used multiscale Molecular Dynamics (MD) simulations to study the protein folding dynamics and lateral mobility of beta-amyloid protein on the cholesterol-enriched and -depleted lipid nano-domains. Several independent simulation replicates of all-atom and coarse-grained MD simulations of beta-amyloid on different lipid bilayer nano-domains have been generated. Using Define Secondary Structure of Proteins (DSSP) algorithm and mean-square-distance (MSD) analysis, the protein conformation and the lateral diffusion coefficients of protein, as well as the lipid and water, were calculated as a function of simulation time up to 200 nanoseconds for atomistic and 2 microseconds for coarse-grained simulations per replicate in different bilayer systems. Subtle differences in the conformation and mobility of the protein were observed in lipid bilayers with and without cholesterol. The structural dynamics information obtained from this work will provide useful insights into understanding the role of protein/lipid interactions in the membrane-associated aggregation of protein on neuronal membranes. HHMI-Trinity University and NIH RC1-GM090897-02

  10. Predicting nematic coupling constants of semiflexible polymers from MD simulations

    NASA Astrophysics Data System (ADS)

    Zhang, Wenlin; Gomez, Enrique; Milner, Scott

    2015-03-01

    The nematic phase is important for many semiflexible polymers. For example, semiflexible polymers with nematic phase can be directly used in many applications, including displays and high strength fibers. The existence of nematic phases also enables better processing of functional semiflexible polymers including conducting conjugated polymers. The nematic coupling constant α, together with the chain stiffness κ, governs chain alignment and the isotropic-to-nematic (IN) transition temperature TIN for semiflexible polymers. For many semiflexible chains, crystallization or thermal degradation can preclude the IN transition, so that TIN cannot be used to estimate α. We combine self-consistent field theory (SCFT) with atomistic molecular dynamics (MD) simulations of semiflexible chains under external tension in the isotropic phase to estimate the nematic coupling constant α. Using our mean-field model, we can obtain the variational free energy of a given polymer, from which the IN transition temperature TIN can be determined. We apply our method to estimate α and TIN of a commonly studied conjugated polymer, poly(3-hexylthiophene) (P3HT). Using the estimated TIN, we predict P3HT is nematic after melting from crystal.

  11. Electroporation of archaeal lipid membranes using MD simulations.

    PubMed

    Polak, Andraž; Tarek, Mounir; Tomšič, Matija; Valant, Janez; Ulrih, Nataša Poklar; Jamnik, Andrej; Kramar, Peter; Miklavčič, Damijan

    2014-12-01

    Molecular dynamics (MD) simulations were used to investigate the electroporation of archaeal lipid bilayers when subjected to high transmembrane voltages induced by a charge imbalance, mimicking therefore millisecond electric pulse experiments. The structural characteristics of the bilayer, a 9:91 mol% 2,3-di-O-sesterterpanyl-sn-glicerol-1-phospho-myo-inositol (AI) and 2,3-di-O-sesterterpanyl-sn-glicerol-1-phospho-1'(2'-O-α-D-glucosyl)-myo-inositol (AGI) were compared to small angle X-ray scattering data. A rather good agreement of the electron density profiles at temperatures of 298 and 343 K was found assessing therefore the validity of the protocols and force fields used in simulations. Compared to dipalmitoyl-phosphatidylcholine (DPPC), the electroporation threshold for the bilayer was found to increase from ~2 V to 4.3 V at 323 K, and to 5.2 V at 298 K. Comparing the electroporation thresholds of the archaeal lipids to those of simple diphytanoyl-phosphatidylcholine (DPhPC) bilayers (2.5 V at 323 K) allowed one to trace back the stability of the membranes to the structure of their lipid head groups. Addition of DPPC in amounts of 50 mol% to the archaeal lipid bilayers decreases their stability and lowers the electroporation thresholds to 3.8 V and 4.1 V at respectively 323 and 298 K. The present study therefore shows how membrane compositions can be selected to cover a wide range of responses to electric stimuli. This provides new routes for the design of liposomes that can be efficiently used as drug delivery carriers, as the selection of their composition allows one to tune in their electroporation threshold for subsequent release of their load. PMID:24461702

  12. Molecular dynamics study of human carbonic anhydrase II in complex with Zn(2+) and acetazolamide on the basis of all-atom force field simulations.

    PubMed

    Wambo, Thierry O; Chen, Liao Y; McHardy, Stanton F; Tsin, Andrew T

    2016-01-01

    Human carbonic anhydrase II (hCAII) represents an ultimate example of the perfectly efficient metalloenzymes, which is capable of catalyzing the hydration of carbon dioxide with a rate approaching the diffusion controlled limit. Extensive experimental studies of this physiologically important metalloprotein have been done to elucidate the fundamentals of its enzymatic actions: what residues anchor the Zn(2+) (or another divalent cation) at the bottom of the binding pocket; how the relevant residues work concertedly with the divalent cation in the reversible conversions between CO2 and HCO3(-); what are the protonation states of the relevant residues and acetazolamide, an inhibitor complexed with hCAII, etc. In this article, we present a detailed computational study on the basis of the all-atom CHARMM force field where Zn(2+) is represented with a simple model of divalent cation using the transferrable parameters available from the current literature. We compute the hydration free energy of Zn(2+), the characteristics of hCAII-Zn(2+) complexation, and the absolute free energy of binding acetazolamide to the hCAII-Zn(2+) complex. In each of these three problems, our computed results agree with the experimental data within the known margin of error without making any case-by-case adjustments to the parameters. The quantitatively accurate insights we gain in this all-atom molecular dynamics study should be helpful in the search and design of more specific inhibitors of this and other carbonic anhydrases. PMID:27232456

  13. 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. PMID:26695055

  14. Study on the structure of Bayer liquor with spectroscopy and MD simulation

    NASA Astrophysics Data System (ADS)

    Chen, Yun; Feng, Qiming; Liu, Kun; Chen, Yuandao; Zhang, Guofan

    2006-05-01

    The combination of spectroscopy analysis (Raman and IR) and MD simulation was applied to explore the structure characters of Bayer liquor. In this work, MD simulation had been used to probe the nature of sodium metal-aluminate ion pairing and its role in the stabilization of clusters. It was found that the maximum concentration of Al(OH)4- occurs in low caustic solutions, but in high caustic solution, the appearance of Al(OH)63- was found. Results of molecular dynamic simulation indicated that the formation of clustering of aluminates in solution, and the clusters stabilized by sodium ions made a contribution to the formation of polyaluminate.

  15. Simulating picosecond X-ray diffraction from crystals using FFT methods on MD output

    SciTech Connect

    Kimminau, Giles; Nagler, Bob; Higginbotham, Andrew; Murphy, William; Wark, Justin; Park, Nigel; Hawreliak, James; Kalantar, Dan; Lorenzana, Hector; Remington, Bruce

    2007-12-12

    Multi-million atom non-equilibrium molecular dynamics (MD) simulations give significant insight into the transient processes that occur under shock compression. Picosecond X-ray diffraction enables the probing of materials on a timescale fast enough to test such effects. In order to simulate diffraction patterns, Fourier methods are required to gain a picture of reciprocal lattice space. We present here results of fast Fourier transforms of atomic coordinates of shocked crystals simulated by MD, and comment on the computing power required as a function of problem size. The relationship between reciprocal space and particular experimental geometries is discussed.

  16. Quantum and all-atom molecular dynamics simulations of protonation and divalent ion binding to phosphatidylinositol 4,5-bisphosphate (PIP2).

    PubMed

    Slochower, David R; Huwe, Peter J; Radhakrishnan, Ravi; Janmey, Paul A

    2013-07-18

    Molecular dynamics calculations have been used to determine the structure of phosphatidylinositol 4,5 bisphosphate (PIP2) at the quantum level and to quantify the propensity for PIP2 to bind two physiologically relevant divalent cations, Mg(2+) and Ca(2+). We performed a geometry optimization at the Hartree-Fock 6-31+G(d) level of theory in vacuum and with a polarized continuum dielectric to determine the conformation of the phospholipid headgroup in the presence of water and its partial charge distribution. The angle between the headgroup and the acyl chains is nearly perpendicular, suggesting that in the absence of other interactions the inositol ring would lie flat along the cytoplasmic surface of the plasma membrane. Next, we employed hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to investigate the protonation state of PIP2 and its interactions with magnesium or calcium. We test the hypothesis suggested by prior experiments that binding of magnesium to PIP2 is mediated by a water molecule that is absent when calcium binds. These results may explain the selective ability of calcium to induce the formation of PIP2 clusters and phase separation from other lipids. PMID:23786273

  17. Quantum and All-Atom Molecular Dynamics Simulations of Protonation and Divalent Ion Binding to Phosphatidylinositol 4,5-Bisphosphate (PIP2)

    PubMed Central

    Slochower, David R.; Huwe, Peter J.; Radhakrishnan, Ravi; Janmey, Paul A.

    2014-01-01

    Molecular dynamics calculations have been used to determine the structure of phosphatidylinositol 4,5 bisphosphate (PIP2) at the quantum level and to quantify the propensity for PIP2 to bind two physiologically relevant divalent cations, Mg2+ and Ca2+. We performed a geometry optimization at the Hartree-Fock 6-31+G(d) level of theory in vacuum and with a polarized continuum dielectric to determine the conformation of the phospholipid headgroup in the presence of water and its partial charge distribution. The angle between the headgroup and the acyl chains is nearly perpendicular, suggesting that in the absence of other interactions, the inositol ring would lie flat along the cytoplasmic surface of the plasma membrane. Next, we employed hybrid quantum mechanics / molecular mechanics (QM/MM) simulations to investigate the protonation state of PIP2 and its interactions with magnesium or calcium. We test the hypothesis suggested by prior experiments that binding of magnesium to PIP2 is mediated by a water molecule that is absent when calcium binds. These results may explain the selective ability of calcium to induce the formation of PIP2 clusters and phase separation from other lipids. PMID:23786273

  18. PuReMD-GPU: A reactive molecular dynamics simulation package for GPUs

    SciTech Connect

    Kylasa, S.B.; Aktulga, H.M.; Grama, A.Y.

    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 we 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.

  19. MD simulations of resistive cooling in HITRAP using GPUs

    SciTech Connect

    Steinmann, J.; Gross, J.; Herfurth, F.; Zwicknagel, G.

    2013-03-19

    In the HITRAP facility at GSI it is planned to store 10{sup 5} highly charged ions up to U{sup 92+} in a cryogenic Penning trap and cool them down to 4 K via electron and resistive cooling. During the cooling process the ion density increases and the characteristics of the ion cloud are increasingly determined by Coulomb interactions. We present a parallel algorithm for the simulation of the resistive cooling for ion clouds in cylindrical Penning traps. For the simulation of the resistive cooling we run an Open Cl code on a single GPU device.

  20. Structure of overheated metal clusters: MD simulation study

    SciTech Connect

    Vorontsov, Alexander

    2015-08-17

    The structure of overheated metal clusters appeared in condensation process was studied by computer simulation techniques. It was found that clusters with size larger than several tens of atoms have three layers: core part, intermediate dense packing layer and a gas- like shell with low density. The change of the size and structure of these layers with the variation of internal energy and the size of cluster is discussed.

  1. Vienna-PTM web server: a toolkit for MD simulations of protein post-translational modifications.

    PubMed

    Margreitter, Christian; Petrov, Drazen; Zagrovic, Bojan

    2013-07-01

    Post-translational modifications (PTMs) play a key role in numerous cellular processes by directly affecting structure, dynamics and interaction networks of target proteins. Despite their importance, our understanding of protein PTMs at the atomistic level is still largely incomplete. Molecular dynamics (MD) simulations, which provide high-resolution insight into biomolecular function and underlying mechanisms, are in principle ideally suited to tackle this problem. However, because of the challenges associated with the development of novel MD parameters and a general lack of suitable computational tools for incorporating PTMs in target protein structures, MD simulations of post-translationally modified proteins have historically lagged significantly behind the studies of unmodified proteins. Here, we present Vienna-PTM web server (http://vienna-ptm.univie.ac.at), a platform for automated introduction of PTMs of choice to protein 3D structures (PDB files) in a user-friendly visual environment. With 256 different enzymatic and non-enzymatic PTMs available, the server performs geometrically realistic introduction of modifications at sites of interests, as well as subsequent energy minimization. Finally, the server makes available force field parameters and input files needed to run MD simulations of modified proteins within the framework of the widely used GROMOS 54A7 and 45A3 force fields and GROMACS simulation package. PMID:23703210

  2. Vienna-PTM web server: a toolkit for MD simulations of protein post-translational modifications

    PubMed Central

    Margreitter, Christian; Petrov, Drazen; Zagrovic, Bojan

    2013-01-01

    Post-translational modifications (PTMs) play a key role in numerous cellular processes by directly affecting structure, dynamics and interaction networks of target proteins. Despite their importance, our understanding of protein PTMs at the atomistic level is still largely incomplete. Molecular dynamics (MD) simulations, which provide high-resolution insight into biomolecular function and underlying mechanisms, are in principle ideally suited to tackle this problem. However, because of the challenges associated with the development of novel MD parameters and a general lack of suitable computational tools for incorporating PTMs in target protein structures, MD simulations of post-translationally modified proteins have historically lagged significantly behind the studies of unmodified proteins. Here, we present Vienna-PTM web server (http://vienna-ptm.univie.ac.at), a platform for automated introduction of PTMs of choice to protein 3D structures (PDB files) in a user-friendly visual environment. With 256 different enzymatic and non-enzymatic PTMs available, the server performs geometrically realistic introduction of modifications at sites of interests, as well as subsequent energy minimization. Finally, the server makes available force field parameters and input files needed to run MD simulations of modified proteins within the framework of the widely used GROMOS 54A7 and 45A3 force fields and GROMACS simulation package. PMID:23703210

  3. 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.

  4. MD Simulation of Particle Orientation in Magnetic Inks

    NASA Astrophysics Data System (ADS)

    Visscher; Günal

    1997-03-01

    We have done molecular-dynamics type simulations of particle re-orientation in a magnetic colloid, by a magnetic field during tape and disk manufacture. The model takes into account switching (in a Stoner- Wohlfarth model) as well as particle translation and rotation in response to magnetic, steric, Brownian, and hydrodynamic drag forces and torques. Magnetic interactions are fully included; hysteresis loops with and without magnetic interaction will be displayed, with corresponding Δ M curves. Images of the network structure at various points of the hysteresis loop will be shown. Further information is available at http:// www.mint.ua.edu/colloids/march.html.

  5. Shock Propagation in Dusty Plasmas by MD Simulations

    NASA Astrophysics Data System (ADS)

    Marciante, Mathieu; Murillo, Michael

    2014-10-01

    The study of shock propagation has become a common way to obtain statistical information on a medium, as one can relate properties of the undisturbed medium to the shock dynamics through the Rankine-Hugoniot (R-H) relations. However, theoretical investigations of shock dynamics are often done through idealized fluid models, which mainly neglect kinetic properties of the medium constituents. Motivated by recent experimental results, we use molecular dynamics simulations to study the propagation of shocks in 2D-dusty plasmas, focusing our attention on the influence of kinetic aspects of the plasma, such as viscosity effects. This study is undertaken on two sides. On a first side, the shock wave is generated by an external electric field acting on the dust particles, giving rise to a shock wave as obtained in a laboratory experiment. On another side, we generate a shock wave by the displacement of a two-dimensional piston at constant velocity, allowing to obtain a steady-state shock wave. Experiment-like shock waves propagate in a highly non-steady state, what should ask for a careful application of the R-H relations in the context of non-steady shocks. Steady-state shock waves show an oscillatory pattern attributed to the dominating dispersive effect of the dusty plasma.

  6. The structure and IR signatures of the arginine-glutamate salt bridge. Insights from the classical MD simulations

    NASA Astrophysics Data System (ADS)

    Vener, M. V.; Odinokov, A. V.; Wehmeyer, C.; Sebastiani, D.

    2015-06-01

    Salt bridges and ionic interactions play an important role in protein stability, protein-protein interactions, and protein folding. Here, we provide the classical MD simulations of the structure and IR signatures of the arginine (Arg)-glutamate (Glu) salt bridge. The Arg-Glu model is based on the infinite polyalanine antiparallel two-stranded β-sheet structure. The 1 μs NPT simulations show that it preferably exists as a salt bridge (a contact ion pair). Bidentate (the end-on and side-on structures) and monodentate (the backside structure) configurations are localized [Donald et al., Proteins 79, 898-915 (2011)]. These structures are stabilized by the short +N-H⋯O- bonds. Their relative stability depends on a force field used in the MD simulations. The side-on structure is the most stable in terms of the OPLS-AA force field. If AMBER ff99SB-ILDN is used, the backside structure is the most stable. Compared with experimental data, simulations using the OPLS all-atom (OPLS-AA) force field describe the stability of the salt bridge structures quite realistically. It decreases in the following order: side-on > end-on > backside. The most stable side-on structure lives several nanoseconds. The less stable backside structure exists a few tenth of a nanosecond. Several short-living species (solvent shared, completely separately solvated ionic groups ion pairs, etc.) are also localized. Their lifetime is a few tens of picoseconds or less. Conformational flexibility of amino acids forming the salt bridge is investigated. The spectral signature of the Arg-Glu salt bridge is the IR-intensive band around 2200 cm-1. It is caused by the asymmetric stretching vibrations of the +N-H⋯O- fragment. Result of the present paper suggests that infrared spectroscopy in the 2000-2800 frequency region may be a rapid and quantitative method for the study of salt bridges in peptides and ionic interactions between proteins. This region is usually not considered in spectroscopic

  7. The structure and IR signatures of the arginine-glutamate salt bridge. Insights from the classical MD simulations

    SciTech Connect

    Vener, M. V.; Odinokov, A. V.; Wehmeyer, C.; Sebastiani, D.

    2015-06-07

    Salt bridges and ionic interactions play an important role in protein stability, protein-protein interactions, and protein folding. Here, we provide the classical MD simulations of the structure and IR signatures of the arginine (Arg)–glutamate (Glu) salt bridge. The Arg-Glu model is based on the infinite polyalanine antiparallel two-stranded β-sheet structure. The 1 μs NPT simulations show that it preferably exists as a salt bridge (a contact ion pair). Bidentate (the end-on and side-on structures) and monodentate (the backside structure) configurations are localized [Donald et al., Proteins 79, 898–915 (2011)]. These structures are stabilized by the short {sup +}N–H⋯O{sup −} bonds. Their relative stability depends on a force field used in the MD simulations. The side-on structure is the most stable in terms of the OPLS-AA force field. If AMBER ff99SB-ILDN is used, the backside structure is the most stable. Compared with experimental data, simulations using the OPLS all-atom (OPLS-AA) force field describe the stability of the salt bridge structures quite realistically. It decreases in the following order: side-on > end-on > backside. The most stable side-on structure lives several nanoseconds. The less stable backside structure exists a few tenth of a nanosecond. Several short-living species (solvent shared, completely separately solvated ionic groups ion pairs, etc.) are also localized. Their lifetime is a few tens of picoseconds or less. Conformational flexibility of amino acids forming the salt bridge is investigated. The spectral signature of the Arg-Glu salt bridge is the IR-intensive band around 2200 cm{sup −1}. It is caused by the asymmetric stretching vibrations of the {sup +}N–H⋯O{sup −} fragment. Result of the present paper suggests that infrared spectroscopy in the 2000–2800 frequency region may be a rapid and quantitative method for the study of salt bridges in peptides and ionic interactions between proteins. This region is

  8. Large-scale MD simulations investigating H plasma interactions with Tungsten surfaces

    NASA Astrophysics Data System (ADS)

    Cusentino, Mary Alice; Wirth, Brian

    2015-11-01

    Tungsten is a prime candidate material for the divertor in future fusion reactors such as ITER. However, the tungsten divertor will need to be able to withstand high fluxes, on the order of 1024m-2s-1, of low energy hydrogen. It is crucial to understand both the tungsten surface response as well as the hydrogen retention and recycling for the divertor region. Molecular dynamics (MD) is a useful tool to study these effects. One issue with MD is that implantation fluxes tend to be very high, on the order of 1027 m-2s-1, due to time and computational limitations. By performing large scale MD on supercomputers, it is possible to reach more realistic fluxes of 1025 m-2s-1. Results will be presented from MD simulations from a 50 nm x 50 nm x 25 nm tungsten box at 1200 K and 2000 K. Hydrogen is implanted every 10 ps based on the 60 eV depth distribution calculated by SRIM, which amounts to a flux of 4 x 1025 m-2s-1. A modified version of the Juslin bond order W-H potential is used to describe the W-H interactions. Preliminary results show an initially high retention of hydrogen that accumulates in a sub-surface region. These simulations provide insight into the early stages of surface deformation as well as hydrogen retention for the tungsten divertor.

  9. Structure of Anion-Conducting Polymers from Waxs and MD Simulations

    NASA Astrophysics Data System (ADS)

    Frisken, Barbara; Tahmasebi, Sepehr; Schibli, Eric; Holdcroft, Steven

    The structure of novel polymers for anion exchange membranes (AEMs) is investigated using wide angle X-ray scattering (WAXS) combined with molecular dynamics (MD) simulations using a united-atom force field model based on the DREIDING force field. The polymers being studied are poly(benzimidazole) (PBI) derivatives including poly(dimethylbenzimidazole) (PDMBI), mesitylene poly(benzimidazole) (mes-PBI), and mesitylene poly(dimethylbenzimidazole) (mes-PDMBI). WAXS reveals an amorphous structure with two main length scales. By comparing simulation results to WAXS data, we attribute features observed in the scattering data to side-to-side spacing between polymer chains and to the parallel-ring stacking of the benzimidazole rings. Overall, we are able to validate the interpretation of scattering data by combining MD simulations and scattering experiments.

  10. 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

  11. Ionic liquid induced dehydration and domain closure in lysozyme: FCS and MD simulation.

    PubMed

    Ghosh, Shirsendu; Parui, Sridip; Jana, Biman; Bhattacharyya, Kankan

    2015-09-28

    Effect of a room temperature ionic liquid (RTIL, [pmim][Br]) on the structure and dynamics of the protein, lysozyme, is investigated by fluorescence correlation spectroscopy (FCS) and molecular dynamic (MD) simulation. The FCS data indicate that addition of the RTIL ([pmim][Br]) leads to reduction in size and faster conformational dynamics of the protein. The hydrodynamic radius (rH) of lysozyme decreases from 18 Å in 0 M [pmim][Br] to 11 Å in 1.5 M [pmim][Br] while the conformational relaxation time decreases from 65 μs to 5 μs. Molecular origin of the collapse (size reduction) of lysozyme in aqueous RTIL is analyzed by MD simulation. The radial distribution function of water, RTIL cation, and RTIL anion from protein clearly indicates that addition of RTIL causes replacement of interfacial water by RTIL cation ([pmim](+)) from the first solvation layer of the protein providing a comparatively dehydrated environment. This preferential solvation of the protein by the RTIL cation extends up to ∼30 Å from the protein surface giving rise to a nanoscopic cage of overall radius 42 Å. In the nanoscopic cage of the RTIL (42 Å), volume fraction of the protein (radius 12 Å) is only about 2%. RTIL anion does not show any preferential solvation near protein surface. Comparison of effective radius obtained from simulation and from FCS data suggests that the "dry" protein (radius 12 Å) alone diffuses in a nanoscopic cage of RTIL (radius 42 Å). MD simulation further reveals a decrease in distance ("domain closure") between the two domains (alpha and beta) of the protein leading to a more compact structure compared to that in the native state. PMID:26429044

  12. Ionic liquid induced dehydration and domain closure in lysozyme: FCS and MD simulation

    NASA Astrophysics Data System (ADS)

    Ghosh, Shirsendu; Parui, Sridip; Jana, Biman; Bhattacharyya, Kankan

    2015-09-01

    Effect of a room temperature ionic liquid (RTIL, [pmim][Br]) on the structure and dynamics of the protein, lysozyme, is investigated by fluorescence correlation spectroscopy (FCS) and molecular dynamic (MD) simulation. The FCS data indicate that addition of the RTIL ([pmim][Br]) leads to reduction in size and faster conformational dynamics of the protein. The hydrodynamic radius (rH) of lysozyme decreases from 18 Å in 0 M [pmim][Br] to 11 Å in 1.5 M [pmim][Br] while the conformational relaxation time decreases from 65 μs to 5 μs. Molecular origin of the collapse (size reduction) of lysozyme in aqueous RTIL is analyzed by MD simulation. The radial distribution function of water, RTIL cation, and RTIL anion from protein clearly indicates that addition of RTIL causes replacement of interfacial water by RTIL cation ([pmim]+) from the first solvation layer of the protein providing a comparatively dehydrated environment. This preferential solvation of the protein by the RTIL cation extends up to ˜30 Å from the protein surface giving rise to a nanoscopic cage of overall radius 42 Å. In the nanoscopic cage of the RTIL (42 Å), volume fraction of the protein (radius 12 Å) is only about 2%. RTIL anion does not show any preferential solvation near protein surface. Comparison of effective radius obtained from simulation and from FCS data suggests that the "dry" protein (radius 12 Å) alone diffuses in a nanoscopic cage of RTIL (radius 42 Å). MD simulation further reveals a decrease in distance ("domain closure") between the two domains (alpha and beta) of the protein leading to a more compact structure compared to that in the native state.

  13. Characterization of the flexible lip regions in bacteriophage lambda lysozyme using MD simulations.

    PubMed

    Smith, Lorna J; van Gunsteren, Wilfred F; Hansen, Niels

    2015-05-01

    The upper and lower lip regions in lysozyme from bacteriophage lambda (λ-lysozyme) are flexible in solution and exhibit two different conformations in crystal structures of the protein. MD simulations have been used to characterize the structure and dynamics of these lip regions, which surround the active site. Ten different simulations have been run including those with restraining to experimental NOE distance and (1)H-(15)N order parameter data. The simulations show that the lower lip region, although undergoing considerable backbone fluctuations, contains two persistent β-strands. In the upper lip region, a wide range of conformations are populated and it is not clear from the available data whether some helical secondary structure is present. The work provides a clear example of the advantages of combining MD simulations with experimental data to obtain a structural interpretation of the latter. In this case, time-averaged order parameter restraining has played an essential role in enabling convergence between two different starting structures and identifying the extent to which flexible regions in solution can contain persistent secondary structure. PMID:25820531

  14. Dynamics of biopolymers on nanomaterials studied by quasielastic neutron scattering and MD simulations

    NASA Astrophysics Data System (ADS)

    Dhindsa, Gurpreet K.

    Neutron scattering has been proved to be a powerful tool to study the dynamics of biological systems under various conditions. This thesis intends to utilize neutron scattering techniques, combining with MD simulations, to develop fundamental understanding of several biologically interesting systems. Our systems include a drug delivery system containing Nanodiamonds with nucleic acid (RNA), and two specific model proteins, beta-Casein and Inorganic Pyrophosphatase (IPPase). RNA and nanodiamond (ND) both are suitable for drug-delivery applications in nano-biotechnology. The architecturally flexible RNA with catalytic functionality forms nanocomposites that can treat life-threatening diseases. The non-toxic ND has excellent mechanical and optical properties and functionalizable high surface area, and thus actively considered for biomedical applications. In this thesis, we utilized two tools, quasielastic neutron scattering (QENS) and Molecular Dynamics Simulations to probe the effect of ND on RNA dynamics. Our work provides fundamental understanding of how hydrated RNA motions are affected in the RNA-ND nanocomposites. From the experimental and Molecular Dynamics Simulation (MD), we found that hydrated RNA motion is faster on ND surface than a freestanding one. MD Simulation results showed that the failure of Stokes Einstein relation results the presence of dynamic heterogeneities in the biomacromolecules. Radial pair distribution function from MD Simulation confirmed that the hydrophilic nature of ND attracts more water than RNA results the de-confinement of RNA on ND. Therefore, RNA exhibits faster motion in the presence of ND than freestanding RNA. In the second project, we studied the dynamics of a natively disordered protein beta-Casein which lacks secondary structures. In this study, the temperature and hydration effects on the dynamics of beta-Casein are explored by Quasielastic Neutron Scattering (QENS). We investigated the mean square displacement (MSD) of

  15. Constant-pH MD Simulations of an Oleic Acid Bilayer.

    PubMed

    Vila-Viçosa, Diogo; Teixeira, Vitor H; Baptista, António M; Machuqueiro, Miguel

    2015-05-12

    Oleic acid is a simple molecule with an aliphatic chain and a carboxylic group whose ionization and, consequently, intermolecular interactions are strongly dependent on the solution pH. The titration curve of these molecules was already obtained using different experimental methods, which have shown the lipid bilayer assemblies to be stable between pH 7.0 and 9.0. In this work, we take advantage of our recent implementations of periodic boundary conditions in Poisson-Boltzmann calculations and ionic strength treatment in simulations of charged lipid bilayers, and we studied the ionization dependent behavior of an oleic acid bilayer using a new extension of the stochastic titration constant-pH MD method. With this new approach, we obtained titration curves that are in good agreement with the experimental data. Also, we were able to estimate the slope of the titration curve from charge fluctuations, which is an important test of thermodynamic consistency for the sampling in a constant-pH MD method. The simulations were performed for ionizations up to 50%, because an experimentally observed macroscopic transition to micelles occurs above this value. As previously seen for a binary mixture of a zwitterionic and an anionic lipid, we were able to reproduce experimental results with simulation boxes usually far from neutrality. This observation further supports the idea that a charged membrane strongly influences the ion distribution in its vicinity and that neutrality is achieved significantly far from the bilayer surface. The good results obtained with this extension of the stochastic titration constant-pH MD method strongly supports its usefulness to sample the coupling between configuration and protonation in these types of biophysical systems. This method stands now as a powerful tool to study more realistic lipid bilayers where pH can influence both the lipids and the solutes interacting with them. PMID:26574431

  16. A gold cyano complex in nitromethane: MD simulation and X-ray diffraction

    NASA Astrophysics Data System (ADS)

    Probst, Michael; Injan, Natcha; Megyes, Tünde; Bako, Imre; Balint, Szabolcz; Limtrakul, Jumras; Nazmutdinov, Renat; Mitev, Pavlin D.; Hermansson, Kersti

    2012-06-01

    The solvation structure around the dicyanoaurate(I) anion (Au(CN)2-) in a dilute nitromethane (CH3NO2) solution is presented from X-ray diffraction measurements and molecular dynamics simulation (NVT ensemble, 460 nitromethane molecules at room temperature). The simulations are based on a new solute-solvent force-field fitted to a training set of quantum-chemically derived interaction energies. Radial distribution functions from experiment and simulation are in good agreement. The solvation structure has been further elucidated from MD data. Several shells can be identified. We obtain a solvation number of 13-17 nitromethane molecules with a strong preference to be oriented with their methyl groups towards the solute.

  17. Mimicking titration experiments with MD simulations: A protocol for the investigation of pH-dependent effects on proteins

    NASA Astrophysics Data System (ADS)

    Socher, Eileen; Sticht, Heinrich

    2016-03-01

    Protein structure and function are highly dependent on the environmental pH. However, the temporal or spatial resolution of experimental approaches hampers direct observation of pH-induced conformational changes at the atomic level. Molecular dynamics (MD) simulation strategies (e.g. constant pH MD) have been developed to bridge this gap. However, one frequent problem is the sampling of unrealistic conformations, which may also lead to poor pKa predictions. To address this problem, we have developed and benchmarked the pH-titration MD (pHtMD) approach, which is inspired by wet-lab titration experiments. We give several examples how the pHtMD protocol can be applied for pKa calculation including peptide systems, Staphylococcus nuclease (SNase), and the chaperone HdeA. For HdeA, pHtMD is also capable of monitoring pH-dependent dimer dissociation in accordance with experiments. We conclude that pHtMD represents a versatile tool for pKa value calculation and simulation of pH-dependent effects in proteins.

  18. Mimicking titration experiments with MD simulations: A protocol for the investigation of pH-dependent effects on proteins

    PubMed Central

    Socher, Eileen; Sticht, Heinrich

    2016-01-01

    Protein structure and function are highly dependent on the environmental pH. However, the temporal or spatial resolution of experimental approaches hampers direct observation of pH-induced conformational changes at the atomic level. Molecular dynamics (MD) simulation strategies (e.g. constant pH MD) have been developed to bridge this gap. However, one frequent problem is the sampling of unrealistic conformations, which may also lead to poor pKa predictions. To address this problem, we have developed and benchmarked the pH-titration MD (pHtMD) approach, which is inspired by wet-lab titration experiments. We give several examples how the pHtMD protocol can be applied for pKa calculation including peptide systems, Staphylococcus nuclease (SNase), and the chaperone HdeA. For HdeA, pHtMD is also capable of monitoring pH-dependent dimer dissociation in accordance with experiments. We conclude that pHtMD represents a versatile tool for pKa value calculation and simulation of pH-dependent effects in proteins. PMID:26936826

  19. Carbon and proton Overhauser DNP from MD simulations and ab initio calculations: TEMPOL in acetone.

    PubMed

    Küçük, Sami Emre; Biktagirov, Timur; Sezer, Deniz

    2015-10-14

    A computational analysis of the Overhauser effect is reported for the proton, methyl carbon, and carbonyl carbon nuclei of liquid acetone doped with the nitroxide radical TEMPOL. A practical methodology for calculating the dynamic nuclear polarization (DNP) coupling factors by accounting for both dipole-dipole and Fermi-contact interactions is presented. The contribution to the dipolar spectral density function of nuclear spins that are not too far from TEMPOL is computed through classical molecular dynamics (MD) simulations, whereas the contribution of distant spins is included analytically. Fermi contacts are obtained by subjecting a few molecules from every MD snapshot to ab initio quantum mechanical calculations. Scalar interaction is found to be an essential part of the (13)C Overhauser DNP. While mostly detrimental to the carbonyl carbon of acetone it is predicted to result in large enhancements of the methyl carbon signal at magnetic fields of 9 T and beyond. In contrast, scalar coupling is shown to be negligible for the protons of acetone. The additional influence of proton polarization on the carbon DNP (three-spin effect) is also analyzed computationally. Its effect, however, is concluded to be practically insignificant for liquid acetone. PMID:26343351

  20. MD simulation of nanoindentation on (001) and (111) surfaces of Ag-Ni multilayers

    NASA Astrophysics Data System (ADS)

    Zhao, Yinbo; Peng, Xianghe; Fu, Tao; Sun, Rong; Feng, Chao; Wang, Zhongchang

    2015-11-01

    We perform MD simulations of the nanoindentation on (001) and (111) surfaces of Ag-Ni multilayers with different modulation periods, and find that both the hardness and maximum force increase with the increase of modulation period, in agreement with the inverse Hall-Petch relation. A prismatic partial dislocation loop is observed in the Ni(111)/Ag(111) sample when the modulation period is relatively large. We also find that misfit dislocation network shows a square shape for the Ni(111)/Ag(111) interface, while a triangle shape for the Ni(001)/Ag(001) interface. The pyramidal defect zones are also observed in Ni(001)/Ag(001) sample, while the intersecting stacking faults are observed in Ni(111)/Ag(111) sample after dislocation traversing interface. The results offer insights into the nanoindentation behaviors in metallic multilayers, which should be important for clarifying strengthening mechanism in many other multilayers.

  1. Dynamics of Molecules Adsorbed in Zeolitic Systems: Neutron Scattering and MD Simulation Studies

    SciTech Connect

    Mitra, S.; Sharma, V. K.; Mukhopadhyay, R.

    2011-07-15

    Zeolites represent a class of technologically important materials because of their characteristic properties of molecular sieving and catalysis, which makes them indispensable in the petroleum industries. While the catalytic properties depend upon many factors, a major role is played by the dynamics of hydrocarbon gases. In order to be able to tailor make these materials for use in industry for catalytic and sieving purposes, it is important to understand the dynamical properties of the guest molecules adsorbed in the zeolitic materials. It is of interest to study the effects of size and shape of guest molecules and also the host zeolitic structure, governing the diffusion mechanism of the adsorbed species. Here we report the results of Quasielastic Neutron Scattering (QENS) and classical molecular dynamics (MD) simulation studies of two hydrocarbons namely acetylene and propylene adsorbed in two structurally different zeolites Na-Y and ZSM-5.

  2. Coupling MD Simulations and X-ray Absorption Spectroscopy to Study Ions in Solution

    SciTech Connect

    Marcos, E. Sanchez; Beret, E. C.; Martinez, J. M.; Pappalardo, R. R.; Ayala, R.; Munoz-Paez, A.

    2007-11-29

    The structure of ionic solutions is a key-point in understanding physicochemical properties of electrolyte solutions. Among the reduced number of experimental techniques which can supply direct information on the ion environment, X-ray Absorption techniques (XAS) have gained importance during the last decades although they are not free of difficulties associated to the data analysis leading to provide reliable structures. Computer simulations of ions in solution is a theoretical alternative to provide information on the solvation structure. Thus, the use of computational chemistry can increase the understanding of these systems although an accurate description of ionic solvation phenomena represents nowadays a significant challenge to theoretical chemistry. We present: (a) the assignment of features in the XANES spectrum to well defined structural motif in the ion environment, (b) MD-based evaluation of EXAFS parameters used in the fitting procedure to make easier the structural resolution, and (c) the use of the agreement between experimental and simulated XANES spectra to help in the choice of a given intermolecular potential for Computer Simulations. Chemical problems examined are: (a) the identification of the second hydration shell in dilute aqueous solutions of highly-charged cations, such as Cr{sup 3+}, Rh{sup 3+}, Ir{sup 3+}, (b) the invisibility by XAS of certain structures characterized by Computer Simulations but exhibiting high dynamical behavior and (c) the solvation of Br{sup -} in acetonitrile.

  3. Carbon Nanotubes in Water: MD Simulations of Internal and External Flow, Self Organization

    NASA Technical Reports Server (NTRS)

    Jaffe, Richard L.; Halicioglu, Timur; Werder, Thomas; Walther, Jens; Koumoutsakos, Petros; Arnold, James (Technical Monitor)

    2001-01-01

    We have developed computational tools, based on particle codes, for molecular dynamics (MD) simulation of carbon nanotubes (CNT) in aqueous environments. The interaction of CNTs with water is envisioned as a prototype for the design of engineering nano-devices, such as artificial sterocillia and molecular biosensors. Large scale simulations involving thousands of water molecules are possible due to our efficient parallel MD code that takes long range electrostatic interactions into account. Since CNTs can be considered as rolled up sheets of graphite, we expect the CNT-water interaction to be similar to the interaction of graphite with water. However, there are fundamental differences between considering graphite and CNTs, since the curvature of CNTs affects their chemical activity and also since capillary effects play an important role for both dynamic and static behaviour of materials inside CNTs. In recent studies Gordillo and Marti described the hydrogen bond structure as well as time dependent properties of water confined in CNTs. We are presenting results from the development of force fields describing the interaction of CNTs and water based on ab-initio quantum mechanical calculations. Furthermore, our results include both water flows external to CNTs and the behaviour of water nanodroplets inside heated CNTs. In the first case (external flows) the hydrophobic behaviour of CNTs is quantified and we analyze structural properties of water in the vicinity of CNTs with diagnostics such as hydrogen bond distribution, water dipole orientation and radial distribution functions. The presence of water leads to attractive forces between CNTs as a result of their hydrophobicity. Through extensive simulations we quantify these attractive forces in terms of the number and separation of the CNT. Results of our simulations involving arrays of CNTs indicate that these exhibit a hydrophobic behaviour that leads to self-organising structures capable of trapping water clusters

  4. Particle Size Effect on Wetting Kinetics of a Nanosuspension Drop: MD Simulations

    NASA Astrophysics Data System (ADS)

    Shi, Baiou; Webb, Edmund

    The behavior of nano-fluids, or fluid suspensions containing nanoparticles, has garnered tremendous attention recently for applications in advanced manufacturing. In our previous results from MD simulations, for a wetting system with different advancing contact angles, cases where self-pinning was observed were compared to cases where it was not and relevant forces on particles at the contact line were computed. To advance this work, the roles of particle size and particle loading are examined. Results presented illustrate how particle size affects spreading kinetics and how this connects to dynamic droplet morphology and relevant forces that exist nearby the contact line region. Furthermore, increased particle size in simulations permits a more detailed investigation of particle/substrate interfacial contributions to behavior observed at the advancing contact line. Based on changes in spreading kinetics with particle size, forces between the particle and liquid front are predicted and compared to those computed from simulations. At high loading, particle/particle interactions become relevant and forces computed between particles entrained to an advancing contact line will be presented.

  5. Estimation of Hydrogen-Exchange Protection Factors from MD Simulation Based on Amide Hydrogen Bonding Analysis.

    PubMed

    Park, In-Hee; Venable, John D; Steckler, Caitlin; Cellitti, Susan E; Lesley, Scott A; Spraggon, Glen; Brock, Ansgar

    2015-09-28

    Hydrogen exchange (HX) studies have provided critical insight into our understanding of protein folding, structure, and dynamics. More recently, hydrogen exchange mass spectrometry (HX-MS) has become a widely applicable tool for HX studies. The interpretation of the wealth of data generated by HX-MS experiments as well as other HX methods would greatly benefit from the availability of exchange predictions derived from structures or models for comparison with experiment. Most reported computational HX modeling studies have employed solvent-accessible-surface-area based metrics in attempts to interpret HX data on the basis of structures or models. In this study, a computational HX-MS prediction method based on classification of the amide hydrogen bonding modes mimicking the local unfolding model is demonstrated. Analysis of the NH bonding configurations from molecular dynamics (MD) simulation snapshots is used to determine partitioning over bonded and nonbonded NH states and is directly mapped into a protection factor (PF) using a logistics growth function. Predicted PFs are then used for calculating deuteration values of peptides and compared with experimental data. Hydrogen exchange MS data for fatty acid synthase thioesterase (FAS-TE) collected for a range of pHs and temperatures was used for detailed evaluation of the approach. High correlation between prediction and experiment for observable fragment peptides is observed in the FAS-TE and additional benchmarking systems that included various apo/holo proteins for which literature data were available. In addition, it is shown that HX modeling can improve experimental resolution through decomposition of in-exchange curves into rate classes, which correlate with prediction from MD. Successful rate class decompositions provide further evidence that the presented approach captures the underlying physical processes correctly at the single residue level. This assessment is further strengthened in a comparison of

  6. Interaction and dynamics of homologous pairing protein 2 (HOP2) and DNA studied by MD simulation

    NASA Astrophysics Data System (ADS)

    Moktan, Hem; Pezza, Roberto; Zhou, Donghua

    2015-03-01

    The homologous pairing protein 2 (Hop2) plays an important role in meiosis and DNA repair. Together with protein Mnd1, Hop2 enhances the strand invasion activity of recombinase Dmc1 by over 30 times, facilitating proper synapsis of homologous chromosomes. We recently determined the NMR structure of the N-terminal domain of Hop2 and proposed a model of Protein-DNA complex based on NMR chemical shift perturbations and mutagenesis studies (Moktan, J Biol Chem 2014 10.1074/jbc.M114.548180). However structure and dynamics of the complex have not been studied at the atomic level yet. Here, we used classical MD simulations to study the interactions between the N-terminal HOP2 and DNA. The simulated results indicate that helix3 (H3) interacts with DNA in major groove and wing1 (W1) interacts mostly in minor groove mainly via direct hydrogen bonds. Also it is found that binding leads to reduced fluctuations in both protein and DNA. Several water bridge interactions have been identified. The residue-wise contributions to the interaction energy were evaluated. Also the functional motion of the protein is analyzed using principal component analysis. The results confirmed the importance of H3 and W1 for the stability of the complex, which is consistent with our previous experimental studies.

  7. Methodologies for the Analysis of Instantaneous Lipid Diffusion in MD Simulations of Large Membrane Systems

    PubMed Central

    Chavent, Matthieu; Reddy, Tyler; Goose, Joseph; Dahl, Anna Caroline E.; Stone, John E.; Jobard, Bruno; Sansom, Mark S.P.

    2014-01-01

    Interactions between lipids and membrane proteins play a key role in determining the nanoscale dynamic and structural properties of biological membranes. Molecular dynamics (MD) simulations provide a valuable tool for studying membrane models, complementing experimental approaches. It is now possible to simulate large membrane systems, such as simplified models of bacterial and viral envelope membranes. Consequently, there is a pressing need to develop tools to visualize and quantify the dynamics of these immense systems, which typically are comprised of millions of particles. To tackle this issue, we have developed visual and quantitative analyses of molecular positions and their velocity field using path line, vector field and streamline techniques. This allows us to highlight large, transient flow-like movements of lipids and to better understand crowding within the lipid bilayer. The current study focuses on visualization and analysis of lipid dynamics. However, the methods are flexible and can be readily applied to e.g. proteins and nanoparticles within large complex membranes. The protocols developed here are readily accessible both as a plugin for the molecular visualization program VMD and as a module for the MDAnalysis library. PMID:25341001

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

    PubMed

    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

  9. 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

  10. QM and QM/MD simulations of the Vinca alkaloids docked to tubulin.

    PubMed

    Kelly, Evan B; Tuszynski, Jack A; Klobukowski, M

    2011-09-01

    The Vinca alkaloids are a class of pharmaceutically relevant binary indole-indoline alkaloids based on and including natural extracts of the periwinkle plant, Catharanthus rosea. Two natural products, vinblastine and vincristine, have been in clinical use as important chemotherapy agents for over four decades. Two semi-synthetic Vinca alkaloids, vindesine and vinorelbine, are currently in investigational chemotherapy programs, and a third semi-synthetic, vinflunine, is in advanced clinical trials. In addition to these five compounds studied in the present work, there are hundreds of other natural and semi-synthetic Vinca alkaloids known, although most are not clinically advantageous. The Vinca alkaloids are anti-mitotic agents that affect the cellular protein tubulin and bind to a specific site known as the Vinca domain located on β-tubulin. While the Vinca domain is well established, the specific binding mode of each drug is not. However, there is much insight into the binding mode and this has provided a strong base of information to begin simulations and to make comparisons against. Complicating the issue, however, is the large size of the Vinca alkaloids and their complex molecular structure, including a rotatable single bond joining the indole and indoline portions of each compound. The differential geometric and tubulin-binding properties of the drugs are not fully known. In the present work, the projection of the potential energy surface on the major torsional angle was calculated at the semi-empirical AM1 level, through in vacuo geometry optimizations. QM/MD simulations were performed, with the drugs at the AM1 level, of each Vinca alkaloid free in TIP3P water, and also bound to β-tubulin. A single equilibrium structure, resembling a known crystallographic vinblastine structure, for the free drugs was found. Further, the 1Z2B crystal structure of vinblastine bound to tubulin appears to be a valid starting point for simulations of all five Vinca alkaloids

  11. Conformation switching of AIM2 PYD domain revealed by NMR relaxation and MD simulation.

    PubMed

    Wang, Haobo; Yang, Lijiang; Niu, Xiaogang

    2016-04-29

    Protein absent in melanoma 2 (AIM2) is a double-strand DNA (ds DNA) sensor mainly located in cytoplasm of cell. It includes one N terminal PYD domain and one C terminal HIN domain. When the ds DNA such as DNA viruses and bacteria entered cytoplasm, the HIN domain of AIM2 will recognize and bind to DNA, and the PYD domain will bind to ASC protein which will result in the formation of AIM2 inflammasome. Three AIM2 PYD domain structures have been solved, but every structure yields a unique conformation around the α3 helix region. To understand why different AIM2 PYD structures show different conformations in this region, we use NMR relaxation techniques to study the backbone dynamics of mouse AIM2 PYD domain and perform molecular dynamics (MD) simulations on both mouse and human AIM2 PYD structures. Our results indicate that this region is highly flexible in both mouse and human AIM2 PYD domains, and the PYD domain may exist as a conformation ensemble in solution. Different environment makes the population vary among pre-existing conformational substrates of the ensemble, which may be the reason why different AIM2 PYD structures were observed under different conditions. Further docking analysis reveals that the conformation switching may be important for the autoinhibition of the AIM2 protein. PMID:27037024

  12. Kinetic Cooperativity, Loop Dynamics, and Allostery from NMR and MD simulations

    NASA Astrophysics Data System (ADS)

    Bruschweiler, Rafael

    The hallmark of glucokinase (GCK), which catalyzes the phosphorylation of glucose during glycolysis, is its kinetic cooperativity whose understanding at atomic detail has remained open since its discovery over 40 years ago. I will discuss how the origin of kinetic cooperativity is rooted in intramolecular protein dynamics using NMR relaxation data of 17 isoleucines distributed over all parts of GCK. Residues of glucose-free GCK located in the small domain display a distinct exchange behavior involving multiple conformers that are substantially populated, whereas in the glucose-bound form these dynamic processes are quenched. The conformational exchange process directly competes with the enzymatic turnover at physiological glucose concentrations, thereby generating the sigmoidal rate dependence that defines kinetic cooperativity. The flexible nature of protein loops and the timescales of their dynamics are critical for many biologically important events at the molecular level, such as protein interaction and recognition processes. Based on a library of proteins, rules about loop dynamics in terms of amplitude and timescales can be derived using molecular dynamics (MD) simulations and NMR data. These rules have been implemented in the new web server ToeLoop (for Timescales Of Every Loop) that permits the prediction of loop dynamics based on an average 3D protein structure (http://spin.ccic.ohio-state.edu/index.php/loop/index).

  13. Distribution of Drug Molecules in Lipid Membranes: Neutron Diffraction and MD Simulations.

    NASA Astrophysics Data System (ADS)

    Boggara, Mohan; Mihailescu, Ella; Krishnamoorti, Ramanan

    2009-03-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Aspirin and Ibuprofen, with chronic usage cause gastro intestinal (GI) toxicity. It has been shown experimentally that NSAIDs pre-associated with phospholipids reduce the GI toxicity and also increase the therapeutic activity of these drugs compared to the unmodified ones. In this study, using neutron diffraction, the DOPC lipid bilayer structure (with and without drug) as well as the distribution of a model NSAID (Ibuprofen) as a function of its position along the membrane normal was obtained at sub-nanometer resolution. It was found that the bilayer thickness reduces as the drug is added. Further, the results are successfully compared with atomistic Molecular Dynamics simulations. Based on this successful comparison and motivated by atomic details from MD, quasi-molecular modeling of the lipid membrane is being carried out and will be presented. The above study is expected to provide an effective methodology to design drug delivery nanoparticles based on a variety of soft condensed matter such as lipids or polymers.

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

    NASA Astrophysics Data System (ADS)

    Ferreira, Tiago Mendes; Ollila, O. H. Samuli; Pigliapochi, Roberta; Dabkowska, Aleksandra P.; Topgaard, Daniel

    2015-01-01

    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 13C or 2H nuclear magnetic resonance (NMR) longitudinal relaxation rates R1, 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 atomically resolved model-free estimation of the C-H bond effective reorientational correlation time τe, 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 13C R1 and R1ρ relaxation rates, as well as 1H-13C 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 τe 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 g1 methylene group of the glycerol backbone. MD simulations performed with a widely used united-atom force-field reproduce the τe-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 τe-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.

  15. 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

    SciTech Connect

    Ferreira, Tiago Mendes; Ollila, O. H. Samuli; Pigliapochi, Roberta; Dabkowska, Aleksandra P.; Topgaard, Daniel

    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 atomically 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

  16. From force-fields to photons: MD simulations of dye-labeled nucleic acids and Monte Carlo modeling of FRET

    NASA Astrophysics Data System (ADS)

    Goldner, Lori

    2012-02-01

    Fluorescence resonance energy transfer (FRET) is a powerful 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 different, faster, time scale. 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 in our study of a 16mer double-stranded RNA. Water is included explicitly in the simulation. Cyanine dyes are attached at either the 3' or 5' ends with a 3 carbon linker, and differences in labeling schemes are discussed.[4pt] Work done in collaboration with Peker Milas, Benjamin D. Gamari, and Louis Parrot.

  17. All-atom force field for molecular dynamics simulations on organotransition metal solids and liquids. Application to M(CO)(n) (M = Cr, Fe, Ni, Mo, Ru, or W) compounds.

    PubMed

    Bernardes, Carlos E S; Canongia Lopes, José N; Minas da Piedade, Manuel E

    2013-10-31

    A previously developed OPLS-based all-atom force field for organometallic compounds was extended to a series of first-, second-, and third-row transition metals based on the study of M(CO)(n) (M = Cr, Fe, Ni, Mo, Ru, or W) complexes. For materials that are solid at ambient temperature and pressure (M = Cr, Mo, W) the validation of the force field was based on reported structural data and on the standard molar enthalpies of sublimation at 298.15 K, experimentally determined by Calvet-drop microcalorimetry using samples corresponding to a specific and well-characterized crystalline phase: Δ(sub)H(m)° = 72.6 ± 0.3 kJ·mol(–1) for Cr(CO)(6), 73.4 ± 0.3 kJ·mol(–1) for Mo(CO)(6), and 77.8 ± 0.3 kJ·mol(–1) for W(CO)(6). For liquids, where problems of polymorphism or phase mixtures are absent, critically analyzed literature data were used. The force field was able to reproduce the volumetric properties of the test set (density and unit cell volume) with an average deviations smaller than 2% and the experimentally determined enthalpies of sublimation and vaporization with an accuracy better than 2.3 kJ·mol(–1). The Lennard-Jones (12-6) potential function parameters used to calculate the repulsive and dispersion contributions of the metals within the framework of the force field were found to be transferable between chromium, iron, and nickel (first row) and between molybdenum and ruthenium (second row). PMID:24079472

  18. An effective all-atom potential for proteins

    PubMed Central

    Irbäck, Anders; Mitternacht, Simon; Mohanty, Sandipan

    2009-01-01

    We describe and test an implicit solvent all-atom potential for simulations of protein folding and aggregation. The potential is developed through studies of structural and thermodynamic properties of 17 peptides with diverse secondary structure. Results obtained using the final form of the potential are presented for all these peptides. The same model, with unchanged parameters, is furthermore applied to a heterodimeric coiled-coil system, a mixed α/β protein and a three-helix-bundle protein, with very good results. The computational efficiency of the potential makes it possible to investigate the free-energy landscape of these 49–67-residue systems with high statistical accuracy, using only modest computational resources by today's standards. PACS Codes: 87.14.E-, 87.15.A-, 87.15.Cc PMID:19356242

  19. Single molecule force spectroscopy data and BD- and MD simulations on the blood protein von Willebrand factor.

    PubMed

    Posch, Sandra; Aponte-Santamaría, Camilo; Schwarzl, Richard; Karner, Andreas; Radtke, Matthias; Gräter, Frauke; Obser, Tobias; König, Gesa; Brehm, Maria A; Gruber, Hermann J; Netz, Roland R; Baldauf, Carsten; Schneppenheim, Reinhard; Tampé, Robert; Hinterdorfer, Peter

    2016-09-01

    We here give information for a deeper understanding of single molecule force spectroscopy (SMFS) data through the example of the blood protein von Willebrand factor (VWF). It is also shown, how fitting of rupture forces versus loading rate profiles in the molecular dynamics (MD) loading-rate range can be used to demonstrate the qualitative agreement between SMFS and MD simulations. The recently developed model by Bullerjahn, Sturm, and Kroy (BSK) was used for this demonstration. Further, Brownian dynamics (BD) simulations, which can be utilized to estimate the lifetimes of intramolecular VWF interactions under physiological shear, are described. For interpretation and discussion of the methods and data presented here, we would like to directly point the reader to the related research paper, "Mutual A domain interactions in the force sensing protein von Willebrand Factor" (Posch et al., 2016) [1]. PMID:27508268

  20. Uncertainty quantification in MD simulations of concentration driven ionic flow through a silica nanopore. II. Uncertain potential parameters

    NASA Astrophysics Data System (ADS)

    Rizzi, F.; Jones, R. E.; Debusschere, B. J.; Knio, O. M.

    2013-05-01

    This article extends the uncertainty quantification analysis introduced in Paper I for molecular dynamics (MD) simulations of concentration driven ionic flow through a silica nanopore. Attention is now focused on characterizing, for a fixed pore diameter of D = 21 Å, the sensitivity of the system to the Lennard-Jones energy parameters, \\varepsilon _{Na^+} and \\varepsilon _{Cl^-}, defining the depth of the potential well for the two ions Na+ and Cl-, respectively. A forward propagation analysis is applied to map the uncertainty in these parameters to the MD predictions of the ionic fluxes. Polynomial chaos expansions and Bayesian inference are exploited to isolate the effect of the intrinsic noise, stemming from thermal fluctuations of the atoms, and properly quantify the impact of parametric uncertainty on the target MD predictions. A Bayes factor analysis is then used to determine the most suitable regression model to represent the MD noisy data. The study shows that the response surface of the Na+ conductance can be effectively inferred despite the substantial noise level, whereas the noise partially hides the underlying trend in the Cl- conductance data over the studied range. Finally, the dependence of the conductances on the uncertain potential parameters is analyzed in terms of correlations with key bulk transport coefficients, namely, viscosity and collective diffusivities, computed using Green-Kubo time correlations.

  1. Dynamics of a globular protein and its hydration water studied by neutron scattering and MD simulations

    DOE PAGESBeta

    Chen, Sow-Hsin; Lagi, Marco; Chu, Xiang-qiang; Zhang, Yang; Kim, Chansoo; Faraone, Antonio; Fratini, Emiliano; Baglioni, Piero

    2010-01-01

    This review article describes our neutron scattering experiments made in the past four years for the understanding of the single-particle (hydrogen atom) dynamics of a protein and its hydration water and the strong coupling between them. We found that the key to this strong coupling is the existence of a fragile-to-strong dynamic crossover (FSC) phenomenon occurring at around T L = 225±5 K in the hydration water. On lowering of the temperature toward FSC, the structure of hydration water makes a transition from predominantly the high density form (HDL), a more fluid state, to predominantly the low density formmore » (LDL), a less fluid state, derived from the existence of a liquid–liquid critical point at an elevated pressure. We show experimentally that this sudden switch in the mobility of hydration water on Lysozyme, B-DNA and RNA triggers the dynamic transition, at a temperature T D = 220 K, for these biopolymers. In the glassy state, below T D , the biopolymers lose their vital conformational flexibility resulting in a substantial diminishing of their biological functions. We also performed molecular dynamics (MD) simulations on a realistic model of hydrated lysozyme powder, which confirms the existence of the FSC and the hydration level dependence of the FSC temperature. Furthermore, we show a striking feature in the short time relaxation ( β -relaxation) of protein dynamics, which is the logarithmic decay spanning 3 decades (from ps to ns). The long time α -relaxation shows instead a diffusive behavior, which supports the liquid-like motions of protein constituents. We then discuss our recent high-resolution X-ray inelastic scattering studies of globular proteins, Lysozyme and Bovine Serum Albumin. We were able to measure the dispersion relations of collective, intra-protein phonon-like excitations in these proteins for the first time. We found that the phonon energies show a marked softening and at the same time their population increases

  2. Omega currents in voltage-gated ion channels: what can we learn from uncovering the voltage-sensing mechanism using MD simulations?

    PubMed

    Tarek, Mounir; Delemotte, Lucie

    2013-12-17

    Ion channels conduct charged species through otherwise impermeable biological membranes. Their activity supports a number of physiological processes, and genetic mutations can disrupt their function dramatically. Among these channels, voltage gated cation channels (VGCCs) are ubiquitous transmembrane proteins involved in electrical signaling. In addition to their selectivity for ions, their function requires membrane-polarization-dependent gating. Triggered by changes in the transmembrane voltage, the activation and deactivation of VGCCs proceed through a sensing mechanism that prompts motion of conserved positively charged (basic) residues within the S4 helix of a four-helix bundle, the voltage sensor domain (VSD). Decades of experimental investigations, using electrophysiology, molecular biology, pharmacology, and spectroscopy, have revealed details about the function of VGCCs. However, in 2005, the resolution of the crystal structure of the activated state of one member of the mammalian voltage gated potassium (Kv) channels family (the Kv1.2) enabled researchers to make significant progress in understanding the structure-function relationship in these proteins on a molecular level. In this Account, we review the use of a complementary technique, molecular dynamics (MD) simulations, that has offered new insights on this timely issue. Starting from the "open-activated state" crystal structure, we have carried out large-scale all atom MD simulations of the Kv1.2 channel embedded in its lipidic environment and submitted to a hyperpolarizing (negative) transmembrane potential. We then used steered MD simulations to complete the full transition to the resting-closed state. Using these procedures, we have followed the operation of the VSDs and uncovered three intermediate states between their activated and deactivated conformations. Each conformational state is characterized by its network of salt bridges and by the occupation of the gating charge transfer center by a

  3. Solvation structure and dynamics of Na+ in liquid ammonia studied by ONIOM-XS MD simulations

    NASA Astrophysics Data System (ADS)

    Sripradite, Jarukorn; Tongraar, Anan; Kerdcharoen, Teerakiat

    2015-12-01

    The molecular dynamics (MD) technique based on the ONIOM-XS method, known as the ONIOM-XS MD, has been applied to investigate the solvation structure and dynamics of Na+ in liquid ammonia. Regarding the ONIOM-XS MD results, it is observed that Na+ is able to order the surrounding ammonia molecules to form its specific first and second solvation shells with the average coordination numbers of 5.1 and 11.2, respectively. The first solvation shell of Na+ is rather well-defined, forming a preferred 5-fold coordinated complex with a distorted square pyramidal geometry. In this respect, the most preferential Na+(NH3)5 species could convert back and forth to the lower probability Na+(NH3)6 and Na+(NH3)4 configurations. The second solvation shell of Na+ is detectable, in which a number of ammonia molecules, ranging from 7 to 14, are involved in this layer and they are arranged according to recognizable influence of the ion.

  4. Peptides (P1, P2 and its mutations) binding with a graphene sheet: an all-atom to all-residue hierarchical coarse-grained approach

    NASA Astrophysics Data System (ADS)

    Kuang, Zhifeng; Farmer, Barry; Pandey, Ras

    2013-03-01

    Binding of peptide P2 (EPLQLKM) [1] and its mutations (P2G, P2Q) to a graphene sheet are studied by a coarse-grained computer simulation. Our hierarchical coarse-grained approach involves all-atom MD simulation to assess the binding interaction of each residue with the graphene sheet. Data from all-atom simulations are then used as input to phenomenological interaction in a coarse-grained MC simulation [2]. Binding of each peptide and its residue in corresponding sequence (P2, P2G, P2Q) are evaluated by analyzing the adsorption of each residue, its mobility, and structural profiles. Although it is difficult to identify overall morphological differences in adsorbed peptides by visual inspections, quantitative analysis of the conformational changes of adsorbed peptides shows variations in size among P2E and its mutations. Results on binding of peptide P1 (HSSYWYAFNNKT) may also be presented if data become available. This work is supported by the Air Force Research Laboratory.

  5. Molecular Dynamics (MD) Simulation Directed Rational Design of Inhibitors Targeting Drug-Resistant Mutants of Influenza A Virus M2

    PubMed Central

    Wang, Jun; Ma, Chunlong; Fiorin, Giacomo; Carnevale, Vincenzo; Wang, Tuo; Hu, Fanghao; Lamb, Robert A.; Pinto, Lawrence H.; Hong, Mei; Klein, Michael L.; DeGrado, William F.

    2012-01-01

    Influenza A virus M2 (A/M2) forms a homotetrameric proton selective channel in the viral membrane. It has been the drug targets of antiviral drugs such as amantadine and rimantadine. However, most of the current virulent influenza A viruses carry drug resistant mutations alongside the drug binding site, such as S31N, V27A, and L26F etc., each of which might be dominant in a given flu season. Among these mutations, the V27A mutation was prevalent among transmissible viruses under drug selection pressure. Until now, V27A has not been successfully targeted by small molecule inhibitors, despite years of extensive medicinal chemistry research efforts and high throughput screening. Guided by molecular dynamics (MD) simulation of drug binding and the influence of drug binding on the dynamics of A/M2 from earlier experimental studies, we designed a series of potent spirane amine inhibitors targeting not only WT, but also both A/M2-27A and L26F mutants with IC50s similar to that seen for amantadine's inhibition of the WT channel. The potencies of these inhibitors were further demonstrated in experimental binding and plaque reduction assays. These results demonstrate the power of MD simulations to probe the mechanism of drug binding as well as the ability to guide design of inhibitors of targets that had previously appeared to be undruggable. PMID:21744829

  6. Investigation of laser shock induced ductile damage at ultra-high strain rate by using large scale MD simulations

    NASA Astrophysics Data System (ADS)

    Cuq-Lelandais, Jean-Paul; Boustie, Michel; Soulard, Laurent; Berthe, Laurent; Bontaz-Carion, Joëlle; de Resseguier, Thibaut

    2011-06-01

    Laser driven shocks allow to investigate materials behavior at very high strain rate (107s-1) and presents a great interest for research applications. Microscopic simulations of ultra-short laser driven shock on micrometric Tantalum single-crystals have been performed by using the CEA-DAM Classical Molecular Dynamics code. This method, complementary to continuum models, provides an analysis the microscopic processes related to damage (ductile pore nucleation and growth) which occurs during spallation. This results are compared to spallation experiments data (VISAR signals, micro-tomography) obtained with the LULI100TW femtosecond laser in order to validate the MD behavior. Moreover, in the framework of a multi-scale approach, we show the possibility to use MD simulation to fit macroscopic damage models. This method is illustrated with an application to the parameters determination of the Kanel criterion. This also shows the high strain rates involved during damage process, around 109s-1, allow to approach the inter-atomic theoretical cohesion stress threshold.

  7. Investigation of laser shock induced ductile damage at ultra-high strain rate by using large scale MD simulations

    NASA Astrophysics Data System (ADS)

    Cuq-Lelandais, Jean-Paul; Boustie, Michel; Soulard, Laurent; Berthe, Laurent; Bontaz-Carion, Joelle; de Resseguier, Thibaut

    2012-03-01

    Laser driven shocks allow an investigation of materials behavior at very high strain rate (107s-1) and present a great interest for research applications. Microscopic simulations of ultra-short laser driven shock on micrometric Tantalum single-crystals have been performed by using the CEADAM Classical Molecular Dynamics code. This method, complementary to continuum models, provides an analysis the microscopic processes related to damage (ductile pore nucleation and growth) which occurs during spallation. These results are compared to spallation experimental data (VISAR signals, micro-tomography) obtained with the LULI100TW femtosecond laser in order to validate the MD behavior. Moreover, in the framework of a multi-scale approach, we show the possibility to use MD simulation to fit macroscopic damage models. This method is illustrated with an application to the parameters determination of Kanel damage model parameters. This also shows the high strain rates involved during damage process, around 109s-1, can approach the inter-atomic theoretical cohesion stress threshold.

  8. Static and dynamic properties of confined, cold ion plasmas: MD (molecular dynamics) simulations

    SciTech Connect

    Schiffer, J.P.

    1989-01-01

    Some four years ago it was suggested that in the new generation of heavy ion accelerator storage rings for multiply charged ions, being planned in Europe, one may well attain internal temperatures that would correspond to very cold plasmas. Since that time, the techniques of electron or laser cooling of such beams has evolved and it may well be possible to reach temperatures corresponding to a plasma coupling parameter {Gamma} >> 100. I was fortunate to have had an opportunity to collaborate during 1986-87 with my former colleague Aneesur Rahman, of Molecular Dynamics fame, and we adapted the MD method to the calculation of the properties of cold confined plasmas. After Rahman's premature death two years ago I have continued the exploration of these systems and would like to summarize the results here. 9 refs., 10 figs.

  9. All-Atom Structural Models of the Transmembrane Domains of Insulin and Type 1 Insulin-Like Growth Factor Receptors

    PubMed Central

    Mohammadiarani, Hossein; Vashisth, Harish

    2016-01-01

    The receptor tyrosine kinase superfamily comprises many cell-surface receptors including the insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) that are constitutively homodimeric transmembrane glycoproteins. Therefore, these receptors require ligand-triggered domain rearrangements rather than receptor dimerization for activation. Specifically, binding of peptide ligands to receptor ectodomains transduces signals across the transmembrane domains for trans-autophosphorylation in cytoplasmic kinase domains. The molecular details of these processes are poorly understood in part due to the absence of structures of full-length receptors. Using MD simulations and enhanced conformational sampling algorithms, we present all-atom structural models of peptides containing 51 residues from the transmembrane and juxtamembrane regions of IR and IGF1R. In our models, the transmembrane regions of both receptors adopt helical conformations with kinks at Pro961 (IR) and Pro941 (IGF1R), but the C-terminal residues corresponding to the juxtamembrane region of each receptor adopt unfolded and flexible conformations in IR as opposed to a helix in IGF1R. We also observe that the N-terminal residues in IR form a kinked-helix sitting at the membrane–solvent interface, while homologous residues in IGF1R are unfolded and flexible. These conformational differences result in a larger tilt-angle of the membrane-embedded helix in IGF1R in comparison to IR to compensate for interactions with water molecules at the membrane–solvent interfaces. Our metastable/stable states for the transmembrane domain of IR, observed in a lipid bilayer, are consistent with a known NMR structure of this domain determined in detergent micelles, and similar states in IGF1R are consistent with a previously reported model of the dimerized transmembrane domains of IGF1R. Our all-atom structural models suggest potentially unique structural organization of kinase domains in each receptor. PMID

  10. All-atom molecular dynamics analysis of multi-peptide systems reproduces peptide solubility in line with experimental observations

    PubMed Central

    Kuroda, Yutaka; Suenaga, Atsushi; Sato, Yuji; Kosuda, Satoshi; Taiji, Makoto

    2016-01-01

    In order to investigate the contribution of individual amino acids to protein and peptide solubility, we carried out 100 ns molecular dynamics (MD) simulations of 106 Å3 cubic boxes containing ~3 × 104 water molecules and 27 tetra-peptides regularly positioned at 23 Å from each other and composed of a single amino acid type for all natural amino acids but cysteine and glycine. The calculations were performed using Amber with a standard force field on a special purpose MDGRAPE-3 computer, without introducing any “artificial” hydrophobic interactions. Tetra-peptides composed of I, V, L, M, N, Q, F, W, Y, and H formed large amorphous clusters, and those containing A, P, S, and T formed smaller ones. Tetra-peptides made of D, E, K, and R did not cluster at all. These observations correlated well with experimental solubility tendencies as well as hydrophobicity scales with correlation coefficients of 0.5 to > 0.9. Repulsive Coulomb interactions were dominant in ensuring high solubility, whereas both Coulomb and van der Waals (vdW) energies contributed to the aggregations of low solubility amino acids. Overall, this very first all-atom molecular dynamics simulation of a multi-peptide system appears to reproduce the basic properties of peptide solubility, essentially in line with experimental observations. PMID:26817663

  11. QMD and classical MD simulation of alpha boron and boron-carbide behavior under pressure

    NASA Astrophysics Data System (ADS)

    Yanilkin, Alexey; Korotaev, Pavel; Kuksin, Alexey; Pokatashkin, Pavel

    2015-06-01

    Boron and some boron-rich compounds are super-hard and light-weighted material with a wide range of different applications. Nevertheless, the question of its behavior under pressure is still open. In the present work we study the equation of state (EOS), stability and deformation of α-B and B4C under high pressure within quantum and classical molecular dynamics (QMD and MD). Based on QMD results the finite temperature EOSs are revealed. CBC chain bending, amorphization and recrystallization of B4C are investigated under hydrostatic, uniform and uniaxial compression. The influence of nonhydrostatic loading is discussed. Angular dependent interatomic potentials are derived by force-matching method. The properties of α-B and B4C, obtained by classical potential, are verified. Structure, bulk modulus, pressure-volume relation, Gruneisen and thermal expansion coefficients are in good agreement with both ab initio and experimental data. These potentials are used to study shock wave propagation in a single crystal of α-B and B4C. Two mechanisms of shear deformation are observed: stacking fault formation and local amorphization. The crystallographic orientations of defects are in a good agreement with experiments.

  12. Monomerization alters the dynamics of the lid region in Campylobacter jejuni CstII: an MD simulation study.

    PubMed

    Prabhakar, Pradeep Kumar; Srivastava, Alka; Rao, K Krishnamurthy; Balaji, Petety V

    2016-04-01

    CstII, a bifunctional (α2,3/8) sialyltransferase from Campylobacter jejuni, is a homotetramer. It has been reported that mutation of the interface residues Phe121 (F121D) or Tyr125 (Y125Q) leads to monomerization and partial loss of enzyme activity, without any change in the secondary or tertiary structures. MD simulations of both tetramer and monomer, with and without bound donor substrate, were performed for the two mutants and WT to understand the reasons for partial loss of activity due to monomerization since the active site is located within each monomer. RMSF values were found to correlate with the crystallographic B-factor values indicating that the simulations are able to capture the flexibility of the molecule effectively. There were no gross changes in either the secondary or tertiary structure of the proteins during MD simulations. However, interface is destabilized by the mutations, and more importantly the flexibility of the lid region (Gly152-Lys190) is affected. The lid region accesses three major conformations named as open, intermediate, and closed conformations. In both Y121Q and F121D mutants, the closed conformation is accessed predominantly. In this conformation, the catalytic base His188 is also displaced. Normal mode analysis also revealed differences in the lid movement in tetramer and monomer. This provides a possible explanation for the partial loss of enzyme activity in both interface mutants. The lid region controls the traffic of substrates and products in and out of the active site, and the dynamics of this region is regulated by tetramerization. Thus, this study provides valuable insights into the role of loop dynamics in enzyme activity of CstII. PMID:26208676

  13. Direct MD Simulations of Terahertz Absorption and 2D Spectroscopy Applied to Explosive Crystals.

    PubMed

    Katz, G; Zybin, S; Goddard, W A; Zeiri, Y; Kosloff, R

    2014-03-01

    A direct molecular dynamics simulation of the THz spectrum of a molecular crystal is presented. A time-dependent electric field is added to a molecular dynamics simulation of a crystal slab. The absorption spectrum is composed from the energy dissipated calculated from a series of applied pulses characterized by a carrier frequency. The spectrum of crystalline cyclotrimethylenetrinitramine (RDX) and triacetone triperoxide (TATP) were simulated with the ReaxFF force field. The proposed direct method avoids the linear response and harmonic approximations. A multidimensional extension of the spectroscopy is suggested and simulated based on the nonlinear response to a single polarized pulse of radiation in the perpendicular polarization direction. PMID:26274066

  14. Assessment of hydrogen bonding effect on ionization of water from ambient to supercritical region-MD simulation approach

    NASA Astrophysics Data System (ADS)

    Swiatla-Wojcik, D.; Mozumder, A.

    2014-04-01

    We present a novel, molecular dynamics (MD) simulation based, strategy to analyze how the degree of hydrogen bonding may influence the ionization and dissociation of water upon heating from ambient to supercritical temperatures. Calculations show a negligible change in the ionization energy up to 200 °C. At higher temperatures the ionization energy increases due to the decreasing degree of hydrogen bonding. The influence of density (pressure) is pronounced in the supercritical region. The ionization is more energy consuming in the less dense fluid. We also show that high temperature and low density may promote dissociation of the electronically excited water molecules. Implications on the initial radiation chemical yields of the hydrated electron, hydrogen atom and hydroxyl radical are discussed.

  15. Simulation of λ-phage DNA in microchannels using a coarse-grained MD method

    NASA Astrophysics Data System (ADS)

    Symeonidis, Vasileios

    2005-11-01

    In this work we present Dissipative Particle Dynamics (dpd) simulations of polymers subject to the Marko-Siggia wormlike chain (wlc) spring law. We demonstrate the advantages of Lowe's dpd method, which simulates high Schmidt numbers for the solvent, and contrast it with the velocity-Verlet scheme. Shear flow results for the wormlike chain (wlc) simulating single dna molecules compare well with average extensions from experiments, irrespective of the number of beads. However, coarse-graining with more than a few beads degrades the agreement of the autocorrelation of the extension.

  16. Exploring Beta-Amyloid Protein Transmembrane Insertion Behavior and Residue-Specific Lipid Interactions in Lipid Bilayers Using Multiscale MD Simulations

    NASA Astrophysics Data System (ADS)

    Qiu, Liming; Vaughn, Mark; Cheng, Kelvin

    2013-03-01

    Beta-amyloid (Abeta) interactions with neurons are linked to Alzheimer's. Using a multiscale MD simulation strategy that combines the high efficiency of phase space sampling of coarse-grained MD (CGD) and the high spatial resolution of Atomistic MD (AMD) simulations, we studied the Abeta insertion dynamics in cholesterol-enriched and -depleted lipid bilayers that mimic the neuronal membranes domains. Forward (AMD-CGD) and reverse (CGD-AMD) mappings were used. At the atomistic level, cholesterol promoted insertion of Abeta with high (folded) or low (unfolded) helical contents of the lipid insertion domain (Lys28-Ala42), and the insertions were stabilized by the Lys28 snorkeling and Ala42-anchoring to the polar lipid groups of the bilayer up to 200ns. After the forward mapping, the folded inserted state switched to a new extended inserted state with the Lys28 descended to the middle of the bilayer while the unfolded inserted state migrated to the membrane surface up to 4000ns. The two new states remained stable for 200ns at the atomistic scale after the reverse mapping. Our results suggested that different Abeta membrane-orientation states separated by free energy barriers can be explored by the multiscale MD more effectively than by Atomistic MD simulations alone. NIH RC1-GM090897-02

  17. An all-atom structure-based potential for proteins: bridging minimal models with all-atom empirical forcefields.

    PubMed

    Whitford, Paul C; Noel, Jeffrey K; Gosavi, Shachi; Schug, Alexander; Sanbonmatsu, Kevin Y; Onuchic, José N

    2009-05-01

    Protein dynamics take place on many time and length scales. Coarse-grained structure-based (Go) models utilize the funneled energy landscape theory of protein folding to provide an understanding of both long time and long length scale dynamics. All-atom empirical forcefields with explicit solvent can elucidate our understanding of short time dynamics with high energetic and structural resolution. Thus, structure-based models with atomic details included can be used to bridge our understanding between these two approaches. We report on the robustness of folding mechanisms in one such all-atom model. Results for the B domain of Protein A, the SH3 domain of C-Src Kinase, and Chymotrypsin Inhibitor 2 are reported. The interplay between side chain packing and backbone folding is explored. We also compare this model to a C(alpha) structure-based model and an all-atom empirical forcefield. Key findings include: (1) backbone collapse is accompanied by partial side chain packing in a cooperative transition and residual side chain packing occurs gradually with decreasing temperature, (2) folding mechanisms are robust to variations of the energetic parameters, (3) protein folding free-energy barriers can be manipulated through parametric modifications, (4) the global folding mechanisms in a C(alpha) model and the all-atom model agree, although differences can be attributed to energetic heterogeneity in the all-atom model, and (5) proline residues have significant effects on folding mechanisms, independent of isomerization effects. Because this structure-based model has atomic resolution, this work lays the foundation for future studies to probe the contributions of specific energetic factors on protein folding and function. PMID:18837035

  18. Synergy between NMR measurements and MD simulations of protein/RNA complexes: application to the RRMs, the most common RNA recognition motifs.

    PubMed

    Krepl, Miroslav; Cléry, Antoine; Blatter, Markus; Allain, Frederic H T; Sponer, Jiri

    2016-07-27

    RNA recognition motif (RRM) proteins represent an abundant class of proteins playing key roles in RNA biology. We present a joint atomistic molecular dynamics (MD) and experimental study of two RRM-containing proteins bound with their single-stranded target RNAs, namely the Fox-1 and SRSF1 complexes. The simulations are used in conjunction with NMR spectroscopy to interpret and expand the available structural data. We accumulate more than 50 μs of simulations and show that the MD method is robust enough to reliably describe the structural dynamics of the RRM-RNA complexes. The simulations predict unanticipated specific participation of Arg142 at the protein-RNA interface of the SRFS1 complex, which is subsequently confirmed by NMR and ITC measurements. Several segments of the protein-RNA interface may involve competition between dynamical local substates rather than firmly formed interactions, which is indirectly consistent with the primary NMR data. We demonstrate that the simulations can be used to interpret the NMR atomistic models and can provide qualified predictions. Finally, we propose a protocol for 'MD-adapted structure ensemble' as a way to integrate the simulation predictions and expand upon the deposited NMR structures. Unbiased μs-scale atomistic MD could become a technique routinely complementing the NMR measurements of protein-RNA complexes. PMID:27193998

  19. Surface signatures of bioactivity: MD simulations of 45S and 65S silicate glasses.

    PubMed

    Tilocca, Antonio; Cormack, Alastair N

    2010-01-01

    The surface of a bioactive (45S) and a bioinactive (65S) glass composition has been modeled using shell-model classical molecular dynamics simulations. Direct comparison of the two structures allowed us to identify the potential role of specific surface features in the processes leading to integration of a bioglass implant with the host tissues, focusing in particular on the initial dissolution of the glass network. The simulations highlight the critical role of network fragmentation and sodium enrichment of the surface in determining the rapid hydrolysis and release of silica fragments in solution, characteristic of highly bioactive compositions. On the other hand, no correlation has been found between the surface density of small (two- and three-membered) rings and bioactivity, thus suggesting that additional factors need to be taken into account to fully understand the role of these sites in the mechanism leading to calcium phosphate deposition on the glass surface. PMID:19725567

  20. Evaluation of GEOS-5 sulfur dioxide simulations during the Frostburg, MD 2010 field campaign

    NASA Astrophysics Data System (ADS)

    Buchard, V.; da Silva, A. M.; Colarco, P.; Krotkov, N.; Dickerson, R. R.; Stehr, J. W.; Mount, G.; Spinei, E.; Arkinson, H. L.; He, H.

    2013-08-01

    Sulfur dioxide (SO2) is a major atmospheric pollutant with a strong anthropogenic component mostly produced by the combustion of fossil fuel and other industrial activities. As a precursor of sulfate aerosols that affect climate, air quality, and human health, this gas needs to be monitored on a global scale. Global climate and chemistry models including aerosol processes along with their radiative effects are important tools for climate and air quality research. Validation of these models against in-situ and satellite measurements is essential to ascertain the credibility of these models and to guide model improvements. In this study the Goddard Chemistry, Aerosol, Radiation, and Transport (GOCART) module running on-line inside the Goddard Earth Observing System version 5 (GEOS-5) model is used to simulate aerosol and SO2 concentrations. Data taken in November 2010 over Frostburg, Maryland during an SO2 field campaign involving ground instrumentation and aircraft are used to evaluate GEOS-5 simulated SO2 concentrations. Preliminary data analysis indicated the model overestimated surface SO2 concentration, which motivated the examination of mixing processes in the model and the specification of SO2 anthropogenic emission rates. As a result of this analysis, a revision of anthropogenic emission inventories in GEOS-5 was implemented, and the vertical placement of SO2 sources was updated. Results show that these revisions improve the model agreement with observations locally and in regions outside the area of this field campaign. In particular, we use the ground-based measurements collected by the United States Environmental Protection Agency (US EPA) for the year 2010 to evaluate the revised model simulations over North America.

  1. Evaluation of GEOS-5 sulfur dioxide simulations during the Frostburg, MD 2010 field campaign

    NASA Astrophysics Data System (ADS)

    Buchard, V.; da Silva, A. M.; Colarco, P.; Krotkov, N.; Dickerson, R. R.; Stehr, J. W.; Mount, G.; Spinei, E.; Arkinson, H. L.; He, H.

    2014-02-01

    Sulfur dioxide (SO2) is a major atmospheric pollutant with a strong anthropogenic component mostly produced by the combustion of fossil fuel and other industrial activities. As a precursor of sulfate aerosols that affect climate, air quality, and human health, this gas needs to be monitored on a global scale. Global climate and chemistry models including aerosol processes along with their radiative effects are important tools for climate and air quality research. Validation of these models against in-situ and satellite measurements is essential to ascertain the credibility of these models and to guide model improvements. In this study, the Goddard Chemistry, Aerosol, Radiation, and Transport (GOCART) module running on-line inside the Goddard Earth Observing System version 5 (GEOS-5) model is used to simulate aerosol and SO2 concentrations. Data taken in November 2010 over Frostburg, Maryland during an SO2 field campaign involving ground instrumentation and aircraft are used to evaluate GEOS-5 simulated SO2 concentrations. Preliminary data analysis indicated the model overestimated surface SO2 concentration, which motivated the examination of the specification of SO2 anthropogenic emission rates. As a result of this analysis, a revision of anthropogenic emission inventories in GEOS-5 was implemented, and the vertical placement of SO2 sources was updated. Results show that these revisions improve the model agreement with observations locally and in regions outside the area of this field campaign. In particular, we use the ground-based measurements collected by the United States Environmental Protection Agency (US EPA) for the year 2010 to evaluate the revised model simulations over North America.

  2. Evaluation of GEOS-5 Sulfur Dioxide Simulations During the Frostburg, MD 2010 Field Campaign.

    NASA Technical Reports Server (NTRS)

    Buchard, V.; Da Silva, A. M.; Colarco, P.; Krotkov, N.; Dickerson, R. R.; Stehr, J. W.; Mount, G.; Spenei, E.; Arkinson, H. L.; He, H.

    2013-01-01

    Sulfur dioxide (SO2) is a major atmospheric pollutant with a strong anthropogenic component mostly produced by the combustion of fossil fuel and other industrial activities. As a precursor of sulfate aerosols that affect climate, air quality, and human health, this gas needs to be monitored on a global scale. Global climate and chemistry models including aerosol processes along with their radiative effects are important tools for climate and air quality research. Validation of these models against in-situ and satellite measurements is essential to ascertain the credibility of these models and to guide model improvements. In this study the Goddard Chemistry, Aerosol, Radiation, and Transport (GOCART) module running on-line inside the Goddard Earth Observing System version 5 (GEOS-5) model is used to simulate aerosol and SO2 concentrations. Data taken in November 2010 over Frostburg, Maryland during an SO2 field campaign involving ground instrumentation and aircraft are used to evaluate GEOS-5 simulated SO2 concentrations. Preliminary data analysis indicated the model overestimated surface SO2 concentration, which motivated the examination of mixing processes in the model and the specification of SO2 anthropogenic emission rates. As a result of this analysis, a revision of anthropogenic emission inventories in GEOS-5 was implemented, and the vertical placement of SO2 sources was updated. Results show that these revisions improve the model agreement with observations locally and in regions outside the area of this field campaign. In particular, we use the ground-based measurements collected by the United States Environmental Protection Agency (US EPA) for the year 2010 to evaluate the revised model simulations over North America.

  3. Carbon nanoscroll from C4H/C4F-type graphene superlattice: MD and MM simulation insights.

    PubMed

    Liu, Zilong; Xue, Qingzhong; Tao, Yehan; Li, Xiaofang; Wu, Tiantian; Jin, Yakang; Zhang, Zhongyang

    2015-02-01

    Morphology manipulation opens up a new avenue for controlling and tailoring the functional properties of graphene, enabling the exploration of graphene-based nanomaterials. Through mixing single-side-hydrogenated graphene (C4H) with fluorinated graphene (C4F) on one single sheet, the C4H/C4F-type graphene superlattices can self-scroll at room temperature. We demonstrate using molecular dynamic (MD) simulations that different proportions, sizes, directions of hydrogenation and fluorination, and geometry of graphene have a great influence on the self-scrolling of superlattices into a variety of well-defined carbon nanoscrolls (CNSs), thus providing a controllable approach to tune their structures. Based on molecular mechanics (MM) simulations, the CNSs bear more than eight times the radial pressure than that of their multiwalled carbon nanotube (MWNT) counterparts, and an excellent radial elasticity of CNSs is also shown. Compared with conventional CNSs, these novel CNSs are endowed with more ample and flexible heterogeneous structures due to the on-demand hydrogenation and fluorination. Besides, this work provides a feasible route to achieve the necessary electronic and optical changes to be applied in graphene device applications. PMID:25531924

  4. MD simulations of phase stability of PuGa alloys: Effects of primary radiation defects and helium bubbles

    DOE PAGESBeta

    Dremov, V. V.; Sapozhnikov, F. A.; Ionov, G. V.; Karavaev, A. V.; Vorobyova, M. A.; Chung, B. W.

    2013-05-14

    We present classical molecular dynamics (MD) with Modified Embedded Atom Model (MEAM) simulations to investigate the role of primary radiation defects and radiogenic helium as factors affecting the phase stability of PuGa alloys in cooling–heating cycles at ambient pressure. The models of PuGa alloys equilibrated at ambient conditions were subjected to cooling–heating cycles in which they were initially cooled down to 100 K and then heated up to 500 K at ambient pressure. The rate of temperature change in the cycles was 10 K/ns. The simulations showed that the initial FCC phase of PuGa alloys undergo polymorphous transition in coolingmore » to a lower symmetry α'-phase. All the alloys undergo direct and reverse polymorphous transitions in the cooling–heating cycles. The alloys containing vacancies shift in both transitions to lower temperatures relative to the defect-free alloys. The radiogenic helium has much less effect on the phase stability compared to that of primary radiation defects (in spite of the fact that helium concentration is twice of that for the primary radiation defects). Lastly, this computational result agrees with experimental data on unconventional stabilization mechanism of PuGa alloys.« less

  5. MD simulations of the formation of stable clusters in mixtures of alkaline salts and imidazolium-based ionic liquids.

    PubMed

    Méndez-Morales, Trinidad; Carrete, Jesús; Bouzón-Capelo, Silvia; Pérez-Rodríguez, Martín; Cabeza, Óscar; Gallego, Luis J; Varela, Luis M

    2013-03-21

    Structural and dynamical properties of room-temperature ionic liquids containing the cation 1-butyl-3-methylimidazolium ([BMIM](+)) and three different anions (hexafluorophosphate, [PF6](-), tetrafluoroborate, [BF4](-), and bis(trifluoromethylsulfonyl)imide, [NTf2](-)) doped with several molar fractions of lithium salts with a common anion at 298.15 K and 1 atm were investigated by means of molecular dynamics simulations. The effect of the size of the salt cation was also analyzed by comparing these results with those for mixtures of [BMIM][PF6] with NaPF6. Lithium/sodium solvation and ionic mobilities were analyzed via the study of radial distribution functions, coordination numbers, cage autocorrelation functions, mean-square displacements (including the analysis of both ballistic and diffusive regimes), self-diffusion coefficients of all the ionic species, velocity and current autocorrelation functions, and ionic conductivity in all the ionic liquid/salt systems. We found that lithium and sodium cations are strongly coordinated in two different positions with the anion present in the mixture. Moreover, [Li](+) and [Na](+) cations were found to form bonded-like, long-lived aggregates with the anions in their first solvation shell, which act as very stable kinetic entities within which a marked rattling motion of salt ions takes place. With very long MD simulation runs, this phenomenon is proved to be on the basis of the decrease of self-diffusion coefficients and ionic conductivities previously reported in experimental and computational results. PMID:23480174

  6. Unraveling the Conformational Landscape of Ligand Binding to Glucose/Galactose-Binding Protein by Paramagnetic NMR and MD Simulations.

    PubMed

    Unione, Luca; Ortega, Gabriel; Mallagaray, Alvaro; Corzana, Francisco; Pérez-Castells, Javier; Canales, Angeles; Jiménez-Barbero, Jesús; Millet, Oscar

    2016-08-19

    Protein dynamics related to function can nowadays be structurally well characterized (i.e., instances obtained by high resolution structures), but they are still ill-defined energetically, and the energy landscapes are only accessible computationally. This is the case for glucose-galactose binding protein (GGBP), where the crystal structures of the apo and holo states provide structural information for the domain rearrangement upon ligand binding, while the time scale and the energetic determinants for such concerted dynamics have been so far elusive. Here, we use GGBP as a paradigm to define a functional conformational landscape, both structurally and energetically, by using an innovative combination of paramagnetic NMR experiments and MD simulations. Anisotropic NMR parameters induced by self-alignment of paramagnetic metal ions was used to characterize the ensemble of conformations adopted by the protein in solution while the rate of interconversion between conformations was elucidated by long molecular dynamics simulation on two states of GGBP, the closed-liganded (holo_cl) and open-unloaded (apo_op) states. Our results demonstrate that, in its apo state, the protein coexists between open-like (68%) and closed-like (32%) conformations, with an exchange rate around 25 ns. Despite such conformational heterogeneity, the presence of the ligand is the ultimate driving force to unbalance the equilibrium toward the holo_cl form, in a mechanism largely governed by a conformational selection mechanism. PMID:27219646

  7. Structure, Stability, and Fragmentation of Sodium bis(2-ethylhexyl)Sulfosuccinate Negatively Charged Aggregates In Vacuo by MD Simulations

    NASA Astrophysics Data System (ADS)

    Longhi, Giovanna; Abbate, Sergio; Ceselli, Alberto; Ceraulo, Leopoldo; Fornili, Sandro L.; Turco Liveri, Vincenzo

    2014-09-01

    Negatively charged supramolecular aggregates formed in vacuo by n bis(2-ethylhexyl)sulfosuccinate (AOT-) anions and n + n c sodium counterions (i.e., [AOT n Na n+nc ] nc ) have been investigated by molecular dynamics (MD) simulations for n = 1 to 20 and n c = -1 to -5. By comparing the maximum excess charge values of negatively and positively charged AOTNa aggregates, it is found that the charge storage capability is higher for the latter systems, the difference decreasing as the aggregation number increases. Statistical analysis of physical properties like gyration radii and moment of inertia tensors of aggregates provides detailed information on their structural properties. Even for n c = -5, all stable aggregates show a reverse micelle-like structure with an internal core, including sodium counterions and surfactant polar heads, surrounded by an external layer consisting of the surfactant alkyl chains. Interestingly, the reverse micelle-like structure is retained also in proximity of fragmentation. Moreover, the aggregate shapes may be approximated by elongated ellipsoids whose longer axis increases with n and | n c |. The fragmentation patterns of a number of these aggregates have also been examined and have been found to markedly depend on the aggregate charge state. The simulated fragmentation patterns of a representative aggregate show good agreement with experimental data obtained using low collision voltages.

  8. Structure, stability, and fragmentation of sodium bis(2-ethylhexyl)sulfosuccinate negatively charged aggregates in vacuo by MD simulations.

    PubMed

    Longhi, Giovanna; Abbate, Sergio; Ceselli, Alberto; Ceraulo, Leopoldo; Fornili, Sandro L; Turco Liveri, Vincenzo

    2014-09-01

    Negatively charged supramolecular aggregates formed in vacuo by n bis(2-ethylhexyl)sulfosuccinate (AOT(-)) anions and n + n(c) sodium counterions (i.e., [AOT(n) Na(n+nc)](nc)) have been investigated by molecular dynamics (MD) simulations for n = 1 to 20 and n(c) = -1 to -5. By comparing the maximum excess charge values of negatively and positively charged AOTNa aggregates, it is found that the charge storage capability is higher for the latter systems, the difference decreasing as the aggregation number increases. Statistical analysis of physical properties like gyration radii and moment of inertia tensors of aggregates provides detailed information on their structural properties. Even for n(c) = -5, all stable aggregates show a reverse micelle-like structure with an internal core, including sodium counterions and surfactant polar heads, surrounded by an external layer consisting of the surfactant alkyl chains. Interestingly, the reverse micelle-like structure is retained also in proximity of fragmentation. Moreover, the aggregate shapes may be approximated by elongated ellipsoids whose longer axis increases with n and |n(c)|. The fragmentation patterns of a number of these aggregates have also been examined and have been found to markedly depend on the aggregate charge state. The simulated fragmentation patterns of a representative aggregate show good agreement with experimental data obtained using low collision voltages. PMID:24969925

  9. MD simulations of phase stability of PuGa alloys: Effects of primary radiation defects and helium bubbles

    SciTech Connect

    Dremov, V. V.; Sapozhnikov, F. A.; Ionov, G. V.; Karavaev, A. V.; Vorobyova, M. A.; Chung, B. W.

    2013-05-14

    We present classical molecular dynamics (MD) with Modified Embedded Atom Model (MEAM) simulations to investigate the role of primary radiation defects and radiogenic helium as factors affecting the phase stability of PuGa alloys in cooling–heating cycles at ambient pressure. The models of PuGa alloys equilibrated at ambient conditions were subjected to cooling–heating cycles in which they were initially cooled down to 100 K and then heated up to 500 K at ambient pressure. The rate of temperature change in the cycles was 10 K/ns. The simulations showed that the initial FCC phase of PuGa alloys undergo polymorphous transition in cooling to a lower symmetry α'-phase. All the alloys undergo direct and reverse polymorphous transitions in the cooling–heating cycles. The alloys containing vacancies shift in both transitions to lower temperatures relative to the defect-free alloys. The radiogenic helium has much less effect on the phase stability compared to that of primary radiation defects (in spite of the fact that helium concentration is twice of that for the primary radiation defects). Lastly, this computational result agrees with experimental data on unconventional stabilization mechanism of PuGa alloys.

  10. MD Simulations and FRET Reveal an Environment-Sensitive Conformational Plasticity of Importin-β

    PubMed Central

    Halder, Kangkan; Dölker, Nicole; Van, Qui; Gregor, Ingo; Dickmanns, Achim; Baade, Imke; Kehlenbach, Ralph H.; Ficner, Ralf; Enderlein, Jörg; Grubmüller, Helmut; Neumann, Heinz

    2015-01-01

    The nuclear pore complex mediates nucleocytoplasmic transport of macromolecules in eukaryotic cells. Transport through the pore is restricted by a hydrophobic selectivity filter comprising disordered phenylalanine-glycine-rich repeats of nuclear pore proteins. Exchange through the pore requires specialized transport receptors, called exportins and importins, that interact with cargo proteins in a RanGTP-dependent manner. These receptors are highly flexible superhelical structures composed of HEAT-repeat motifs that adopt various degrees of extension in crystal structures. Here, we performed molecular-dynamics simulations using crystal structures of Importin-β in its free form or in complex with nuclear localization signal peptides as the starting conformation. Our simulations predicted that initially compact structures would adopt extended conformations in hydrophilic buffers, while contracted conformations would dominate in more hydrophobic solutions, mimicking the environment of the nuclear pore. We confirmed this experimentally by Förster resonance energy transfer experiments using dual-fluorophore-labeled Importin-β. These observations explain seemingly contradictory crystal structures and suggest a possible mechanism for cargo protection during passage of the nuclear pore. Such hydrophobic switching may be a general principle for environmental control of protein function. PMID:26200863

  11. Properties of ultrathin cholesterol and phospholipid layers surrounding silicon-carbide nanotube: MD simulations.

    PubMed

    Raczyński, Przemysław; Raczyńska, Violetta; Górny, Krzysztof; Gburski, Zygmunt

    2015-08-15

    Computer simulation technique was used to study the dynamics of cholesterol and POPC phospholipid molecules forming a thin layer on the surface of the carbon and silicon-carbide nanotubes. Each nanotube was surrounded by an ultra-thin film formed by n lipid molecules, where n varies from 15 to 50. All studies were done for five temperatures, including physiological one (T=260, 285, 310, 335 and 360K). The influence of a nanotube on the dynamics of cholesterol or phospholipid molecules in a layer is presented and discussed. The water is ubiquitous in all biological milieus, where the cholesterol or lipids occur. Thus, simulations were performed in a water environment. Moreover, to show different behavior of lipids in systems with water the results were compared with the samples without it. The dynamical and structural observables, such as the mean square displacement, diffusion coefficient, radial distribution function, and activation energy were calculated to qualitatively investigate the behavior of cholesterol and phospholipid molecules in the layers. We observed remarkable differences between the cholesterol dynamics depending whether the ultrathin film surrounds carbon or silicon-carbide nanotube and whether the water environment appeared. PMID:26113257

  12. α-tocopherol is well designed to protect polyunsaturated phospholipids: MD simulations

    DOE PAGESBeta

    Leng, Xiaoling; Kinnun, Jacob A.; Marquardt, Drew; Ghefli, Mikel; Kucerka, Norbert; Katsaras, John; Atkinson, Jeffrey; Harroun, Thad A.; Feller, Scott E.; Wassall, Stephen

    2015-10-20

    Here, the presumptive function for alpha-tocopherol (αtoc) in membranes is to protect polyunsaturated lipids against oxidation. Although the chemistry of the process is well established, the role played by molecular structure that we address here with atomistic molecular-dynamics simulations remains controversial. The simulations were run in the constant particle NPT ensemble on hydrated lipid bilayers composed of SDPC (1-stearoyl-2-docosahexaenoylphosphatidylcholine, 18:0-22:6PC) and SOPC (1-stearoyl-2-oleoylphosphatidylcholine, 18:0-18:1PC) in the presence of 20 mol % αtoc at 37°C. SDPC with SA (stearic acid) for the sn-1 chain and DHA (docosahexaenoic acid) for the sn-2 chain is representative of polyunsaturated phospholipids, while SOPC with OAmore » (oleic acid) substituted for the sn-2 chain serves as a monounsaturated control. Solid-state 2H nuclear magnetic resonance and neutron diffraction experiments provide validation. The simulations demonstrate that high disorder enhances the probability that DHA chains at the sn-2 position in SDPC rise up to the bilayer surface, whereby they encounter the chromanol group on αtoc molecules. This behavior is reflected in the van der Waals energy of interaction between αtoc and acyl chains, and illustrated by density maps of distribution for acyl chains around αtoc molecules that were constructed. An ability to more easily penetrate deep into the bilayer is another attribute conferred upon the chromanol group in αtoc by the high disorder possessed by DHA. By examining the trajectory of single molecules, we found that αtoc flip-flops across the SDPC bilayer on a submicrosecond timescale that is an order-of-magnitude greater than in SOPC. Our results reveal mechanisms by which the sacrificial hydroxyl group on the chromanol group can trap lipid peroxyl radicals within the interior and near the surface of a polyunsaturated membrane. At the same time, water-soluble reducing agents that regenerate αtoc can access

  13. α-tocopherol is well designed to protect polyunsaturated phospholipids: MD simulations

    SciTech Connect

    Leng, Xiaoling; Kinnun, Jacob A.; Marquardt, Drew; Ghefli, Mikel; Kucerka, Norbert; Katsaras, John; Atkinson, Jeffrey; Harroun, Thad A.; Feller, Scott E.; Wassall, Stephen

    2015-10-20

    Here, the presumptive function for alpha-tocopherol (αtoc) in membranes is to protect polyunsaturated lipids against oxidation. Although the chemistry of the process is well established, the role played by molecular structure that we address here with atomistic molecular-dynamics simulations remains controversial. The simulations were run in the constant particle NPT ensemble on hydrated lipid bilayers composed of SDPC (1-stearoyl-2-docosahexaenoylphosphatidylcholine, 18:0-22:6PC) and SOPC (1-stearoyl-2-oleoylphosphatidylcholine, 18:0-18:1PC) in the presence of 20 mol % αtoc at 37°C. SDPC with SA (stearic acid) for the sn-1 chain and DHA (docosahexaenoic acid) for the sn-2 chain is representative of polyunsaturated phospholipids, while SOPC with OA (oleic acid) substituted for the sn-2 chain serves as a monounsaturated control. Solid-state 2H nuclear magnetic resonance and neutron diffraction experiments provide validation. The simulations demonstrate that high disorder enhances the probability that DHA chains at the sn-2 position in SDPC rise up to the bilayer surface, whereby they encounter the chromanol group on αtoc molecules. This behavior is reflected in the van der Waals energy of interaction between αtoc and acyl chains, and illustrated by density maps of distribution for acyl chains around αtoc molecules that were constructed. An ability to more easily penetrate deep into the bilayer is another attribute conferred upon the chromanol group in αtoc by the high disorder possessed by DHA. By examining the trajectory of single molecules, we found that αtoc flip-flops across the SDPC bilayer on a submicrosecond timescale that is an order-of-magnitude greater than in SOPC. Our results reveal mechanisms by which the sacrificial hydroxyl group on the chromanol group can trap lipid peroxyl radicals within the interior and near the surface of a polyunsaturated membrane. At the same time, water-soluble reducing agents that regenerate αtoc can access the

  14. α-Tocopherol Is Well Designed to Protect Polyunsaturated Phospholipids: MD Simulations.

    PubMed

    Leng, Xiaoling; Kinnun, Jacob J; Marquardt, Drew; Ghefli, Mikel; Kučerka, Norbert; Katsaras, John; Atkinson, Jeffrey; Harroun, Thad A; Feller, Scott E; Wassall, Stephen R

    2015-10-20

    The presumptive function for alpha-tocopherol (αtoc) in membranes is to protect polyunsaturated lipids against oxidation. Although the chemistry of the process is well established, the role played by molecular structure that we address here with atomistic molecular-dynamics simulations remains controversial. The simulations were run in the constant particle NPT ensemble on hydrated lipid bilayers composed of SDPC (1-stearoyl-2-docosahexaenoylphosphatidylcholine, 18:0-22:6PC) and SOPC (1-stearoyl-2-oleoylphosphatidylcholine, 18:0-18:1PC) in the presence of 20 mol % αtoc at 37°C. SDPC with SA (stearic acid) for the sn-1 chain and DHA (docosahexaenoic acid) for the sn-2 chain is representative of polyunsaturated phospholipids, while SOPC with OA (oleic acid) substituted for the sn-2 chain serves as a monounsaturated control. Solid-state (2)H nuclear magnetic resonance and neutron diffraction experiments provide validation. The simulations demonstrate that high disorder enhances the probability that DHA chains at the sn-2 position in SDPC rise up to the bilayer surface, whereby they encounter the chromanol group on αtoc molecules. This behavior is reflected in the van der Waals energy of interaction between αtoc and acyl chains, and illustrated by density maps of distribution for acyl chains around αtoc molecules that were constructed. An ability to more easily penetrate deep into the bilayer is another attribute conferred upon the chromanol group in αtoc by the high disorder possessed by DHA. By examining the trajectory of single molecules, we found that αtoc flip-flops across the SDPC bilayer on a submicrosecond timescale that is an order-of-magnitude greater than in SOPC. Our results reveal mechanisms by which the sacrificial hydroxyl group on the chromanol group can trap lipid peroxyl radicals within the interior and near the surface of a polyunsaturated membrane. At the same time, water-soluble reducing agents that regenerate αtoc can access the chromanol

  15. Engineering and control of surfactant-laden flows: experiments and MD simulations

    NASA Astrophysics Data System (ADS)

    Kovalchuk, Nina; Theodorakis, Panayiotis; Muller, Erich; Craster, Richard; Starov, Victor; Matar, Omar

    2013-11-01

    The dynamics of surfactant-laden flows remain full of surprises. For hydrophobic substrates with a water contact angle of less than 110°, certain types of surfactants, known as superspreaders, can lead to an increase in the spreading factor by two orders of magnitude over water droplets; spreading takes place with speeds between 1-10 mm/s. The superspreading effect occurs provided the concentration of superspreaders is above the critical wetting concentration (CWC), which, in turn, exceeds (by several times) the critical aggregation concentration. The CWC is dependent on the type of surfactant but independent of the nature of the substrate. In this study, we use a combination of molecular dynamics simulation, and direct experimentation to analyse the spreading behaviour of well-known superspreaders. We correlate this behaviour in terms of the physic-chemical properties of the surfactant (sorption kinetics, aggregation formation, and dynamic surface tension). EPSRC Grant (EP/J010502/1).

  16. X-ray structure, thermodynamics, elastic properties and MD simulations of cardiolipin/dimyristoylphosphatidylcholine mixed membranes.

    PubMed

    Boscia, Alexander L; Treece, Bradley W; Mohammadyani, Dariush; Klein-Seetharaman, Judith; Braun, Anthony R; Wassenaar, Tsjerk A; Klösgen, Beate; Tristram-Nagle, Stephanie

    2014-02-01

    Cardiolipins (CLs) are important biologically for their unique role in biomembranes that couple phosphorylation and electron transport like bacterial plasma membranes, chromatophores, chloroplasts and mitochondria. CLs are often tightly coupled to proteins involved in oxidative phosphorylation. The first step in understanding the interaction of CL with proteins is to obtain the pure CL structure, and the structure of mixtures of CL with other lipids. In this work we use a variety of techniques to characterize the fluid phase structure, material properties and thermodynamics of mixtures of dimyristoylphosphatidylcholine (DMPC) with tetramyristoylcardiolipin (TMCL), both with 14-carbon chains, at several mole percentages. X-ray diffuse scattering was used to determine structure, including bilayer thickness and area/lipid, the bending modulus, KC, and SXray, a measure of chain orientational order. Our results reveal that TMCL thickens DMPC bilayers at all mole percentages, with a total increase of ∼6 Å in pure TMCL, and increases AL from 64 Å(2) (DMPC at 35 °C) to 109 Å(2) (TMCL at 50 °C). KC increases by ∼50%, indicating that TMCL stiffens DMPC membranes. TMCL also orders DMPC chains by a factor of ∼2 for pure TMCL. Coarse grain molecular dynamics simulations confirm the experimental thickening of 2 Å for 20mol% TMCL and locate the TMCL headgroups near the glycerol-carbonyl region of DMPC; i.e., they are sequestered below the DMPC phosphocholine headgroup. Our results suggest that TMCL plays a role similar to cholesterol in that it thickens and stiffens DMPC membranes, orders chains, and is positioned under the umbrella of the PC headgroup. CL may be necessary for hydrophobic matching to inner mitochondrial membrane proteins. Differential scanning calorimetry, SXray and CGMD simulations all suggest that TMCL does not form domains within the DMPC bilayers. We also determined the gel phase structure of TMCL, which surprisingly displays diffuse X

  17. X-ray structure, thermodynamics, elastic properties and MD simulations of cardiolipin/dimyristoylphosphatidylcholine mixed membranes

    PubMed Central

    Boscia, Alexander L.; Treece, Bradley W.; Mohammadyani, Dariush; Klein-Seetharaman, Judith; Braun, Anthony R.; Wassenaar, Tsjerk A.; Klösgen, Beate; Tristram-Nagle, Stephanie

    2014-01-01

    Cardiolipins (CLs) are important biologically for their unique role in biomembranes that couple phosphorylation and electron transport like bacterial plasma membranes, chromatophores, chloroplasts and mitochondria. CLs are often tightly coupled to proteins involved in oxidative phosphorylation. The first step in understanding the interaction of CL with proteins is to obtain the pure CL structure, and the structure of mixtures of CL with other lipids. In this work we use a variety of techniques to characterize the fluid phase structure, material properties and thermodynamics of mixtures of dimyristoylphosphatidylcholine (DMPC) with tetramyristoylcardiolipin (TMCL), both with 14-carbon chains, at several mole percentages. X-ray diffuse scattering was used to determine structure, including bilayer thickness and area/lipid, the bending modulus, KC, and Sxray, a measure of chain orientational order. Our results reveal that TMCL thickens DMPC bilayers at all mole percentages, with a total increase of ~6 Å in pure TMCL, and increases AL from 64 Å2 (DMPC at 35°C) to 109 Å2 (TMCL at 50°C). KC increases by ~50%, indicating that TMCL stiffens DMPC membranes. TMCL also orders DMPC chains by a factor of ~2 for pure TMCL. Coarse grain molecular dynamics simulations confirm the experimental thickening of 2 Å for 20 mol% TMCL and locate the TMCL headgroups near the glycerol-carbonyl region of DMPC; i.e., they are sequestered below the DMPC phosphocholine headgroup. Our results suggest that TMCL plays a role similar to cholesterol in that it thickens and stiffens DMPC membranes, orders chains, and is positioned under the umbrella of the PC headgroup. CL may be necessary for hydrophobic matching to inner mitochondrial membrane proteins. Differential scanning calorimetry, Sxray and CGMD simulations all suggest that TMCL does not form domains within the DMPC bilayers. We also determined the gel phase structure of TMCL, which surprisingly displays diffuse X-ray scattering, like a

  18. Spectroscopic and MD simulation studies on unfolding processes of mitochondrial carbonic anhydrase VA induced by urea.

    PubMed

    Idrees, Danish; Prakash, Amresh; Haque, Md Anzarul; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-09-01

    Carbonic anhydrase VA (CAVA) is primarily expressed in the mitochondria and involved in numerous physiological processes including lipogenesis, insulin secretion from pancreatic cells, ureagenesis, gluconeogenesis and neuronal transmission. To understand the biophysical properties of CAVA, we carried out a reversible urea-induced isothermal denaturation at pH 7.0 and 25°C. Spectroscopic probes, [θ]222 (mean residue ellipticity at 222 nm), F344 (Trp-fluorescence emission intensity at 344 nm) and Δε280 (difference absorption at 280 nm) were used to monitor the effect of urea on the structure and stability of CAVA. The urea-induced reversible denaturation curves were used to estimate [Formula: see text], Gibbs free energy in the absence of urea; Cm, the mid-point of the denaturation curve, i.e. molar urea concentration ([urea]) at which ΔGD = 0; and m, the slope (=∂ΔGD/∂[urea]). Coincidence of normalized transition curves of all optical properties suggests that unfolding/refolding of CAVA is a two-state process. We further performed 40 ns molecular dynamics simulation of CAVA to see the dynamics at different urea concentrations. An excellent agreement was observed between in silico and in vitro studies. PMID:26421381

  19. Self-assembly of polyelectrolyte surfactant complexes using large scale MD simulation

    NASA Astrophysics Data System (ADS)

    Goswami, Monojoy; Sumpter, Bobby

    2014-03-01

    Polyelectrolytes (PE) and surfactants are known to form interesting structures with varied properties in aqueous solutions. The morphological details of the PE-surfactant complexes depend on a combination of polymer backbone, electrostatic interactions and hydrophobic interactions. We study the self-assembly of cationic PE and anionic surfactants complexes in dilute condition. The importance of such complexes of PE with oppositely charged surfactants can be found in biological systems, such as immobilization of enzymes in polyelectrolyte complexes or nonspecific association of DNA with protein. Many useful properties of PE surfactant complexes come from the highly ordered structures of surfactant self-assembly inside the PE aggregate which has applications in industry. We do large scale molecular dynamics simulation using LAMMPS to understand the structure and dynamics of PE-surfactant systems. Our investigation shows highly ordered pearl-necklace structures that have been observed experimentally in biological systems. We investigate many different properties of PE-surfactant complexation for different parameter ranges that are useful for pharmaceutical, engineering and biological applications.

  20. Effect of Aggregation on the Mechanical Properties of Ionomers from MD Simulations

    NASA Astrophysics Data System (ADS)

    Sampath, Janani; Hall, Lisa M.

    Ionomers are polymers with a small fraction of charged monomers; these bound ions, along with free counterions, tend to aggregate together strongly in the absence of solvent. Ionic aggregates can act like temporary cross-links, giving rise to interesting mechanical properties. We perform coarse-grained molecular dynamics simulations of ionomers with various spacings of charges along the chain, representing experimental precisely spaced, neutralized poly(ethylene-co-acrylic acid) materials. We calculate aggregate morphology, dynamics, and scattering profiles and study the systems during uniaxial tensile strain to understand how aggregate structure changes under deformation and affects mechanical properties. Anisotropic structure factors (parallel and perpendicular to the direction of pull) and visualization shows that the aggregates align, in qualitative agreement with experimental findings. Stress-strain curves at different strain rates are also obtained. A modification of the model to account for unneutralized acid groups by adjusting their Lennard-Jones interaction strengths with each other and with ionic groups will also be discussed. This material is based upon work supported by the National Science Foundation under Grant 1463103.

  1. Bicelles and Other Membrane Mimics: Comparison of Structure, Properties, and Dynamics from MD Simulations.

    PubMed

    Vestergaard, Mikkel; Kraft, Johan F; Vosegaard, Thomas; Thøgersen, Lea; Schiøtt, Birgit

    2015-12-31

    The increased interest in studying membrane proteins has led to the development of new membrane mimics such as bicelles and nanodiscs. However, only limited knowledge is available of how these membrane mimics are affected by embedded proteins and how well they mimic a lipid bilayer. Herein, we present molecular dynamics simulations to elucidate structural and dynamic properties of small bicelles and compare them to a large alignable bicelle, a small nanodisc, and a lipid bilayer. Properties such as lipid packing and properties related to embedding both an α-helical peptide and a transmembrane protein are investigated. The small bicelles are found to be very dynamic and mainly assume a prolate shape substantiating that small bicelles cannot be regarded as well-defined disclike structures. However, addition of a peptide results in an increased tendency to form disc-shaped bicelles. The small bicelles and the nanodiscs show increased peptide solvation and difference in peptide orientation compared to embedding in a bilayer. The large bicelle imitated a bilayer well with respect to both curvature and peptide solvation, although peripheral binding of short tailed lipids to the embedded proteins is observed, which could hinder ligand binding or multimer formation. PMID:26610232

  2. Conformational Preadjustment in Aqueous Claisen Rearrangement Revealed by SITS-QM/MM MD Simulations.

    PubMed

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

    2015-04-30

    An efficient sampling method was implemented in QM/MM hybrid molecular simulations to study aliphatic Claisen rearrangement in aqueous solutions. On the basis of the computational results, the necessary conformational adjustment to trap the reactant into a favorable compact conformation specifically in water was observed. The conformational equilibrium was shown to be important to the elucidation of the "water-acceleration" effect of Claisen rearrangement. Thus, a two-step process of aqueous Claisen rearrangement was proposed. It was similar to the pseudodiaxial-pseudodiequatorial conformational equilibrium observed in the enzymatic reaction of chorismate acid but with explicit inclusion of the solvent coordinates to explain the solvation effects. Polarization was found to occur during the reactant conformational transition. A solvent with high cohesive energy density (CED) like water was suggested to accommodate compact conformers better, thus facilitating the following reaction by concentrating the real "active" reactant. The substituent effects also manifested, leading to varied conformational distributions of different substituted allyl vinyl ethers (AVEs). The application of the enhanced sampling method allowed a systematic analysis of thermodynamic information without loss of solvent coordinates. These data showed the conformational transition of AVEs was an entropy-driving process which was sensitive to the substituent, and enthalpy played an important role in the solvation effect on the conformational equilibrium. PMID:25849201

  3. The Unfolding MD Simulations of Cyclophilin: Analyzed by Surface Contact Networks and Their Associated Metrics

    PubMed Central

    Roy, Sourav; Basu, Sankar; Dasgupta, Dipak; Bhattacharyya, Dhananjay; Banerjee, Rahul

    2015-01-01

    Currently, considerable interest exists with regard to the dissociation of close packed aminoacids within proteins, in the course of unfolding, which could result in either wet or dry moltenglobules. The progressive disjuncture of residues constituting the hydrophobic core ofcyclophilin from L. donovani (LdCyp) has been studied during the thermal unfolding of the molecule, by molecular dynamics simulations. LdCyp has been represented as a surface contactnetwork (SCN) based on the surface complementarity (Sm) of interacting residues within themolecular interior. The application of Sm to side chain packing within proteins make it a very sensitive indicator of subtle perturbations in packing, in the thermal unfolding of the protein. Network based metrics have been defined to track the sequential changes in the disintegration ofthe SCN spanning the hydrophobic core of LdCyp and these metrics prove to be highly sensitive compared to traditional metrics in indicating the increased conformational (and dynamical) flexibility in the network. These metrics have been applied to suggest criteria distinguishing DMG, WMG and transition state ensembles and to identify key residues involved in crucial conformational/topological events during the unfolding process. PMID:26545107

  4. Mechanical Unfolding of Acylphosphatase Studied by Single-Molecule Force Spectroscopy and MD Simulations

    PubMed Central

    Arad-Haase, Gali; Chuartzman, Silvia G.; Dagan, Shlomi; Nevo, Reinat; Kouza, Maksim; Mai, Binh Khanh; Nguyen, Hung Tien; Li, Mai Suan; Reich, Ziv

    2010-01-01

    Abstract Single-molecule manipulation methods provide a powerful means to study protein transitions. Here we combined single-molecule force spectroscopy and steered molecular-dynamics simulations to study the mechanical properties and unfolding behavior of the small enzyme acylphosphatase (AcP). We find that mechanical unfolding of AcP occurs at relatively low forces in an all-or-none fashion and is decelerated in the presence of a ligand, as observed in solution measurements. The prominent energy barrier for the transition is separated from the native state by a distance that is unusually long for α/β proteins. Unfolding is initiated at the C-terminal strand (βT) that lies at one edge of the β-sheet of AcP, followed by unraveling of the strand located at the other. The central strand of the sheet and the two helices in the protein unfold last. Ligand binding counteracts unfolding by stabilizing contacts between an arginine residue (Arg-23) and the catalytic loop, as well as with βT of AcP, which renders the force-bearing units of the protein resistant to force. This stabilizing effect may also account for the decelerated unfolding of ligand-bound AcP in the absence of force. PMID:20655852

  5. Slow-Onset Inhibition of Mycobacterium tuberculosis InhA: Revealing Molecular Determinants of Residence Time by MD Simulations

    PubMed Central

    Merget, Benjamin; Sotriffer, Christoph A.

    2015-01-01

    An important kinetic parameter for drug efficacy is the residence time of a compound at a drug target, which is related to the dissociation rate constant koff. For the essential antimycobacterial target InhA, this parameter is most likely governed by the ordering of the flexible substrate binding loop (SBL). Whereas the diphenyl ether inhibitors 6PP and triclosan (TCL) do not show loop ordering and thus, no slow-binding inhibition and high koff values, the slightly modified PT70 leads to an ordered loop and a residence time of 24 minutes. To assess the structural differences of the complexes from a dynamic point of view, molecular dynamics (MD) simulations with a total sampling time of 3.0 µs were performed for three ligand-bound and two ligand-free (perturbed) InhA systems. The individual simulations show comparable conformational features with respect to both the binding pocket and the SBL, allowing to define five recurring conformational families. Based on their different occurrence frequencies in the simulated systems, the conformational preferences could be linked to structural differences of the respective ligands to reveal important determinants of residence time. The most abundant conformation besides the stable EI* state is characterized by a shift of Ile202 and Val203 toward the hydrophobic pocket of InhA. The analyses revealed potential directions for avoiding this conformational change and, thus, hindering rapid dissociation: (1) an anchor group in 2'-position of the B-ring for scaffold stabilization, (2) proper occupation of the hydrophobic pocket, and (3) the introduction of a barricade substituent in 5'-position of the diphenyl ether B-ring. PMID:25996598

  6. Impact of 2′-hydroxyl sampling on the conformational properties of RNA: Update of the CHARMM all-atom additive force field for RNA

    PubMed Central

    Denning, Elizabeth J.; Priyakumar, U. Deva; Nilsson, Lennart; MacKerell, Alexander D.

    2011-01-01

    Here, we present an update of the CHARMM27 all-atom additive force field for nucleic acids that improves the treatment of RNA molecules. The original CHARMM27 force field parameters exhibit enhanced Watson-Crick (WC) base pair opening which is not consistent with experiment while analysis of MD simulations show the 2′-hydroxyl moiety to almost exclusively sample the O3′ orientation. Quantum mechanical studies of RNA related model compounds indicate the energy minimum associated with the O3′ orientation to be too favorable, consistent with the MD results. Optimization of the dihedral parameters dictating the energy of the 2′-hydroxyl proton targeting the QM data yielded several parameter sets, which sample both the base and O3′ orientations of the 2′-hydroxyl to varying degrees. Selection of the final dihedral parameters was based on reproduction of hydration behavior as related to a survey of crystallographic data and better agreement with experimental NMR J-coupling values. Application of the model, designated CHARMM36, to a collection of canonical and non-canonical RNA molecules reveals overall improved agreement with a range of experimental observables as compared to CHARMM27. The results also indicate the sensitivity of the conformational heterogeneity of RNA to the orientation of the 2′-hydroxyl moiety and support a model whereby the 2′-hydroxyl can enhance the probability of conformational transitions in RNA. PMID:21469161

  7. Membrane association of the PTEN tumor suppressor: Neutron scattering and MD simulations reveal the structure of protein-membranes complexes

    PubMed Central

    Nanda, Hirsh; Heinrich, Frank; Lösche, Mathias

    2014-01-01

    Neutron reflection (NR) from planar interfaces is an emerging technology that provides unique and otherwise inaccessible structural information on disordered molecular systems such as membrane proteins associated with fluid bilayers, thus addressing one of the remaining challenges of structural biology. Although intrinsically a low-resolution technique, using structural information from crystallography or NMR allows the construction of NR models that describe the architecture of protein-membrane complexes at high resolution. In addition, a combination of these methods with molecular dynamics (MD) simulations has the potential to reveal the dynamics of protein interactions with the bilayer in atomistic detail. We review recent advances in this area by discussing the application of these techniques to the complex formed by the PTEN phosphatase with the plasma membrane. These studies provide insights in the cellular regulation of PTEN, its interaction with PI(4,5)P2 in the inner plasma membrane and the pathway by which its substrate, PI(3,4,5)P3, accesses the PTEN catalytic site. PMID:25461777

  8. Understanding cage effects in imidazolium ionic liquids by 129Xe NMR: MD simulations and relativistic DFT calculations.

    PubMed

    Saielli, Giacomo; Bagno, Alessandro; Castiglione, Franca; Simonutti, Roberto; Mauri, Michele; Mele, Andrea

    2014-12-01

    (129)Xe NMR has been recently employed to probe the local structure of ionic liquids (ILs). However, no theoretical investigation has been yet reported addressing the problem of the dependence of the chemical shift of xenon on the cage structure of the IL. Therefore, we present here a study of the chemical shift of (129)Xe in two ionic liquids, [bmim][Cl] and [bmim][PF6], by a combination of classical MD simulations and relativistic DFT calculations of the xenon shielding constant. The bulk structure of the two ILs is investigated by means of the radial distribution functions, paying special attention to the local structure, volume, and charge distribution of the cage surrounding the xenon atom. Relativistic DFT calculations, based on the ZORA formalism, on clusters extracted from the trajectory files of the two systems, yield an average relative chemical shift in good agreement with the experimental data. Our results demonstrate the importance of the cage volume and the average charge surrounding the xenon nucleus in the IL cage as the factors determining the effective shielding. PMID:25394282

  9. MD simulations of the binding of alcohols and diols by a calixarene in water: connections between microscopic and macroscopic properties.

    PubMed

    Ghoufi, A; Morel, J P; Morel-Desrosiers, N; Malfreyt, P

    2005-12-15

    We report results of molecular dynamics (MD) simulations of the complexes of p-sulfonatocalix[4]arene with linear alcohols from ethanol to heptanol in water at 25 degrees C. We show that these complexes are of the inclusion type and are governed by van der Waals interactions between the calixarene cavity and the inserted alkyl chain of the alcohol. We establish a correlation between the experimental Delta(r)H degrees values and the number of atoms inserted into the calixarene cavity. We also focus on the desolvation of the host and guest to establish the importance, at the enthalpic level, of the formation of hydrogen bond bridges between the calixarene and the alcohol molecule. The fact that methanol is not complexed by p-sulfonatocalix[4]arene is explained by calculating the cost of the desolvation of the guest upon complexation. We complete this study by modeling the complexes formed with 1,4-butanediol and 1,5-pentanediol. To explain the difference between the thermodynamic properties for the binding of 1,4-butanediol and butanol, we examine the insertion rate and the solvation of each hydroxy group. We show a specific behavior of one of the two hydroxy groups at the structural and energetic levels. PMID:16375334

  10. Degradation of the Adhesive Properties of MD-944 Diode Tape by Simulated Low Earth Orbit Environmental Factors

    NASA Technical Reports Server (NTRS)

    Albyn, K.; Finckenor, M.

    2006-01-01

    The International Space Station (ISS) solar arrays utilize MD-944 diode tape with silicone pressure-sensitive adhesive to protect the underlying diodes and also provide a high-emittance surface. On-orbit, the silicone adhesive will be exposed and ultimately convert to a glass-like silicate due to atomic oxygen (AO). The current operational plan is to retract ISS solar array P6 and leave it stored under load for a long duration (6 mo or more). The exposed silicone adhesive must not cause the solar array to stick to itself or cause the solar array to fail during redeployment. The Environmental Effects Branch at Marshall Space Flight Center, under direction from the ISS Program Office Environments Team, performed simulated space environment exposures with 5-eV AO, near ultraviolet radiation and ionizing radiation. The exposed diode tape samples were put under preload and then the resulting blocking force was measured using a tensile test machine. Test results indicate that high-energy AO, ultraviolet radiation, and electron ionizing radiation exposure all reduce the blocking force for a silicone-to-silicone bond. AO exposure produces the most significant reduction in blocking force

  11. Coupling between protonation and conformation in cytochrome c oxidase: Insights from constant-pH MD simulations.

    PubMed

    Oliveira, A Sofia F; Campos, Sara R R; Baptista, António M; Soares, Cláudio M

    2016-06-01

    Cytochrome c oxidases (CcOs) are the terminal enzymes of the respiratory chain in mitochondria and most bacteria. These enzymes reduce dioxygen (O2) to water and, simultaneously, generate a transmembrane electrochemical proton gradient. Despite their importance in the aerobic metabolism and the large amount of structural and biochemical data available for the A1-type CcO family, there is still no consensually accepted description of the molecular mechanisms operating in this protein. A substantial number of questions about the CcO's working mechanism remain to be answered, including how the protonation behavior of some key residues is modulated during a reduction cycle and how is the conformation of the protein affected by protonation. The main objective of this work was to study the protonation-conformation coupling in CcOs and identify the molecular factors that control the protonation state of some key residues. In order to directly capture the interplay between protonation and conformational effects, we have performed constant-pH MD simulations of an A1-type CcO inserted into a lipid bilayer in two redox states (oxidized and reduced) at physiological pH. From the simulations, we were able to identify several groups with unusual titration behavior that are highly dependent on the protein redox state, including the A-propionate from heme a and the D-propionate from heme a3, two key groups possibly involved in proton pumping. The protonation state of these two groups is heavily influenced by subtle conformational changes in the protein (notably of R481I and R482I) and by small changes in the hydrogen bond network. PMID:27033303

  12. An all-atom force field developed for Zn₄O(RCO₂)₆ metal organic frameworks.

    PubMed

    Sun, Yingxin; Sun, Huai

    2014-03-01

    An all-atom force field is developed for metal organic frameworks Zn₄O(RCO₂)₆ by fitting to quantum mechanics data. Molecular simulations are conducted to validate the force field by calculating thermal expansion coefficients, crystal bulk and Young's moduli, power spectra, self-diffusion coefficients, and activation energies of self-diffusions for benzene and n-hexane. The calculated results are in good agreement with available experimental data. The proposed force field is suitable for simulations of adsorption or diffusion of organic molecules with flexible frameworks. PMID:24562858

  13. Effects of different self-assembled monolayers on thin-film morphology: a combined DFT/MD simulation protocol.

    PubMed

    Alberga, Domenico; Mangiatordi, Giuseppe Felice; Motta, Alessandro; Nicolotti, Orazio; Lattanzi, Gianluca

    2015-10-01

    Organic thin film transistors (OTFTs) are multilayer field-effect transistors that employ an organic conjugated material as semiconductor. Several experimental groups have recently demonstrated that the insertion of an organic self-assembled monolayer (SAM) between the dielectric and the semiconductive layer is responsible for a sensible improvement of the OTFT performances in terms of an increased charge carrier mobility caused by a higher degree of order in the organic semiconductor layer. Here, we describe a combined periodic density functional theory (DFT) and classical molecular dynamics (MD) protocol applied to four different SAMs and a pentacene monolayer deposited onto their surfaces. In particular, we investigate the morphology and the surface of the four SAMs and the translational, orientational, and nematic order of the monolayer through the calculation of several distribution functions and order parameters pointing out the differences among the systems and relating them to known experimental results. Our calculations also suggest that small differences in the SAM molecular design will produce remarkable differences in the SAM surface and monolayer order. In particular, our simulations explain how a SAM with a bulky terminal group results in an irregular and rough surface that determines the deposition of a disordered semiconductive monolayer. On the contrary, SAMs with a small terminal group generate smooth surfaces with uninterrupted periodicity, thus favoring the formation of an ordered pentacene monolayer that increases the mobility of charge carriers and improves the overall performances of the OTFT devices. Our results clearly point out that the in silico procedure presented here might be of help in tuning the design of SAMs in order to improve the quality of OTFT devices. PMID:26367250

  14. Conformational Ensemble of the Poliovirus 3CD Precursor Observed by MD Simulations and Confirmed by SAXS: A Strategy to Expand the Viral Proteome?

    PubMed Central

    Moustafa, Ibrahim M.; Gohara, David W.; Uchida, Akira; Yennawar, Neela; Cameron, Craig E.

    2015-01-01

    The genomes of RNA viruses are relatively small. To overcome the small-size limitation, RNA viruses assign distinct functions to the processed viral proteins and their precursors. This is exemplified by poliovirus 3CD protein. 3C protein is a protease and RNA-binding protein. 3D protein is an RNA-dependent RNA polymerase (RdRp). 3CD exhibits unique protease and RNA-binding activities relative to 3C and is devoid of RdRp activity. The origin of these differences is unclear, since crystal structure of 3CD revealed “beads-on-a-string” structure with no significant structural differences compared to the fully processed proteins. We performed molecular dynamics (MD) simulations on 3CD to investigate its conformational dynamics. A compact conformation of 3CD was observed that was substantially different from that shown crystallographically. This new conformation explained the unique properties of 3CD relative to the individual proteins. Interestingly, simulations of mutant 3CD showed altered interface. Additionally, accelerated MD simulations uncovered a conformational ensemble of 3CD. When we elucidated the 3CD conformations in solution using small-angle X-ray scattering (SAXS) experiments a range of conformations from extended to compact was revealed, validating the MD simulations. The existence of conformational ensemble of 3CD could be viewed as a way to expand the poliovirus proteome, an observation that may extend to other viruses. PMID:26610545

  15. 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. PMID:26848515

  16. Local Structure in Terms of Nearest-Neighbor Approach in 1-Butyl-3-methylimidazolium-Based Ionic Liquids: MD Simulations.

    PubMed

    Marekha, Bogdan A; Koverga, Volodymyr A; Chesneau, Erwan; Kalugin, Oleg N; Takamuku, Toshiyuki; Jedlovszky, Pál; Idrissi, Abdenacer

    2016-06-01

    Description of the local microscopic structure in ionic liquids (ILs) is a prerequisite to obtain a comprehensive understanding of the influence of the nature of ions on the properties of ILs. The local structure is mainly determined by the spatial arrangement of the nearest neighboring ions. Therefore, the main interaction patterns in ILs, such as cation-anion H-bond-like motifs, cation-cation alkyl tail aggregation, and ring stacking, were considered within the framework of the nearest-neighbor approach with respect to each particular interaction site. We employed classical molecular dynamics (MD) simulations to study in detail the spatial, radial, and orientational relative distribution of ions in a set of imidazolium-based ILs, in which the 1-butyl-3-methylimidazolium (C4mim(+)) cation is coupled with the acetate (OAc(-)), chloride (Cl(-)), tetrafluoroborate (BF4(-)), hexafluorophosphate (PF6(-)), trifluoromethanesulfonate (TfO(-)), or bis(trifluoromethanesulfonyl)amide (TFSA(-)) anion. It was established that several structural properties are strongly anion-specific, while some can be treated as universally applicable to ILs, regardless of the nature of the anion. Namely, strongly basic anions, such as OAc(-) and Cl(-), prefer to be located in the imidazolium ring plane next to the C-H(2/4-5) sites. By contrast, the other four bulky and weakly coordinating anions tend to occupy positions above/below the plane. Similarly, the H-bond-like interactions involving the H(2) site are found to be particularly enhanced in comparison with the ones at H(4-5) in the case of asymmetric and/or more basic anions (C4mimOAc, C4mimCl, C4mimTfO, and C4mimTFSA), in accordance with recent spectroscopic and theoretical findings. Other IL-specific details related to the multiple H-bond-like binding and cation stacking issues are also discussed in this paper. The secondary H-bonding of anions with the alkyl hydrogen atoms of cations as well as the cation-cation alkyl chain

  17. Hydration Properties and Solvent Effects for All-Atom Solutes in Polarizable Coarse-Grained Water.

    PubMed

    Yan, Xin Cindy; Tirado-Rives, Julian; Jorgensen, William L

    2016-08-25

    Due to the importance of water in chemical and biological systems, a coarse-grained representation of the solvent can greatly simplify the description of the system while retaining key thermodynamic properties of the medium. A multiscale solvation model that couples all-atom solutes and polarizable Martini coarse-grained water (AAX/CGS) is developed to reproduce free energies of hydration of organic solutes. Using Monte Carlo/free energy perturbation (MC/FEP) calculations, results from multiscale and all-atom simulations are compared. Improved accuracy is obtained with the AAX/CGS approach for hydrophobic and sulfur- or halogen-containing solutes, but larger deviations are found for polar solute molecules where hydrogen bonding is featured. Furthermore, solvent effects on conformational and tautomeric equilibria of AA solutes were investigated using AA, CG, and GB/SA solvent models. It is found that the CG solvent model can reproduce well the medium effects from experiment and AA simulations; however, the GB/SA solvent model fails in some cases. A 7-30-fold reduction in computational cost is found for the present AAX/CGS multiscale simulations compared to the AA alternative. PMID:26901452

  18. All-Atom Molecular Dynamics of Virus Capsids as Drug Targets.

    PubMed

    Perilla, Juan R; Hadden, Jodi A; Goh, Boon Chong; Mayne, Christopher G; Schulten, Klaus

    2016-05-19

    Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid-protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways. When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Here, the current challenges of performing all-atom capsid-drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets. PMID:27128262

  19. All-Atom Molecular Dynamics of Virus Capsids as Drug Targets

    PubMed Central

    2016-01-01

    Virus capsids are protein shells that package the viral genome. Although their morphology and biological functions can vary markedly, capsids often play critical roles in regulating viral infection pathways. A detailed knowledge of virus capsids, including their dynamic structure, interactions with cellular factors, and the specific roles that they play in the replication cycle, is imperative for the development of antiviral therapeutics. The following Perspective introduces an emerging area of computational biology that focuses on the dynamics of virus capsids and capsid–protein assemblies, with particular emphasis on the effects of small-molecule drug binding on capsid structure, stability, and allosteric pathways. When performed at chemical detail, molecular dynamics simulations can reveal subtle changes in virus capsids induced by drug molecules a fraction of their size. Here, the current challenges of performing all-atom capsid–drug simulations are discussed, along with an outlook on the applicability of virus capsid simulations to reveal novel drug targets. PMID:27128262

  20. A simple and transferable all-atom/coarse-grained hybrid model to study membrane processes.

    PubMed

    Genheden, Samuel; Essex, Jonathan W

    2015-10-13

    We present an efficient all-atom/coarse-grained hybrid model and apply it to membrane processes. This model is an extension of the all-atom/ELBA model applied previously to processes in water. Here, we improve the efficiency of the model by implementing a multiple-time step integrator that allows the atoms and the coarse-grained beads to be propagated at different timesteps. Furthermore, we fine-tune the interaction between the atoms and the coarse-grained beads by computing the potential of mean force of amino acid side chain analogs along the membrane normal and comparing to atomistic simulations. The model was independently validated on the calculation of small-molecule partition coefficients. Finally, we apply the model to membrane peptides. We studied the tilt angle of the Walp23 and Kalp23 helices in two different model membranes and the stability of the glycophorin A dimer. The model is efficient, accurate, and straightforward to use, as it does not require any extra interaction particles, layers of atomistic solvent molecules or tabulated potentials, thus offering a novel, simple approach to study membrane processes. PMID:26574264

  1. An All-Atom Model of the Structure of Human Copper Transporter 1

    PubMed Central

    Sharikov, Yuriy; Greenberg, Jerry P.; Miller, Mark A.; Kouznetsova, Valentina L.; Larson, Christopher A.; Howell, Stephen B.

    2013-01-01

    Human copper transporter 1 (hCTR1) is the major high affinity copper influx transporter in mammalian cells that also mediates uptake of the cancer chemotherapeutic agent cisplatin. A low resolution structure of hCTR1 determined by cryoelectron microscopy was recently published. Several protein structure simulation techniques were used to create an all-atom model of this important transporter using the low resolution structure as a starting point. The all-atom model provides new insights into the roles of specific residues of the N-terminal extracellular domain, the intracellular loop, and C-terminal region in metal ion transport. In particular, the model demonstrates that the central region of the pore contains four sets of methionine triads in the intramembranous region. The structure confirms that two triads of methionine residues delineate the intramembranous region of the transporter, and further identifies two additional methionine triads that are located in the extracellular N-terminal part of the transporter. Together, the four triads create a structure that promotes stepwise transport of metal ions into and then through the intramembranous channel of the transporter via transient thioether bonds to methionine residues. Putative copper-binding sites in the hCTR1 trimer were identified by a program developed by us for prediction of metal-binding sites. These sites correspond well with the known effects of mutations on the ability of the protein to transport copper and cisplatin. PMID:22569840

  2. Rapid Heme Transfer Reactions between NEAr Transporter Domains of Staphylococcus aureus: A Theoretical Study Using QM/MM and MD Simulations

    PubMed Central

    Moriwaki, Yoshitaka; Terada, Tohru; Tsumoto, Kouhei; Shimizu, Kentaro

    2015-01-01

    In vertebrates, most iron is present as heme or is chelated by proteins. Thus, Gram-positive pathogens such as Staphylococcus aureus have evolved an iron-regulated surface determinant (Isd) system that transports heme across thick cell walls into the cytoplasm. Recent studies have demonstrated that heme is rapidly transferred between the NEAr Transporter (NEAT) domains of the Isd system, despite its high affinity toward each domain, suggesting the presence of an intermediate NEAT•heme•NEAT complex. In the present study, we performed short restrained molecular dynamics (MD) simulations to dock the acceptor NEAT domain to the donor NEAT•heme complex and obtained models where the two NEAT domains were arranged with two-fold pseudo symmetry around the heme molecule. After turning off the restraints, complex structures were stably maintained during subsequent unrestrained MD simulations, except for the hydrogen bond between the propionate group of the heme molecule and the donor NEAT domain, potentially facilitating the transition of heme from the donor to the acceptor. Subsequent structural optimization using the quantum mechanics/molecular mechanics (QM/MM) method showed that two tyrosine residues, one from each NEAT domain, were simultaneously coordinated to the ferric heme iron in the intermediate complex only if they were deprotonated. Based on these results, we propose a reaction scheme for heme transfer between NEAT domains. PMID:26658942

  3. Interionic hydration structures of NaCl in aqueous solution: a combined study of quantum mechanical cluster calculations and QM/EFP-MD simulations.

    PubMed

    Ghosh, Manik K; Re, Suyong; Feig, Michael; Sugita, Yuji; Choi, Cheol Ho

    2013-01-10

    The association process of NaCl in aqueous solution was studied by a combination of quantum mechanical calculations on NaCl(H(2)O)(n) (n = 1-6) clusters and quantum mechanical/effective fragment potential-molecular dynamics (QM/EFP-MD) simulations for NaCl in 292 EFP waters. The interionic hydration structures (IHSs) were topologically classified as "ring" (R), "half-bridge" (H), and "full-bridge" (F) types on the basis of the quantum mechanical calculations. Subsequent IHS analysis on QM/EFP-MD simulations revealed that the NaCl contact ion pair (CIP) mainly involved R type hydration structures while the solvent-separated ion pair (SSIP) was composed of two different groups of F-type hydration structures. Our IHS analysis also discovered H type hydration even at large separation interionic distances (∼7 Å), which is denoted as a dissociating ion pair (DIP). The analysis was able to reveal the most complete interionic structures and their reorganizations of the association process. A strong correlation between the IHSs and interionic distance suggests that not only the solvent reorganization but also the local IHS changes are equally important. Mechanistically, it is suggested that the conversion between ring-type and full-bridge hydration structures is the main rate-determining step of ion-pair association. PMID:23231378

  4. LDRD Final Report (08-ERD-037): Important Modes to Drive Protein MD Simulations to the Next Conformational Level

    SciTech Connect

    Sadigh, B

    2011-04-07

    Every action in biology is performed by dynamic proteins that convert between multiple states in order to engage their functions. Often binding to various ligands is essential for the rates of desired transitions to be enhanced. The goal of computational biology is to study these transitions and discover the different states to fully understand the protein's normal and diseased function, design drugs to target/bias specific states, and understand all of the interactions in between. We have developed a new methodology that is capable of calculating the absolute free energy of proteins while taking into account all the interactions with the solvent molecules. The efficiency of the new scheme is an order of magnitude greater than any existing technique. This method is now implemented in the massively parallel popular MD program package NAMD. This now makes it possible to calculate the relative stability of different conformational states of biological macromolecules as well as their binding free energies to various ligands.

  5. Local order parameters for use in driving homogeneous ice nucleation with all-atom models of water.

    PubMed

    Reinhardt, Aleks; Doye, Jonathan P K; Noya, Eva G; Vega, Carlos

    2012-11-21

    We present a local order parameter based on the standard Steinhardt-Ten Wolde approach that is capable both of tracking and of driving homogeneous ice nucleation in simulations of all-atom models of water. We demonstrate that it is capable of forcing the growth of ice nuclei in supercooled liquid water simulated using the TIP4P/2005 model using over-biassed umbrella sampling Monte Carlo simulations. However, even with such an order parameter, the dynamics of ice growth in deeply supercooled liquid water in all-atom models of water are shown to be very slow, and so the computation of free energy landscapes and nucleation rates remains extremely challenging. PMID:23181323

  6. Energy Landscape of All-Atom Protein-Protein Interactions Revealed by Multiscale Enhanced Sampling

    PubMed Central

    Moritsugu, Kei; Terada, Tohru; Kidera, Akinori

    2014-01-01

    Protein-protein interactions are regulated by a subtle balance of complicated atomic interactions and solvation at the interface. To understand such an elusive phenomenon, it is necessary to thoroughly survey the large configurational space from the stable complex structure to the dissociated states using the all-atom model in explicit solvent and to delineate the energy landscape of protein-protein interactions. In this study, we carried out a multiscale enhanced sampling (MSES) simulation of the formation of a barnase-barstar complex, which is a protein complex characterized by an extraordinary tight and fast binding, to determine the energy landscape of atomistic protein-protein interactions. The MSES adopts a multicopy and multiscale scheme to enable for the enhanced sampling of the all-atom model of large proteins including explicit solvent. During the 100-ns MSES simulation of the barnase-barstar system, we observed the association-dissociation processes of the atomistic protein complex in solution several times, which contained not only the native complex structure but also fully non-native configurations. The sampled distributions suggest that a large variety of non-native states went downhill to the stable complex structure, like a fast folding on a funnel-like potential. This funnel landscape is attributed to dominant configurations in the early stage of the association process characterized by near-native orientations, which will accelerate the native inter-molecular interactions. These configurations are guided mostly by the shape complementarity between barnase and barstar, and lead to the fast formation of the final complex structure along the downhill energy landscape. PMID:25340714

  7. New insight into the architecture of oxy-anion pocket in unliganded conformation of GAT domains: A MD-simulation study.

    PubMed

    Bairagya, Hridoy R; Bansal, Manju

    2016-03-01

    Human Guanine Monophosphate Synthetase (hGMPS) converts XMP to GMP, and acts as a bifunctional enzyme with N-terminal "glutaminase" (GAT) and C-terminal "synthetase" domain. The enzyme is identified as a potential target for anti-cancer and immunosuppressive therapies. GAT domain of enzyme plays central role in metabolism, and contains conserved catalytic residues Cys104, His190, and Glu192. MD simulation studies on GAT domain suggest that position of oxyanion in unliganded conformation is occupied by one conserved water molecule (W1), which also stabilizes that pocket. This position is occupied by a negatively charged atom of the substrate or ligand in ligand bound crystal structures. In fact, MD simulation study of Ser75 to Val indicates that W1 conserved water molecule is stabilized by Ser75, while Thr152, and His190 also act as anchor residues to maintain appropriate architecture of oxyanion pocket through water mediated H-bond interactions. Possibly, four conserved water molecules stabilize oxyanion hole in unliganded state, but they vacate these positions when the enzyme (hGMPS)-substrate complex is formed. Thus this study not only reveals functionally important role of conserved water molecules in GAT domain, but also highlights essential role of other non-catalytic residues such as Ser75 and Thr152 in this enzymatic domain. The results from this computational study could be of interest to experimental community and provide a testable hypothesis for experimental validation. Conserved sites of water molecules near and at oxyanion hole highlight structural importance of water molecules and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site. PMID:26756917

  8. Step-edge self-assembly during graphene nucleation on a nickel surface: QM/MD simulations.

    PubMed

    Wang, Ying; Page, Alister J; Li, Hai-Bei; Qian, Hu-Jun; Jiao, Meng-Gai; Wu, Zhi-Jian; Morokuma, Keiji; Irle, Stephan

    2014-01-01

    Quantum chemical molecular dynamics simulations of graphene nucleation on the Ni(111) surface show that graphene creates its own step-edge as it forms. This "step-edge self-assembly" is driven by the formation of thermodynamically favorable Ni-C σ-bonds at the graphene edge. This dynamic aspect of the Ni(111) catalyst is in contrast to the commonly accepted view that graphene nucleates on a pre-existing, static catalyst step-edge. Simulations also show that, simply by manipulating the subsurface carbon density, preferential formation of single-layer graphene instead of multi-layer graphene can be achieved on nickel catalysts. PMID:24202187

  9. Quasielastic neutron scattering measurements and ab initio MD-simulations on single ion motions in molten NaF.

    PubMed

    Demmel, F; Mukhopadhyay, S

    2016-01-01

    The ionic stochastic motions in the molten alkali halide NaF are investigated by quasielastic neutron scattering and first principles molecular dynamics simulation. Quasielastic neutron scattering was employed to extract the diffusion behavior of the sodium ions in the melt. An extensive first principles based simulation on a box of up to 512 particles has been performed to complement the experimental data. From that large box, a smaller 64-particle box has then been simulated over a runtime of 60 ps. A good agreement between calculated and neutron data on the level of spectral shape has been obtained. The obtained sodium diffusion coefficients agree very well. The simulation predicts a fluorine diffusion coefficient similar to the sodium one. Applying the Nernst-Einstein equation, a remarkable large cross correlation between both ions can be deduced. The velocity cross correlations demonstrate a positive correlation between the ions over a period of 0.1 ps. That strong correlation is evidence that the unlike ions do not move completely statistically independent and have a strong association over a short period of time. PMID:26747811

  10. Quasielastic neutron scattering measurements and ab initio MD-simulations on single ion motions in molten NaF

    NASA Astrophysics Data System (ADS)

    Demmel, F.; Mukhopadhyay, S.

    2016-01-01

    The ionic stochastic motions in the molten alkali halide NaF are investigated by quasielastic neutron scattering and first principles molecular dynamics simulation. Quasielastic neutron scattering was employed to extract the diffusion behavior of the sodium ions in the melt. An extensive first principles based simulation on a box of up to 512 particles has been performed to complement the experimental data. From that large box, a smaller 64-particle box has then been simulated over a runtime of 60 ps. A good agreement between calculated and neutron data on the level of spectral shape has been obtained. The obtained sodium diffusion coefficients agree very well. The simulation predicts a fluorine diffusion coefficient similar to the sodium one. Applying the Nernst-Einstein equation, a remarkable large cross correlation between both ions can be deduced. The velocity cross correlations demonstrate a positive correlation between the ions over a period of 0.1 ps. That strong correlation is evidence that the unlike ions do not move completely statistically independent and have a strong association over a short period of time.

  11. CHARMM Additive All-Atom Force Field for Acyclic Polyalcohols, Acyclic Carbohydrates and Inositol

    PubMed Central

    Hatcher, Elizabeth; Guvench, Olgun; MacKerell, Alexander D.

    2009-01-01

    Parametrization of the additive all-atom CHARMM force field for acyclic polyalcohols, acyclic carbohydrates and inositol is conducted. Initial parameters were transferred from the alkanes and hexopyranose carbohydrates, with subsequent development and optimization of parameters unique to the molecules considered in this study. Using the model compounds acetone and acetaldehyde, nonbonded parameters for carbonyls were optimized targeting quantum mechanical interaction data for solute-water pairs and pure solvent thermodynamic data. Bond and angle parameters were adjusted by comparing optimized geometries to small molecule crystal survey data and by performing vibrational analyses on acetone, acetaldehyde and glycerol. C-C-C-C, C-C-C-O, C-C-OH and O-C-C-O torsional parameters for polyol chains were fit to quantum mechanical dihedral potential energy scans comprising over 1500 RIMP2/cc-pVTZ//MP2/6-31G(d) conformations using an automated Monte Carlo simulated annealing procedure. Comparison of computed condensed-phase data, including crystal lattice parameters and densities, NMR proton-proton couplings, densities and diffusion coefficients of aqueous solutions, to experimental data validated the optimized parameters. Parameter development for these compounds proved particularly challenging because of the flexibility of the acyclic sugars and polyalcohols as well as the intramolecular hydrogen bonding between vicinal hydroxyls for all of the compounds. The newly optimized additive CHARMM force field parameters are anticipated to be of utility for atomic level of detail simulations of acyclic polyalcohols, acyclic carbohydrates and inositol in solution. PMID:20160980

  12. Fusion Simulation Project. Workshop Sponsored by the U.S. Department of Energy, Rockville, MD, May 16-18, 2007

    SciTech Connect

    Kritz, A.; Keyes, D.

    2007-05-18

    The mission of the Fusion Simulation Project is to develop a predictive capability for the integrated modeling of magnetically confined plasmas. This FSP report adds to the previous activities that defined an approach to integrated modeling in magnetic fusion. These previous activities included a Fusion Energy Sciences Advisory Committee panel that was charged to study integrated simulation in 2002. The report of that panel [Journal of Fusion Energy 20, 135 (2001)] recommended the prompt initiation of a Fusion Simulation Project. In 2003, the Office of Fusion Energy Sciences formed a steering committee that developed a project vision, roadmap, and governance concepts [Journal of Fusion Energy 23, 1 (2004)]. The current FSP planning effort involved forty-six physicists, applied mathematicians and computer scientists, from twenty-one institutions, formed into four panels and a coordinating committee. These panels were constituted to consider: Status of Physics Components, Required Computational and Applied Mathematics Tools, Integration and Management of Code Components, and Project Structure and Management. The ideas, reported here, are the products of these panels, working together over several months and culminating in a three-day workshop in May 2007.

  13. Fusion Simulation Project. Workshop sponsored by the U.S. Department of Energy Rockville, MD, May 16-18, 2007

    SciTech Connect

    2007-05-16

    The mission of the Fusion Simulation Project is to develop a predictive capability for the integrated modeling of magnetically confined plasmas. This FSP report adds to the previous activities that defined an approach to integrated modeling in magnetic fusion. These previous activities included a Fusion Energy Sciences Advisory Committee panel that was charged to study integrated simulation in 2002. The report of that panel [Journal of Fusion Energy 20, 135 (2001)] recommended the prompt initiation of a Fusion Simulation Project. In 2003, the Office of Fusion Energy Sciences formed a steering committee that developed a project vision, roadmap, and governance concepts [Journal of Fusion Energy 23, 1 (2004)]. The current FSP planning effort involved forty-six physicists, applied mathematicians and computer scientists, from twenty-one institutions, formed into four panels and a coordinating committee. These panels were constituted to consider: Status of Physics Components, Required Computational and Applied Mathematics Tools, Integration and Management of Code Components, and Project Structure and Management. The ideas, reported here, are the products of these panels, working together over several months and culminating in a three-day workshop in May 2007.

  14. A MD Simulation and Analysis for Aggregation Behaviors of Nanoscale Zero-Valent Iron Particles in Water via MS

    PubMed Central

    Liu, Dongmei; Tang, Huan; Lu, Jing; Cui, Fuyi

    2014-01-01

    With the development of nanotechnology, more nanomaterials will enter into water environment system. Studying the existing form of nanomaterials in water environment will help people benefit from the correct use of them and to reduce the harm to human caused by them for some nanomaterials can bring polluting effect. Aggregation is a main behavior for nanoparticle in water environment. NZVI are used widely in many fields resulting in more NZVI in water environment. Molecular dynamics simulations and Materials Studio software are used to investigate the microaggregation behaviors of NZVI particles. Two scenes are involved: (1) particle size of NZVI in each simulation system is the same, but initial distance of two NZVI particles is different; (2) initial distance of two NZVI particles in each simulation system is the same, but particle size of NZVI is different. Atomistic trajectory, NP activity, total energy, and adsorption of H2O are analyzed with MS. The method provides new quantitative insight into the structure, energy, and dynamics of the aggregation behaviors of NZVI particles in water. It is necessary to understand microchange of NPs in water because it can provide theoretical research that is used to reduce polluting effect of NPs on water environment. PMID:25250388

  15. Elucidation of Enzymatic Mechanism of Phenazine Biosynthetic Protein PhzF Using QM/MM and MD Simulations

    PubMed Central

    Liu, Fei; Zhao, Yi-Lei; Wang, Xiaolei; Hu, Hongbo; Peng, Huasong; Wang, Wei; Wang, Jing-Fang; Zhang, Xuehong

    2015-01-01

    The phenazine biosynthetic pathway is of considerable importance for the pharmaceutical industry. The pathway produces two products: phenazine-1,6-dicarboxylic acid and phenazine-1-carboxylic acid. PhzF is an isomerase that catalyzes trans-2,3-dihydro-3-hydroxyanthranilic acid isomerization and plays an essential role in the phenazine biosynthetic pathway. Although the PhzF crystal structure has been determined recently, an understanding of the detailed catalytic mechanism and the roles of key catalytic residues are still lacking. In this study, a computational strategy using a combination of molecular modeling, molecular dynamics simulations, and quantum mechanics/molecular mechanics simulations was used to elucidate these important issues. The Apo enzyme, enzyme–substrate complexes with negatively charged Glu45, enzyme–transition state analog inhibitor complexes with neutral Glu45, and enzyme–product complexes with negatively charged Glu45 structures were optimized and modeled using a 200 ns molecular dynamics simulation. Residues such as Gly73, His74, Asp208, Gly212, Ser213, and water, which play important roles in ligand binding and the isomerization reaction, were comprehensively investigated. Our results suggest that the Glu45 residue at the active site of PhzF acts as a general base/acid catalyst during proton transfer. This study provides new insights into the detailed catalytic mechanism of PhzF and the results have important implications for PhzF modification. PMID:26414009

  16. Effect of pH on the structure, function, and stability of human calcium/calmodulin-dependent protein kinase IV: combined spectroscopic and MD simulation studies.

    PubMed

    Naz, Huma; Shahbaaz, Mohd; Bisetty, Krishna; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-06-01

    Human calcium/calmodulin-dependent protein kinase IV (CAMKIV) is a member of Ser/Thr protein kinase family. It is regulated by the calcium-calmodulin dependent signal through a secondary messenger, Ca(2+), which leads to the activation of its autoinhibited form. The over-expression and mutation in CAMKIV as well as change in Ca(2+) concentration is often associated with numerous neurodegenerative diseases and cancers. We have successfully cloned, expressed, and purified a functionally active kinase domain of human CAMKIV. To observe the effect of different pH conditions on the structural and functional properties of CAMKIV, we have used spectroscopic techniques such as circular diachroism (CD) absorbance and fluorescence. We have observed that within the pH range 5.0-11.5, CAMKIV maintained both its secondary and tertiary structures, along with its function, whereas significant aggregation was observed at acidic pH (2.0-4.5). We have also performed ATPase activity assays under different pH conditions and found a significant correlation between the structure and enzymatic activities of CAMKIV. In-silico validations were further carried out by modeling the 3-dimensional structure of CAMKIV and then subjecting it to molecular dynamics (MD) simulations to understand its conformational behavior in explicit water conditions. A strong correlation between spectroscopic observations and the output of molecular dynamics simulation was observed for CAMKIV. PMID:27032767

  17. Effects of HO-/MeO-PBDEs on androgen receptor: in vitro investigation and helix 12-involved MD simulation.

    PubMed

    Wang, Xiaoxiang; Yang, Huaiyu; Hu, Xinxin; Zhang, Xiaowei; Zhang, Qiansen; Jiang, Hualiang; Shi, Wei; Yu, Hongxia

    2013-10-15

    Hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) have received increasing attention for their potential endocrine disrupting activities and widely environmental distribution. However, little information is available for the anti-androgenic activities, and the molecular mechanism of interactions with androgen receptor (AR) is not fully understood. In the present study, cell line assay and computational simulation were integrated to systematically explore the molecular mechanism of interactions between chemicals and AR. The metabolites with similar molecular structures exhibited different anti-androgenic activity while none of them showed androgenic activity. According to the multisystem molecular dynamics simulation, minute differences in the structure of ligands induced dramatic different conformational transition of AR-ligand binding domain (LBD). The Helix12 (H12) component of active ligands occupied AR-LBD could become stable, but this component continued to fluctuate in inactive ligands occupied AR-LBD. Settling time and reposition of H12 obtained in dynamics process are important factors governing anti-androgenic activities. The related settling times were characteristic of anti-androgenic potencies of the tested chemicals. Overall, in our study, the stable reposition of H12 is characterized as a computational mark for identifying AR antagonists from PBDE metabolites, or even other various environmental pollutants. PMID:24044724

  18. Surface Catalysis Modeling of Air-SiO2 Systems Under Hypersonic Conditions Using ReaxFF MD Simulation

    NASA Astrophysics Data System (ADS)

    Norman, Paul; Schwartzentruber, Tom; Cozmuta, Ioana

    2009-11-01

    The high-speed entry of a blunt body into Earth's atmosphere brings about the dissociation of diatomic nitrogen and oxygen molecules via the shockwave formed in front of the body. Through surface catalysis, these dissociated atoms can recombine on the heat shield of the body, increasing its overall heating. The goal of this project is to study surface catalysis on amorphous silicon-dioxide (SiO2), a significant component in the reusable thermal protection system used on the Space Shuttle. Specifically, our objective is to determine the rates of recombination of monatomic N and O for the range of temperatures and pressures experienced by a heat shield during Earth re-entry. Additionally, we aim to determine the rates of specific reaction mechanisms on a SiO2 surface, including adsorption, desorption, surface diffusion, and various recombination processes. This is accomplished by performing large reactive molecular dynamics simulations using the ReaxFF force field, which naturally allows bond formation/breaking to occur during the course of a molecular dynamics simulation. Several methods for speeding up the equilibration and collection of rates for low-pressure gas-surface systems (typical of re-entry conditions) where events become infrequent will also be discussed.

  19. Multiscale approach for the construction of equilibrated all-atom models of a poly(ethylene glycol)-based hydrogel.

    PubMed

    Li, Xianfeng; Murthy, N Sanjeeva; Becker, Matthew L; Latour, Robert A

    2016-06-01

    A multiscale modeling approach is presented for the efficient construction of an equilibrated all-atom model of a cross-linked poly(ethylene glycol) (PEG)-based hydrogel using the all-atom polymer consistent force field (PCFF). The final equilibrated all-atom model was built with a systematic simulation toolset consisting of three consecutive parts: (1) building a global cross-linked PEG-chain network at experimentally determined cross-link density using an on-lattice Monte Carlo method based on the bond fluctuation model, (2) recovering the local molecular structure of the network by transitioning from the lattice model to an off-lattice coarse-grained (CG) model parameterized from PCFF, followed by equilibration using high performance molecular dynamics methods, and (3) recovering the atomistic structure of the network by reverse mapping from the equilibrated CG structure, hydrating the structure with explicitly represented water, followed by final equilibration using PCFF parameterization. The developed three-stage modeling approach has application to a wide range of other complex macromolecular hydrogel systems, including the integration of peptide, protein, and/or drug molecules as side-chains within the hydrogel network for the incorporation of bioactivity for tissue engineering, regenerative medicine, and drug delivery applications. PMID:27013229

  20. Conformational properties of α- or β-(1→6)-linked oligosaccharides: Hamiltonian replica exchange MD simulations and NMR experiments.

    PubMed

    Patel, Dhilon S; Pendrill, Robert; Mallajosyula, Sairam S; Widmalm, Göran; MacKerell, Alexander D

    2014-03-20

    Conformational sampling for a set of 10 α- or β-(1→6)-linked oligosaccharides has been studied using explicit solvent Hamiltonian replica exchange (HREX) simulations and NMR spectroscopy techniques. Validation of the force field and simulation methodology is done by comparing calculated transglycosidic J coupling constants and proton-proton distances with the corresponding NMR data. Initial calculations showed poor agreement, for example, with >3 Hz deviation of the calculated (3)J(H5,H6R) values from the experimental data, prompting optimization of the ω torsion angle parameters associated with (1→6)-linkages. The resulting force field is in overall good agreement (i.e., within ∼0.5 Hz deviation) from experimental (3)J(H5,H6R) values, although some small limitations are evident. Detailed hydrogen bonding analysis indicates that most of the compounds lack direct intramolecular H-bonds between the two monosaccharides; however, minor sampling of the O6···HO2' hydrogen bond is present in three compounds. The results verify the role of the gauche effect between O5 and O6 atoms in gluco- and manno-configured pyranosides causing the ω torsion angle to sample an equilibrium between the gt and gg rotamers. Conversely, galacto-configured pyranosides sample a population distribution in equilibrium between gt and tg rotamers, while the gg rotamer populations are minor. Water radial distribution functions suggest decreased accessibility to the O6 atom in the (1→6)-linkage as compared to the O6' atom in the nonreducing sugar. The role of bridging water molecules between two sugar moieties on the distributions of ω torsion angles in oligosaccharides is also explored. PMID:24552401

  1. Conformational Properties of α- or β-(1→6)-Linked Oligosaccharides: Hamiltonian Replica Exchange MD Simulations and NMR Experiments

    PubMed Central

    2015-01-01

    Conformational sampling for a set of 10 α- or β-(1→6)-linked oligosaccharides has been studied using explicit solvent Hamiltonian replica exchange (HREX) simulations and NMR spectroscopy techniques. Validation of the force field and simulation methodology is done by comparing calculated transglycosidic J coupling constants and proton–proton distances with the corresponding NMR data. Initial calculations showed poor agreement, for example, with >3 Hz deviation of the calculated 3J(H5,H6R) values from the experimental data, prompting optimization of the ω torsion angle parameters associated with (1→6)-linkages. The resulting force field is in overall good agreement (i.e., within ∼0.5 Hz deviation) from experimental 3J(H5,H6R) values, although some small limitations are evident. Detailed hydrogen bonding analysis indicates that most of the compounds lack direct intramolecular H-bonds between the two monosaccharides; however, minor sampling of the O6···HO2′ hydrogen bond is present in three compounds. The results verify the role of the gauche effect between O5 and O6 atoms in gluco- and manno-configured pyranosides causing the ω torsion angle to sample an equilibrium between the gt and gg rotamers. Conversely, galacto-configured pyranosides sample a population distribution in equilibrium between gt and tg rotamers, while the gg rotamer populations are minor. Water radial distribution functions suggest decreased accessibility to the O6 atom in the (1→6)-linkage as compared to the O6′ atom in the nonreducing sugar. The role of bridging water molecules between two sugar moieties on the distributions of ω torsion angles in oligosaccharides is also explored. PMID:24552401

  2. Liquid-liquid extraction of uranyl by TBP: the TBP and ions models and related interfacial features revisited by MD and PMF simulations.

    PubMed

    Benay, G; Wipff, G

    2014-03-20

    We report a molecular dynamics (MD) study of biphasic systems involved in the liquid-liquid extraction of uranyl nitrate by tri-n-butylphosphate (TBP) to hexane, from "pH neutral" or acidic (3 M nitric acid) aqueous solutions, to assess the model dependence of the surface activity and partitioning of TBP alone, of its UO2(NO3)2(TBP)2 complex, and of UO2(NO3)2 or UO2(2+) uncomplexed. For this purpose, we first compare several electrostatic representations of TBP with regards to its polarity and conformational properties, its interactions with H2O, HNO3, and UO2(NO3)2 species, its relative free energies of solvation in water or oil environments, the properties of the pure TBP liquid and of the pure-TBP/water interface. The free energies of transfer of TBP, UO2(NO3)2, UO2(2+), and the UO2(NO3)2(TBP)2 complex across the water/oil interface are then investigated by potential of mean force (PMF) calculations, comparing different TBP models and two charge models of uranyl nitrate. Describing uranyl and nitrate ions with integer charges (+2 and -1, respectively) is shown to exaggerate the hydrophilicity and surface activity of the UO2(NO3)2(TBP)2 complex. With more appropriate ESP charges, mimicking charge transfer and polarization effects in the UO2(NO3)2 moiety or in the whole complex, the latter is no more surface active. This feature is confirmed by MD, PMF, and mixing-demixing simulations with or without polarization. Furthermore, with ESP charges, pulling the UO2(NO3)2 species to the TBP phase affords the formation of UO2(NO3)2(TBP)2 at the interface, followed by its energetically favorable extraction. The neutral complexes should therefore not accumulate at the interface during the extraction process, but diffuse to the oil phase. A similar feature is found for an UO2(NO3)2(Amide)2 neutral complex with fatty amide extracting ligands, calling for further simulations and experimental studies (e.g., time evolution of the nonlinear spectroscopic signature and of surface

  3. Preformed template fluctuations promote fibril formation: Insights from lattice and all-atom models

    SciTech Connect

    Kouza, Maksim Kolinski, Andrzej; Co, Nguyen Truong; Nguyen, Phuong H.; Li, Mai Suan

    2015-04-14

    Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Despite the fact that the fibril formation process is very slow and thus poses a significant challenge for theoretical and experimental studies, a number of alternative pictures of molecular mechanisms of amyloid fibril formation have been recently proposed. What seems to be common for the majority of the proposed models is that fibril elongation involves the formation of pre-nucleus seeds prior to the creation of a critical nucleus. Once the size of the pre-nucleus seed reaches the critical nucleus size, its thermal fluctuations are expected to be small and the resulting nucleus provides a template for sequential (one-by-one) accommodation of added monomers. The effect of template fluctuations on fibril formation rates has not been explored either experimentally or theoretically so far. In this paper, we make the first attempt at solving this problem by two sets of simulations. To mimic small template fluctuations, in one set, monomers of the preformed template are kept fixed, while in the other set they are allowed to fluctuate. The kinetics of addition of a new peptide onto the template is explored using all-atom simulations with explicit water and the GROMOS96 43a1 force field and simple lattice models. Our result demonstrates that preformed template fluctuations can modulate protein aggregation rates and pathways. The association of a nascent monomer with the template obeys the kinetics partitioning mechanism where the intermediate state occurs in a fraction of routes to the protofibril. It was shown that template immobility greatly increases the time of incorporating a new peptide into the preformed template compared to the fluctuating template case. This observation has also been confirmed by simulation using lattice models and may be invoked to understand the role of template fluctuations in

  4. Preformed template fluctuations promote fibril formation: Insights from lattice and all-atom models

    NASA Astrophysics Data System (ADS)

    Kouza, Maksim; Co, Nguyen Truong; Nguyen, Phuong H.; Kolinski, Andrzej; Li, Mai Suan

    2015-04-01

    Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite the fact that the fibril formation process is very slow and thus poses a significant challenge for theoretical and experimental studies, a number of alternative pictures of molecular mechanisms of amyloid fibril formation have been recently proposed. What seems to be common for the majority of the proposed models is that fibril elongation involves the formation of pre-nucleus seeds prior to the creation of a critical nucleus. Once the size of the pre-nucleus seed reaches the critical nucleus size, its thermal fluctuations are expected to be small and the resulting nucleus provides a template for sequential (one-by-one) accommodation of added monomers. The effect of template fluctuations on fibril formation rates has not been explored either experimentally or theoretically so far. In this paper, we make the first attempt at solving this problem by two sets of simulations. To mimic small template fluctuations, in one set, monomers of the preformed template are kept fixed, while in the other set they are allowed to fluctuate. The kinetics of addition of a new peptide onto the template is explored using all-atom simulations with explicit water and the GROMOS96 43a1 force field and simple lattice models. Our result demonstrates that preformed template fluctuations can modulate protein aggregation rates and pathways. The association of a nascent monomer with the template obeys the kinetics partitioning mechanism where the intermediate state occurs in a fraction of routes to the protofibril. It was shown that template immobility greatly increases the time of incorporating a new peptide into the preformed template compared to the fluctuating template case. This observation has also been confirmed by simulation using lattice models and may be invoked to understand the role of template fluctuations in

  5. Preformed template fluctuations promote fibril formation: insights from lattice and all-atom models.

    PubMed

    Kouza, Maksim; Co, Nguyen Truong; Nguyen, Phuong H; Kolinski, Andrzej; Li, Mai Suan

    2015-04-14

    Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite the fact that the fibril formation process is very slow and thus poses a significant challenge for theoretical and experimental studies, a number of alternative pictures of molecular mechanisms of amyloid fibril formation have been recently proposed. What seems to be common for the majority of the proposed models is that fibril elongation involves the formation of pre-nucleus seeds prior to the creation of a critical nucleus. Once the size of the pre-nucleus seed reaches the critical nucleus size, its thermal fluctuations are expected to be small and the resulting nucleus provides a template for sequential (one-by-one) accommodation of added monomers. The effect of template fluctuations on fibril formation rates has not been explored either experimentally or theoretically so far. In this paper, we make the first attempt at solving this problem by two sets of simulations. To mimic small template fluctuations, in one set, monomers of the preformed template are kept fixed, while in the other set they are allowed to fluctuate. The kinetics of addition of a new peptide onto the template is explored using all-atom simulations with explicit water and the GROMOS96 43a1 force field and simple lattice models. Our result demonstrates that preformed template fluctuations can modulate protein aggregation rates and pathways. The association of a nascent monomer with the template obeys the kinetics partitioning mechanism where the intermediate state occurs in a fraction of routes to the protofibril. It was shown that template immobility greatly increases the time of incorporating a new peptide into the preformed template compared to the fluctuating template case. This observation has also been confirmed by simulation using lattice models and may be invoked to understand the role of template fluctuations in

  6. All-atom molecular dynamics calculation study of entire poliovirus empty capsids in solution

    SciTech Connect

    Andoh, Y.; Yoshii, N.; Yamada, A.; Kojima, H.; Mizutani, K.; Okazaki, S.; Fujimoto, K.; Nakagawa, A.; Nomoto, A.

    2014-10-28

    Small viruses that belong, for example, to the Picornaviridae, such as poliovirus and foot-and-mouth disease virus, consist simply of capsid proteins and a single-stranded RNA (ssRNA) genome. The capsids are quite stable in solution to protect the genome from the environment. Here, based on long-time and large-scale 6.5 × 10{sup 6} all-atom molecular dynamics calculations for the Mahoney strain of poliovirus, we show microscopic properties of the viral capsids at a molecular level. First, we found equilibrium rapid exchange of water molecules across the capsid. The exchange rate is so high that all water molecules inside the capsid (about 200 000) can leave the capsid and be replaced by water molecules from the outside in about 25 μs. This explains the capsid's tolerance to high pressures and deactivation by exsiccation. In contrast, the capsid did not exchange ions, at least within the present simulation time of 200 ns. This implies that the capsid can function, in principle, as a semipermeable membrane. We also found that, similar to the xylem of trees, the pressure of the solution inside the capsid without the genome was negative. This is caused by coulombic interaction of the solution inside the capsid with the capsid excess charges. The negative pressure may be compensated by positive osmotic pressure by the solution-soluble ssRNA and the counter ions introduced into it.

  7. Refined OPLS all-atom force field for saturated phosphatidylcholine bilayers at full hydration.

    PubMed

    Maciejewski, Arkadiusz; Pasenkiewicz-Gierula, Marta; Cramariuc, Oana; Vattulainen, Ilpo; Rog, Tomasz

    2014-05-01

    We report parametrization of dipalmitoyl-phosphatidylcholine (DPPC) in the framework of the Optimized Parameters for Liquid Simulations all-atom (OPLS-AA) force field. We chose DPPC as it is one of the most studied phospholipid species and thus has plenty of experimental data necessary for model validation, and it is also one of the highly important and abundant lipid types, e.g., in lung surfactant. Overall, PCs have not been previously parametrized in the OPLS-AA force field; thus, there is a need to derive its bonding and nonbonding parameters for both the polar and nonpolar parts of the molecule. In the present study, we determined the parameters for torsion angles in the phosphatidylcholine and glycerol moieties and in the acyl chains, as well the partial atomic charges. In these calculations, we used three methods: (1) Hartree-Fock (HF), (2) second order Møller-Plesset perturbation theory (MP2), and (3) density functional theory (DFT). We also tested the effect of the polar environment by using the polarizable continuum model (PCM), and for acyl chains the van der Waals parameters were also adjusted. In effect, six parameter sets were generated and tested on a DPPC bilayer. Out of these six sets, only one was found to be able to satisfactorily reproduce experimental data for the lipid bilayer. The successful DPPC model was obtained from MP2 calculations in an implicit polar environment (PCM). PMID:24745688

  8. All-atom molecular dynamics calculation study of entire poliovirus empty capsids in solution

    NASA Astrophysics Data System (ADS)

    Andoh, Y.; Yoshii, N.; Yamada, A.; Fujimoto, K.; Kojima, H.; Mizutani, K.; Nakagawa, A.; Nomoto, A.; Okazaki, S.

    2014-10-01

    Small viruses that belong, for example, to the Picornaviridae, such as poliovirus and foot-and-mouth disease virus, consist simply of capsid proteins and a single-stranded RNA (ssRNA) genome. The capsids are quite stable in solution to protect the genome from the environment. Here, based on long-time and large-scale 6.5 × 106 all-atom molecular dynamics calculations for the Mahoney strain of poliovirus, we show microscopic properties of the viral capsids at a molecular level. First, we found equilibrium rapid exchange of water molecules across the capsid. The exchange rate is so high that all water molecules inside the capsid (about 200 000) can leave the capsid and be replaced by water molecules from the outside in about 25 μs. This explains the capsid's tolerance to high pressures and deactivation by exsiccation. In contrast, the capsid did not exchange ions, at least within the present simulation time of 200 ns. This implies that the capsid can function, in principle, as a semipermeable membrane. We also found that, similar to the xylem of trees, the pressure of the solution inside the capsid without the genome was negative. This is caused by coulombic interaction of the solution inside the capsid with the capsid excess charges. The negative pressure may be compensated by positive osmotic pressure by the solution-soluble ssRNA and the counter ions introduced into it.

  9. Characterization of Zebrafish Cardiac and Slow Skeletal Troponin C Paralogs by MD Simulation and ITC.

    PubMed

    Stevens, Charles M; Rayani, Kaveh; Genge, Christine E; Singh, Gurpreet; Liang, Bo; Roller, Janine M; Li, Cindy; Li, Alison Yueh; Tieleman, D Peter; van Petegem, Filip; Tibbits, Glen F

    2016-07-12

    Zebrafish, as a model for teleost fish, have two paralogous troponin C (TnC) genes that are expressed in the heart differentially in response to temperature acclimation. Upon Ca(2+) binding, TnC changes conformation and exposes a hydrophobic patch that interacts with troponin I and initiates cardiac muscle contraction. Teleost-specific TnC paralogs have not yet been functionally characterized. In this study we have modeled the structures of the paralogs using molecular dynamics simulations at 18°C and 28°C and calculated the different Ca(2+)-binding properties between the teleost cardiac (cTnC or TnC1a) and slow-skeletal (ssTnC or TnC1b) paralogs through potential-of-mean-force calculations. These values are compared with thermodynamic binding properties obtained through isothermal titration calorimetry (ITC). The modeled structures of each of the paralogs are similar at each temperature, with the exception of helix C, which flanks the Ca(2+) binding site; this region is also home to paralog-specific sequence substitutions that we predict have an influence on protein function. The short timescale of the potential-of-mean-force calculation precludes the inclusion of the conformational change on the ΔG of Ca(2+) interaction, whereas the ITC analysis includes the Ca(2+) binding and conformational change of the TnC molecule. ITC analysis has revealed that ssTnC has higher Ca(2+) affinity than cTnC for Ca(2+) overall, whereas each of the paralogs has increased affinity at 28°C compared to 18°C. Microsecond-timescale simulations have calculated that the cTnC paralog transitions from the closed to the open state more readily than the ssTnC paralog, an unfavorable transition that would decrease the ITC-derived Ca(2+) affinity while simultaneously increasing the Ca(2+) sensitivity of the myofilament. We propose that the preferential expression of cTnC at lower temperatures increases myofilament Ca(2+) sensitivity by this mechanism, despite the lower Ca(2+) affinity

  10. Low-mass molecular dynamics simulation: A simple and generic technique to enhance configurational sampling

    SciTech Connect

    Pang, Yuan-Ping

    2014-09-26

    Highlights: • Reducing atomic masses by 10-fold vastly improves sampling in MD simulations. • CLN025 folded in 4 of 10 × 0.5-μs MD simulations when masses were reduced by 10-fold. • CLN025 folded as early as 96.2 ns in 1 of the 4 simulations that captured folding. • CLN025 did not fold in 10 × 0.5-μs MD simulations when standard masses were used. • Low-mass MD simulation is a simple and generic sampling enhancement technique. - Abstract: CLN025 is one of the smallest fast-folding proteins. Until now it has not been reported that CLN025 can autonomously fold to its native conformation in a classical, all-atom, and isothermal–isobaric molecular dynamics (MD) simulation. This article reports the autonomous and repeated folding of CLN025 from a fully extended backbone conformation to its native conformation in explicit solvent in multiple 500-ns MD simulations at 277 K and 1 atm with the first folding event occurring as early as 66.1 ns. These simulations were accomplished by using AMBER forcefield derivatives with atomic masses reduced by 10-fold on Apple Mac Pros. By contrast, no folding event was observed when the simulations were repeated using the original AMBER forcefields of FF12SB and FF14SB. The results demonstrate that low-mass MD simulation is a simple and generic technique to enhance configurational sampling. This technique may propel autonomous folding of a wide range of miniature proteins in classical, all-atom, and isothermal–isobaric MD simulations performed on commodity computers—an important step forward in quantitative biology.

  11. Multiscale simulation of polymer nano-composites (PNC) using molecular dynamics (MD) and generalized interpolation material point method (GIMP)

    NASA Astrophysics Data System (ADS)

    Nair, Abilash R.

    Recent mechanical characterization experiments with pultruded E-Glass / polypropylene (PP) and compression molded E-Glass/Nylon-6 composite samples with 3-4 weight% nanoclay and baseline polymer (polymer without nanoclay) confirmed significant improvements in compressive strength (˜122%) and shear strength (˜60%) in the nanoclay modified nanocomposites, in comparison with baseline properties. Uniaxial tensile tests showed a small increase in tensile strength (˜3.4%) with 3 wt % nanoclay loading. While the synergistic reinforcing influence of nanoparticle reinforcement is obvious, a simple rule-of-mixtures approach fails to quantify the dramatic increase in mechanical properties. Consequently, there is an immediate need to investigate and understand the mechanisms at the nanoscale that are responsible for such unprecedented strength enhancements. In this work, an innovative and effective method to model nano-structured components in a thermoplastic polymer matrix is proposed. Effort will be directed towards finding fundamental answers to the reasons for significant changes in mechanical properties of nanoparticle-reinforced thermoplastic composites. This research ensues a multiscale modeling approach in which (a) a concurrent simulations scheme is developed to visualize atomistic behavior of polymer molecules as a function of continuum scale loading conditions and (b) a novel nanoscale damage mechanics model is proposed to capture the constitutive behavior of polymer nano composites (PNC). The proposed research will contribute towards the understanding of advanced nanostructured composite materials, which should subsequently benefit the composites manufacturing industry.

  12. Corresponding Functional Dynamics across the Hsp90 Chaperone Family: Insights from a Multiscale Analysis of MD Simulations

    PubMed Central

    Morra, Giulia; Potestio, Raffaello; Micheletti, Cristian; Colombo, Giorgio

    2012-01-01

    Understanding how local protein modifications, such as binding small-molecule ligands, can trigger and regulate large-scale motions of large protein domains is a major open issue in molecular biology. We address various aspects of this problem by analyzing and comparing atomistic simulations of Hsp90 family representatives for which crystal structures of the full length protein are available: mammalian Grp94, yeast Hsp90 and E.coli HtpG. These chaperones are studied in complex with the natural ligands ATP, ADP and in the Apo state. Common key aspects of their functional dynamics are elucidated with a novel multi-scale comparison of their internal dynamics. Starting from the atomic resolution investigation of internal fluctuations and geometric strain patterns, a novel analysis of domain dynamics is developed. The results reveal that the ligand-dependent structural modulations mostly consist of relative rigid-like movements of a limited number of quasi-rigid domains, shared by the three proteins. Two common primary hinges for such movements are identified. The first hinge, whose functional role has been demonstrated by several experimental approaches, is located at the boundary between the N-terminal and Middle-domains. The second hinge is located at the end of a three-helix bundle in the Middle-domain and unfolds/unpacks going from the ATP- to the ADP-state. This latter site could represent a promising novel druggable allosteric site common to all chaperones. PMID:22457611

  13. Comparative MD Simulations Indicate a Dual Role for Arg1323.50 in Dopamine-Dependent D2R Activation

    PubMed Central

    Kling, Ralf C.; Clark, Timothy; Gmeiner, Peter

    2016-01-01

    Residue Arg3.50 belongs to the highly conserved DRY-motif of class A GPCRs, which is located at the bottom of TM3. On the one hand, Arg3.50 has been reported to help stabilize the inactive state of GPCRs, but on the other hand has also been shown to be crucial for stabilizing active receptor conformations and mediating receptor-G protein coupling. The combined results of these studies suggest that the exact function of Arg3.50 is likely to be receptor-dependent and must be characterized independently for every GPCR. Consequently, we now present comparative molecular-dynamics simulations that use our recently described inactive-state and Gα-bound active-state homology models of the dopamine D2 receptor (D2R), which are either bound to dopamine or ligand-free, performed to identify the function of Arg1323.50 in D2R. Our results are consistent with a dynamic model of D2R activation in which Arg1323.50 adopts a dual role, both by stabilizing the inactive-state receptor conformation and enhancing dopamine-dependent D2R-G protein coupling. PMID:26741139

  14. Crystal structure and MD simulation of mouse EndoV reveal wedge motif plasticity in this inosine-specific endonuclease

    PubMed Central

    Nawaz, Meh Sameen; Vik, Erik Sebastian; Ronander, Mia Elise; Solvoll, Anne Marthe; Blicher, Pernille; Bjørås, Magnar; Alseth, Ingrun; Dalhus, Bjørn

    2016-01-01

    Endonuclease V (EndoV) is an enzyme with specificity for deaminated adenosine (inosine) in nucleic acids. EndoV from Escherichia coli (EcEndoV) acts both on inosines in DNA and RNA, whereas the human homolog cleaves only at inosines in RNA. Inosines in DNA are mutagenic and the role of EndoV in DNA repair is well established. In contrast, the biological function of EndoV in RNA processing is largely unexplored. Here we have characterized a second mammalian EndoV homolog, mouse EndoV (mEndoV), and show that mEndoV shares the same RNA selectivity as human EndoV (hEndoV). Mouse EndoV cleaves the same inosine-containing substrates as hEndoV, but with reduced efficiencies. The crystal structure of mEndoV reveals a conformation different from the hEndoV and prokaryotic EndoV structures, particularly for the conserved tyrosine in the wedge motif, suggesting that this strand separating element has some flexibility. Molecular dynamics simulations of mouse and human EndoV reveal alternative conformations for the invariant tyrosine. The configuration of the active site, on the other hand, is very similar between the prokaryotic and mammalian versions of EndoV. PMID:27108838

  15. Structural characterization of MG and pre-MG states of proteins by MD simulations, NMR, and other techniques.

    PubMed

    Naiyer, Abdullah; Hassan, Md Imtaiyaz; Islam, Asimul; Sundd, Monica; Ahmad, Faizan

    2015-01-01

    Almost all proteins fold via a number of partially structured intermediates such as molten globule (MG) and pre-molten globule states. Understanding the structure of these intermediates at atomic level is often a challenge, as these states are observed under extreme conditions of pH, temperature, and chemical denaturants. Furthermore, several other processes such as chemical modification, site-directed mutagenesis (or point mutation), and cleavage of covalent bond of natural proteins often lead to MG like partially unfolded conformation. However, the dynamic nature of proteins in these states makes them unsuitable for most structure determination at atomic level. Intermediate states studied so far have been characterized mostly by circular dichroism, fluorescence, viscosity, dynamic light scattering measurements, dye binding, infrared techniques, molecular dynamics simulations, etc. There is a limited amount of structural data available on these intermediate states by nuclear magnetic resonance (NMR) and hence there is a need to characterize these states at the molecular level. In this review, we present characterization of equilibrium intermediates by biophysical techniques with special reference to NMR. PMID:25586676

  16. Crystal structure and MD simulation of mouse EndoV reveal wedge motif plasticity in this inosine-specific endonuclease.

    PubMed

    Nawaz, Meh Sameen; Vik, Erik Sebastian; Ronander, Mia Elise; Solvoll, Anne Marthe; Blicher, Pernille; Bjørås, Magnar; Alseth, Ingrun; Dalhus, Bjørn

    2016-01-01

    Endonuclease V (EndoV) is an enzyme with specificity for deaminated adenosine (inosine) in nucleic acids. EndoV from Escherichia coli (EcEndoV) acts both on inosines in DNA and RNA, whereas the human homolog cleaves only at inosines in RNA. Inosines in DNA are mutagenic and the role of EndoV in DNA repair is well established. In contrast, the biological function of EndoV in RNA processing is largely unexplored. Here we have characterized a second mammalian EndoV homolog, mouse EndoV (mEndoV), and show that mEndoV shares the same RNA selectivity as human EndoV (hEndoV). Mouse EndoV cleaves the same inosine-containing substrates as hEndoV, but with reduced efficiencies. The crystal structure of mEndoV reveals a conformation different from the hEndoV and prokaryotic EndoV structures, particularly for the conserved tyrosine in the wedge motif, suggesting that this strand separating element has some flexibility. Molecular dynamics simulations of mouse and human EndoV reveal alternative conformations for the invariant tyrosine. The configuration of the active site, on the other hand, is very similar between the prokaryotic and mammalian versions of EndoV. PMID:27108838

  17. Swift heavy ion induced recrystallization in cubic silicon carbide: New insights from designed experiments and MD simulations

    NASA Astrophysics Data System (ADS)

    Debelle, A.; Backman, M.; Thomé, L.; Nordlund, K.; Djurabekova, F.; Weber, W. J.; Monnet, I.; Pakarinen, O. H.; Garrido, F.; Paumier, F.

    2014-05-01

    3C-SiC single crystals have been initially irradiated in the nuclear energy loss regime with 100 keV Fe ions to fluences ranging from 4 × 1013 to 4 × 1014 cm-2 (i.e. 0.07-0.7 dpa). RBS/C measurements indicate that SiC rapidly becomes amorphous (at ∼0.4 dpa). Two damaged SiC crystals exhibiting a different defective structure have been subsequently irradiated in the electronic energy loss regime with 870 MeV swift heavy (Pb) ions (SHIs) up to a fluence of 4 × 1013 cm-2. Initially fully amorphous SiC layers showed a decrease in size after SHI irradiation with a recrystallization occurring at the amorphous-crystalline interface. On the contrary, partially amorphous crystals for which onset of amorphization just initiated at the damage peak recovered over the entire damage thickness. Variation of amorphous thickness or disorder level has been monitored as a function of Pb ion fluence, which allowed deriving recrystallization kinetics. Data have been fitted with the direct-impact model and recrystallization cross-sections and threshold values for recovery have been determined for both types of initially defective structures. Differences are qualitatively discussed in terms of nature and density of irradiation defects. All experimental trends have been successfully reproduced by molecular dynamics simulations that mimicked thermal spikes induced by SHIs.

  18. Modeling the Self-Assembly and Stability of DHPC Micelles Using Atomic Resolution and Coarse Grained MD Simulations.

    PubMed

    Kraft, Johan F; Vestergaard, Mikkel; Schiøtt, Birgit; Thøgersen, Lea

    2012-05-01

    Membrane mimics such as micelles and bicelles are widely used in experiments involving membrane proteins. With the aim of being able to carry out molecular dynamics simulations in environments comparable to experimental conditions, we set out to test the ability of both coarse grained and atomistic resolution force fields to model the experimentally observed behavior of the lipid 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC), which is a widely used lipid for biophysical characterization of membrane proteins. It becomes clear from our results that a satisfactory modeling of DHPC aggregates in solution poses different demands to the force field than do the modeling of bilayers. First, the representation of the short tailed lipid DHPC in the coarse grained force field MARTINI is assessed with the intend of successfully self-assemble micelles with structural characteristics comparable to experimental data. Then, the use of the recently presented polarizable water model in MARTINI is shown to be essential for producing micelles that are structurally in accordance with experiments. For the atomistic representations of DHPC micelles in solution the GROMOS96 force field with lipid parameters by A. Kukol fails to maintain stable micelles, whereas the most recent CHARMM36 lipid parameters and GROMOS96 with the so-called Berger lipid parameters both succeed in this regard. PMID:26593649

  19. Crystal structure and MD simulation of mouse EndoV reveal wedge motif plasticity in this inosine-specific endonuclease

    NASA Astrophysics Data System (ADS)

    Nawaz, Meh Sameen; Vik, Erik Sebastian; Ronander, Mia Elise; Solvoll, Anne Marthe; Blicher, Pernille; Bjørås, Magnar; Alseth, Ingrun; Dalhus, Bjørn

    2016-04-01

    Endonuclease V (EndoV) is an enzyme with specificity for deaminated adenosine (inosine) in nucleic acids. EndoV from Escherichia coli (EcEndoV) acts both on inosines in DNA and RNA, whereas the human homolog cleaves only at inosines in RNA. Inosines in DNA are mutagenic and the role of EndoV in DNA repair is well established. In contrast, the biological function of EndoV in RNA processing is largely unexplored. Here we have characterized a second mammalian EndoV homolog, mouse EndoV (mEndoV), and show that mEndoV shares the same RNA selectivity as human EndoV (hEndoV). Mouse EndoV cleaves the same inosine-containing substrates as hEndoV, but with reduced efficiencies. The crystal structure of mEndoV reveals a conformation different from the hEndoV and prokaryotic EndoV structures, particularly for the conserved tyrosine in the wedge motif, suggesting that this strand separating element has some flexibility. Molecular dynamics simulations of mouse and human EndoV reveal alternative conformations for the invariant tyrosine. The configuration of the active site, on the other hand, is very similar between the prokaryotic and mammalian versions of EndoV.

  20. MD simulation study of direct permeation of a nanoparticle across the cell membrane under an external electric field

    NASA Astrophysics Data System (ADS)

    Shimizu, Kenta; Nakamura, Hideya; Watano, Satoru

    2016-06-01

    Nanoparticles (NPs) have been attracting much attention for biomedical and pharmaceutical applications. In most of the applications, NPs are required to translocate across the cell membrane and to reach the cell cytosol. Experimental studies have reported that by applying an electric field NPs can directly permeate across the cell membrane without the confinement of NPs by endocytic vesicles. However, damage to the cell can often be a concern. Understanding of the mechanism underlying the direct permeation of NPs under an external electric field can greatly contribute to the realization of a technology for the direct delivery of NPs. Here we investigated the permeation of a cationic gold NP across a phospholipid bilayer under an external electric field using a coarse-grained molecular dynamics simulation. When an external electric field that is equal to the membrane breakdown intensity was applied, a typical NP delivery by electroporation was shown: the cationic gold NP directly permeated across a lipid bilayer without membrane wrapping of the NP, while a persistent transmembrane pore was formed. However, when a specific range of the electric field that is lower than the membrane breakdown intensity was applied, a unique permeation pathway was exhibited: the generated transmembrane pore immediately resealed after the direct permeation of NP. Furthermore, we found that the affinity of the NP for the membrane surface is a key for the self-resealing of the pore. Our finding suggests that by applying an electric field in a suitable range NPs can be directly delivered into the cell with less cellular damage.Nanoparticles (NPs) have been attracting much attention for biomedical and pharmaceutical applications. In most of the applications, NPs are required to translocate across the cell membrane and to reach the cell cytosol. Experimental studies have reported that by applying an electric field NPs can directly permeate across the cell membrane without the confinement of

  1. Constant-pH MD Simulations Portray the Protonation and Structural Behavior of Four Decapeptides Designed to Coordinate Cu(2+).

    PubMed

    Campos, Sara R R; Iranzo, Olga; Baptista, António M

    2016-02-18

    The cyclic decapeptide C-Asp, containing one Asp residue and three His residues, was designed by Fragoso et al. (Chem. Eur. J. 2013, 19, 2076) to bind Cu(2+) exclusively through the side chain groups and mimic copper coordination in metalloproteins. A variant of the cyclodecapeptide where Asp is substituted by Asn (C-Asn) has also been synthesized in addition to the linear ("open") counterparts of both forms (O-Asp and O-Asn), testing the importance of cyclization and the presence of Asp in Cu(2+) coordination (Chem. Eur. J. 2013, 19, 2076; Dalton Trans. 2013, 42, 6182). All peptides formed a major species at neutral pH that was able to coordinate Cu(2+) exclusively through the neutral imidazole groups and the Asp side chain, when present, with C-Asp being the most effective. A detailed description of the protonation behavior of each histidine could help understanding the coordination species being formed in the pH range and eventually further optimizing the peptide's design. However, the standard current methods (NMR titrations) are not very suited for proximal groups titrating in the same pH range. In this work, we used the stochastic titration constant-pH molecular dynamics method to calculate the protonation curves and pKa of each titrable residue in the four decapeptides, in the absence of Cu(2+) ions. The global protonation curves obtained in our simulations are in very good agreement with the existing potentiometric titration curves. The histidines are titrating very closely, and the Asp forms abundant salt bridges with the basic residues, displaying an unusually low pKa value. In addition, we could observe that the four peptides are very unstructured in the absence of copper, and not even the cyclic forms exhibit a significant β-sheet, unlike what could be expected from the presence of β-turn inducer units in this type of scaffold. PMID:26813109

  2. Structure and water exchange dynamics of hydrated oxo halo ions in aqueous solution using QMCF MD simulation, large angle X-ray scattering and EXAFS

    PubMed Central

    Eklund, Lars; Hofer, Tomas S.

    2014-01-01

    Theoretical ab initio quantum mechanical charge field molecular dynamics (QMCF MD) has been applied in conjunction with experimental large angle X-ray scattering (LAXS) and EXAFS measurements to study structure and dynamics of the hydrated oxo chloro anions chlorite, ClO2−, chlorate, ClO3−, and perchlorate, ClO4−. In addition, the structures of the hydrated hypochlorite, ClO−, bromate, BrO3−, iodate, IO3− and metaperiodate, IO4−, ions have been determined in aqueous solution by means of LAXS. The structures of the bromate, metaperiodate, and orthoperiodate, H2IO63−, ions have been determined by EXAFS as solid sodium salts and in aqueous solution as well. The results show clearly that the only form of periodate present in aqueous solution is metaperiodate. The Cl-O bond distances in the hydrated oxo chloro anions as determined by LAXS and obtained in the QMCF MD simulations are in excellent agreement, being 0.01–0.02 Å longer than in solid anhydrous salts due to hydration through hydrogen bonding to water molecules. The oxo halo anions, all with unit negative charge, have low charge density making them typical structure breakers, thus the hydrogen bonds formed to the hydrating water molecules are weaker and more short-lived than those between water molecules in pure water. The water exchange mechanism of the oxo chloro anions resembles those of the oxo sulfur anions with a direct exchange at the oxygen atoms for perchlorate and sulfate. The water exchange rate for the perchlorate ion is significantly faster, τ0.5=1.4 ps, compared to the hydrated sulfate ion and pure water, τ0.5=2.6 and 1.7 ps, respectively. The angular radial distribution functions show that the chlorate and sulfite ions have a more complex water exchange mechanism. As the chlorite and chlorate ions are more weakly hydrated than the sulfite ion the spatial occupancy is less well-defined and it is not possible to follow any well-defined migration pattern as it is difficult to

  3. Structure and water exchange dynamics of hydrated oxo halo ions in aqueous solution using QMCF MD simulation, large angle X-ray scattering and EXAFS.

    PubMed

    Eklund, Lars; Hofer, Tomas S; Persson, Ingmar

    2015-01-28

    Theoretical ab initio quantum mechanical charge field molecular dynamics (QMCF MD) has been applied in conjunction with experimental large angle X-ray scattering (LAXS) and EXAFS measurements to study structure and dynamics of the hydrated oxo chloro anions chlorite, ClO2(-), chlorate, ClO3(-), and perchlorate, ClO4(-). In addition, the structures of the hydrated hypochlorite, ClO(-), bromate, BrO3(-), iodate, IO3(-) and metaperiodate, IO4(-), ions have been determined in aqueous solution by means of LAXS. The structures of the bromate, metaperiodate, and orthoperiodate, H2IO6(3-), ions have been determined by EXAFS as solid sodium salts and in aqueous solution as well. The results show clearly that the only form of periodate present in aqueous solution is metaperiodate. The Cl-O bond distances in the hydrated oxo chloro anions as determined by LAXS and obtained in the QMCF MD simulations are in excellent agreement, being 0.01-0.02 Å longer than in solid anhydrous salts due to hydration through hydrogen bonding to water molecules. The oxo halo anions, all with unit negative charge, have low charge density making them typical structure breakers, thus the hydrogen bonds formed to the hydrating water molecules are weaker and more short-lived than those between water molecules in pure water. The water exchange mechanism of the oxo chloro anions resembles those of the oxo sulfur anions with a direct exchange at the oxygen atoms for perchlorate and sulfate. The water exchange rate for the perchlorate ion is significantly faster, τ0.5 = 1.4 ps, compared to the hydrated sulfate ion and pure water, τ0.5 = 2.6 and 1.7 ps, respectively. The angular radial distribution functions show that the chlorate and sulfite ions have a more complex water exchange mechanism. As the chlorite and chlorate ions are more weakly hydrated than the sulfite ion the spatial occupancy is less well-defined and it is not possible to follow any well-defined migration pattern as it is difficult to

  4. 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.

  5. Hybrid MD-Nernst Planck Model of Alpha-hemolysin Conductance Properties

    NASA Technical Reports Server (NTRS)

    Cozmuta, Ioana; O'Keefer, James T.; Bose, Deepak; Stolc, Viktor

    2006-01-01

    Motivated by experiments in which an applied electric field translocates polynucleotides through an alpha-hemolysin protein channel causing ionic current transient blockade, a hybrid simulation model is proposed to predict the conductance properties of the open channel. Time scales corresponding to ion permeation processes are reached using the Poisson-Nemst-Planck (PNP) electro-diffusion model in which both solvent and local ion concentrations are represented as a continuum. The diffusion coefficients of the ions (K(+) and Cl(-)) input in the PNP model are, however, calculated from all-atom molecular dynamics (MD). In the MD simulations, a reduced representation of the channel is used. The channel is solvated in a 1 M KCI solution, and an external electric field is applied. The pore specific diffusion coefficients for both ionic species are reduced 5-7 times in comparison to bulk values. Significant statistical variations (17-45%) of the pore-ions diffusivities are observed. Within the statistics, the ionic diffusivities remain invariable for a range of external applied voltages between 30 and 240mV. In the 2D-PNP calculations, the pore stem is approximated by a smooth cylinder of radius approx. 9A with two constriction blocks where the radius is reduced to approx. 6A. The electrostatic potential includes the contribution from the atomistic charges. The MD-PNP model shows that the atomic charges are responsible for the rectifying behaviour and for the slight anion selectivity of the a-hemolysin pore. Independent of the hierarchy between the anion and cation diffusivities, the anionic contribution to the total ionic current will dominate. The predictions of the MD-PNP model are in good agreement with experimental data and give confidence in the present approach of bridging time scales by combining a microscopic and macroscopic model.

  6. Ab initio prediction of protein structure with both all-atom and simplified force fields

    NASA Astrophysics Data System (ADS)

    Scheraga, Harold

    2004-03-01

    Using only a physics-based ab initio method, and both all-atom (ECEPP/3) and simplified united-residue (UNRES) force fields, global optimization of both potential functions with Monte Carlo-plus-Minimization (MCM) and Conformational Space Annealing (CSA), respectively, provides predicted structures of proteins without use of knowledge-based information. The all-atom approach has been applied to the 46-residue protein A, and the UNRES approach has been applied to larger CASP targets. The predicted structures will be described.

  7. Toward a Rational Design of Bioactive Glasses with Optimal Structural Features: Composition–Structure Correlations Unveiled by Solid-State NMR and MD Simulations

    PubMed Central

    2013-01-01

    The physiological responses of silicate-based bioactive glasses (BGs) are known to depend critically on both the P content (nP) of the glass and its silicate network connectivity (N̅BOSi). However, while the bioactivity generally displays a nonmonotonic dependence on nP itself, recent work suggest that it is merely the net orthophosphate content that directly links to the bioactivity. We exploit molecular dynamics (MD) simulations combined with 31P and 29Si solid-state nuclear magnetic resonance (NMR) spectroscopy to explore the quantitative relationships between N̅BOSi, nP, and the silicate and phosphate speciations in a series of Na2O–CaO–SiO2–P2O5 glasses spanning 2.1 ≤ N̅BOSi ≤ 2.9 and variable P2O5 contents up to 6.0 mol %. The fractional population of the orthophosphate groups remains independent of nP at a fixed N̅BOSi-value, but is reduced slightly as N̅BOSi increases. Nevertheless, P remains predominantly as readily released orthophosphate ions, whose content may be altered essentially independently of the network connectivity, thereby offering a route to optimize the glass bioactivity. We discuss the observed composition-structure links in relation to known composition-bioactivity correlations, and define how Na2O–CaO–SiO2–P2O5 compositions exhibiting an optimal bioactivity can be designed by simultaneously altering three key parameters: the silicate network connectivity, the (ortho)phosphate content, and the nNa/nCa molar ratio. PMID:24364818

  8. All-atom polarizable force field for DNA based on the classical Drude oscillator model.

    PubMed

    Savelyev, Alexey; MacKerell, Alexander D

    2014-06-15

    Presented is a first generation atomistic force field (FF) for DNA in which electronic polarization is modeled based on the classical Drude oscillator formalism. The DNA model is based on parameters for small molecules representative of nucleic acids, including alkanes, ethers, dimethylphosphate, and the nucleic acid bases and empirical adjustment of key dihedral parameters associated with the phosphodiester backbone, glycosidic linkages, and sugar moiety of DNA. Our optimization strategy is based on achieving a compromise between satisfying the properties of the underlying model compounds in the gas phase targeting quantum mechanical (QM) data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude FF yields stable DNA duplexes on the 100-ns time scale and satisfactorily reproduce (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII substates of B form DNA. Consistency with the gas phase QM data for the model compounds is significantly better for the Drude model as compared to the CHARMM36 additive FF, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA. PMID:24752978

  9. All-Atom Polarizable Force Field for DNA Based on the Classical Drude Oscillator Model

    PubMed Central

    Savelyev, Alexey; MacKerell, Alexander D.

    2014-01-01

    Presented is a first generation atomistic force field for DNA in which electronic polarization is modeled based on the classical Drude oscillator formalism. The DNA model is based on parameters for small molecules representative of nucleic acids, including alkanes, ethers, dimethylphosphate, and the nucleic acid bases and empirical adjustment of key dihedral parameters associated with the phosphodiester backbone, glycosidic linkages and sugar moiety of DNA. Our optimization strategy is based on achieving a compromise between satisfying the properties of the underlying model compounds in the gas phase targeting QM data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude force field yields stable DNA duplexes on the 100 ns time scale and satisfactorily reproduces (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII sub-states of B form DNA. Consistency with the gas phase QM data for the model compounds is significantly better for the Drude model as compared to the CHARMM36 additive force field, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA. PMID:24752978

  10. MD-2 binds cholesterol.

    PubMed

    Choi, Soo-Ho; Kim, Jungsu; Gonen, Ayelet; Viriyakosol, Suganya; Miller, Yury I

    2016-02-19

    Cholesterol is a structural component of cellular membranes, which is transported from liver to peripheral cells in the form of cholesterol esters (CE), residing in the hydrophobic core of low-density lipoprotein. Oxidized CE (OxCE) is often found in plasma and in atherosclerotic lesions of subjects with cardiovascular disease. Our earlier studies have demonstrated that OxCE activates inflammatory responses in macrophages via toll-like receptor-4 (TLR4). Here we demonstrate that cholesterol binds to myeloid differentiation-2 (MD-2), a TLR4 ancillary molecule, which is a binding receptor for bacterial lipopolysaccharide (LPS) and is indispensable for LPS-induced TLR4 dimerization and signaling. Cholesterol binding to MD-2 was competed by LPS and by OxCE-modified BSA. Furthermore, soluble MD-2 in human plasma and MD-2 in mouse atherosclerotic lesions carried cholesterol, the finding supporting the biological significance of MD-2 cholesterol binding. These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis. PMID:26806306

  11. Constraining binding hot spots: NMR and MD simulations provide a structural explanation for enthalpy-entropy compensation in SH2-ligand binding

    PubMed Central

    Ward, Joshua M.; Gorenstein, Nina M.; Tian, Jianhua; Martin, Stephen F.; Post, Carol Beth

    2010-01-01

    NMR spectroscopy and molecular dynamics (MD) simulations were used to probe the structure and dynamics of complexes of three phosphotyrosine-derived peptides with the Src SH2 domain in an effort to uncover a structural explanation for enthalpy-entropy compensation observed in the binding thermodynamics. The series of phosphotyrosine peptide derivatives comprises the natural pYEEI Src SH2 ligand, a constrained mimic, in which the phosphotyrosine (pY) residue is preorganized in the bound conformation for the purpose of gaining an entropic advantage to binding, and a flexible analog of the constrained mimic. The expected gain in binding entropy of the constrained mimic was realized; however, a balancing loss in binding enthalpy was also observed that could not be rationalized from the crystallographic structures. We examined protein dynamics to evaluate whether the observed enthalpic penalty might be the result of effects arising from altered motions in the complex. 15N-relaxation studies and positional fluctuations from molecular dynamics indicate that the main-chain dynamics of the protein show little variation among the three complexes. Root mean squared (RMS) coordinate deviations vary by less than 1.5 Å for all non-hydrogen atoms for the crystal structures and in the ensemble average structures calculated from the simulations. In contrast to this striking similarity in the structures and dynamics, there are a number of large chemical shift differences from residues across the binding interface, but particularly from key Src SH2 residues that interact with pY, the ‘hot spot’ residue, which contributes about half of the binding free energy. Rank order correlations between chemical shifts and ligand binding enthalpy for several pY-binding residues, coupled with available mutagenesis and calorimetric data, suggest that subtle structural perturbations (< 1 Å) from the conformational constraint of the pY residue sufficiently alter the geometry of enthalpically

  12. Extensive all-atom Monte Carlo sampling and QM/MM corrections in the SAMPL4 hydration free energy challenge.

    PubMed

    Genheden, Samuel; Cabedo Martinez, Ana I; Criddle, Michael P; Essex, Jonathan W

    2014-03-01

    We present our predictions for the SAMPL4 hydration free energy challenge. Extensive all-atom Monte Carlo simulations were employed to sample the compounds in explicit solvent. While the focus of our study was to demonstrate well-converged and reproducible free energies, we attempted to address the deficiencies in the general Amber force field force field with a simple QM/MM correction. We show that by using multiple independent simulations, including different starting configurations, and enhanced sampling with parallel tempering, we can obtain well converged hydration free energies. Additional analysis using dihedral angle distributions, torsion-root mean square deviation plots and thermodynamic cycles support this assertion. We obtain a mean absolute deviation of 1.7 kcal mol(-1) and a Kendall's τ of 0.65 compared with experiment. PMID:24488307

  13. Assembling a xylanase-lichenase chimera through all-atom molecular dynamics simulations.

    PubMed

    Cota, Junio; Oliveira, Leandro C; Damásio, André R L; Citadini, Ana P; Hoffmam, Zaira B; Alvarez, Thabata M; Codima, Carla A; Leite, Vitor B P; Pastore, Glaucia; de Oliveira-Neto, Mario; Murakami, Mario T; Ruller, Roberto; Squina, Fabio M

    2013-08-01

    Multifunctional enzyme engineering can improve enzyme cocktails for emerging biofuel technology. Molecular dynamics through structure-based models (SB) is an effective tool for assessing the tridimensional arrangement of chimeric enzymes as well as for inferring the functional practicability before experimental validation. This study describes the computational design of a bifunctional xylanase-lichenase chimera (XylLich) using the xynA and bglS genes from Bacillus subtilis. In silico analysis of the average solvent accessible surface area (SAS) and the root mean square fluctuation (RMSF) predicted a fully functional chimera, with minor fluctuations and variations along the polypeptide chains. Afterwards, the chimeric enzyme was built by fusing the xynA and bglS genes. XylLich was evaluated through small-angle X-ray scattering (SAXS) experiments, resulting in scattering curves with a very accurate fit to the theoretical protein model. The chimera preserved the biochemical characteristics of the parental enzymes, with the exception of a slight variation in the temperature of operation and the catalytic efficiency (kcat/Km). The absence of substantial shifts in the catalytic mode of operation was also verified. Furthermore, the production of chimeric enzymes could be more profitable than producing a single enzyme separately, based on comparing the recombinant protein production yield and the hydrolytic activity achieved for XylLich with that of the parental enzymes. PMID:23459129

  14. 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

  15. Reconciling Structural and Thermodynamic Predictions Using All-Atom and Coarse-Grain Force Fields: The Case of Charged Oligo-Arginine Translocation into DMPC Bilayers

    PubMed Central

    2015-01-01

    Using the translocation of short, charged cationic oligo-arginine peptides (mono-, di-, and triarginine) from bulk aqueous solution into model DMPC bilayers, we explore the question of the similarity of thermodynamic and structural predictions obtained from molecular dynamics simulations using all-atom and Martini coarse-grain force fields. Specifically, we estimate potentials of mean force associated with translocation using standard all-atom (CHARMM36 lipid) and polarizable and nonpolarizable Martini force fields, as well as a series of modified Martini-based parameter sets. We find that we are able to reproduce qualitative features of potentials of mean force of single amino acid side chain analogues into model bilayers. In particular, modifications of peptide–water and peptide–membrane interactions allow prediction of free energy minima at the bilayer–water interface as obtained with all-atom force fields. In the case of oligo-arginine peptides, the modified parameter sets predict interfacial free energy minima as well as free energy barriers in almost quantitative agreement with all-atom force field based simulations. Interfacial free energy minima predicted by a modified coarse-grained parameter set are −2.51, −4.28, and −5.42 for mono-, di-, and triarginine; corresponding values from all-atom simulations are −0.83, −3.33, and −3.29, respectively, all in units of kcal/mol. We found that a stronger interaction between oligo-arginine and the membrane components and a weaker interaction between oligo-arginine and water are crucial for producing such minima in PMFs using the polarizable CG model. The difference between bulk aqueous and bilayer center states predicted by the modified coarse-grain force field are 11.71, 14.14, and 16.53 kcal/mol, and those by the all-atom model are 6.94, 8.64, and 12.80 kcal/mol; those are of almost the same order of magnitude. Our simulations also demonstrate a remarkable similarity in the structural aspects of

  16. Quantum Mechanics/Molecular Mechanics Method Combined with Hybrid All-Atom and Coarse-Grained Model: Theory and Application on Redox Potential Calculations.

    PubMed

    Shen, Lin; Yang, Weitao

    2016-04-12

    We developed a new multiresolution method that spans three levels of resolution with quantum mechanical, atomistic molecular mechanical, and coarse-grained models. The resolution-adapted all-atom and coarse-grained water model, in which an all-atom structural description of the entire system is maintained during the simulations, is combined with the ab initio quantum mechanics and molecular mechanics method. We apply this model to calculate the redox potentials of the aqueous ruthenium and iron complexes by using the fractional number of electrons approach and thermodynamic integration simulations. The redox potentials are recovered in excellent accordance with the experimental data. The speed-up of the hybrid all-atom and coarse-grained water model renders it computationally more attractive. The accuracy depends on the hybrid all-atom and coarse-grained water model used in the combined quantum mechanical and molecular mechanical method. We have used another multiresolution model, in which an atomic-level layer of water molecules around redox center is solvated in supramolecular coarse-grained waters for the redox potential calculations. Compared with the experimental data, this alternative multilayer model leads to less accurate results when used with the coarse-grained polarizable MARTINI water or big multipole water model for the coarse-grained layer. PMID:26930454

  17. UV - GAITHERSBURG MD

    EPA Science Inventory

    Brewer 105 is located in Gaithersburg MD, measuring ultraviolet solar radiation. Irradiance and column ozone are derived from this data. Ultraviolet solar radiation is measured with a Brewer Mark IV, single-monochrometer, spectrophotometer manufactured by SCI-TEC Instruments, Inc...

  18. Folding peptides and proteins with all-atom physics: methods and applications

    NASA Astrophysics Data System (ADS)

    Shell, M. Scott

    2008-03-01

    Computational methods offer powerful tools for investigating proteins and peptides at the molecular-level; however, it has proven challenging to reproduce the long time scale folding processes of these molecules at a level that is both faithful to the atomic driving forces and attainable with modern commodity cluster computing. Alternatively, the past decade has seen significant progress in using bioinformatics-based approaches to infer the three dimensional native structures of proteins, drawing upon extensive knowledge databases of known protein structures [1]. These methods work remarkably well when a homologous protein can be found to provide a structural template for a candidate sequence. However, in cases where homology to database proteins is low, where the folding pathway is of interest, or where conformational flexibility is substantial---as in many emerging protein and peptide technologies---bioinformatics methods perform poorly. There is therefore great interest in seeing purely physics-based approaches succeed. We discuss a purely physics-based, database-free folding method, relying on proper thermal sampling (replica exchange molecular dynamics) and molecular potential energy functions. In order to surmount the tremendous computational demands of all-atom folding simulations, our approach implements a conformational search strategy based on a putative protein folding mechanism called zipping and assembly [2-4]. That is, we explicitly seek out potential folding pathways inferred from short simulations, and iteratively pursue all such routes by coaxing a polypeptide chain along them. The method is called the Zipping and Assembly Method (ZAM) and it works in two parts: (1) the full polypeptide chain is broken into small fragments that are first simulated independently and then successively re-assembled into larger segments with further sampling, and (2) consistently stable structure in fragments is detected and locked into place, in order to avoid re

  19. All-Atom Internal Coordinate Mechanics (ICM) Force Field for Hexopyranoses and Glycoproteins

    PubMed Central

    2016-01-01

    We present an extension of the all-atom internal-coordinate force field, ICMFF, that allows for simulation of heterogeneous systems including hexopyranose saccharides and glycan chains in addition to proteins. A library of standard glycan geometries containing α- and β-anomers of the most common hexapyranoses, i.e., d-galactose, d-glucose, d-mannose, d-xylose, l-fucose, N-acetylglucosamine, N-acetylgalactosamine, sialic, and glucuronic acids, is created based on the analysis of the saccharide structures reported in the Cambridge Structural Database. The new force field parameters include molecular electrostatic potential-derived partial atomic charges and the torsional parameters derived from quantum mechanical data for a collection of minimal molecular fragments and related molecules. The ϕ/ψ torsional parameters for different types of glycosidic linkages are developed using model compounds containing the key atoms in the full carbohydrates, i.e., glycosidic-linked tetrahydropyran–cyclohexane dimers. Target data for parameter optimization include two-dimensional energy surfaces corresponding to the ϕ/ψ glycosidic dihedral angles in the disaccharide analogues, as determined by quantum mechanical MP2/6-31G** single-point energies on HF/6-31G** optimized structures. To achieve better agreement with the observed geometries of glycosidic linkages, the bond angles at the O-linkage atoms are added to the internal variable set and the corresponding bond bending energy term is parametrized using quantum mechanical data. The resulting force field is validated on glycan chains of 1–12 residues from a set of high-resolution X-ray glycoprotein structures based on heavy atom root-mean-square deviations of the lowest-energy glycan conformations generated by the biased probability Monte Carlo (BPMC) molecular mechanics simulations from the native structures. The appropriate BPMC distributions for monosaccharide–monosaccharide and protein–glycan linkages are derived

  20. Collision-Induced Dissociation of Electrosprayed Protein Complexes: An All-Atom Molecular Dynamics Model with Mobile Protons.

    PubMed

    Popa, Vlad; Trecroce, Danielle A; McAllister, Robert G; Konermann, Lars

    2016-06-16

    Electrospray ionization mass spectrometry (ESI-MS) has become an indispensable technique for examining noncovalent protein complexes. Collision-induced dissociation (CID) of these multiply protonated gaseous ions usually culminates in ejection of a single subunit with a disproportionately large amount of charge. Experiments suggest that this process involves subunit unfolding prior to separation from the residual complex, as well as H(+) migration onto the unravelling chain. Molecular dynamics (MD) simulations are a promising avenue for gaining detailed insights into these CID events. Unfortunately, typical MD algorithms do not allow for mobile protons. Here we address this limitation by implementing a strategy that combines atomistic force fields (such as OPLS/AA and CHARMM36) with a proton hopping algorithm, focusing on the tetrameric complexes transthyretin and streptavidin. Protons are redistributed over all acidic and basic sites in 20 ps intervals, subject to an energy function that reflects electrostatic interactions and proton affinities. Our simulations predict that nativelike conformers at the onset of collisional heating contain multiple salt bridges. Collisional heating initially causes subtle structural changes that lead to a gradual decline of these zwitterionic patterns. Many of the MD runs show gradual unfolding of a single subunit in conjunction with H(+) migration, culminating in subunit separation from the complex. However, there are also instances where two or more chains start to unfold simultaneously, giving rise to charge competition. The scission point where the "winning" subunit separates from the complex can be attained for different degrees of unfolding, giving rise to product ions in various charge states. The simulated product ion distributions are in close agreement with experimental CID data. Proton enrichment in the departing subunit is driven by charge-charge repulsion, but the combination of salt bridge depletion, charge migration

  1. Developing the MD Explorer

    NASA Astrophysics Data System (ADS)

    Howie, Philip V.

    1993-04-01

    The MD Explorer is an eight-seat twin-turbine engine helicopter which is being developed using integrated product definition (IPD) team methodology. New techniques include NOTAR antitorque system for directional control, a composite fuselage, an all-composite bearingless main rotor, and digital cockpit displays. Three-dimensional CAD models are the basis of the entire Explorer design. Solid models provide vendor with design clarification, removing much of the normal drawing interpretation errors.

  2. Multiscale Free Energy Simulations: An Efficient Method for Connecting Classical MD Simulations to QM or QM/MM Free Energies Using Non-Boltzmann Bennett Reweighting Schemes

    PubMed Central

    2015-01-01

    The reliability of free energy simulations (FES) is limited by two factors: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Free energy differences are then calculated based on the QM or QM/MM energies using either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmann free energy perturbation (NB-FEP). Both approaches are applied to calculate relative and absolute solvation free energies in explicit and implicit solvent environments. Solvation free energy differences (relative and absolute) between ethane and methanol in explicit solvent are used as the initial test case for QM-NBB. Next, implicit solvent methods are employed in conjunction with both QM-NBB and NB-FEP to compute absolute solvation free energies for 21 compounds. These compounds range from small molecules such as ethane and methanol to fairly large, flexible solutes, such as triacetyl glycerol. Several technical aspects were investigated. Ultimately some best practices are suggested for improving methods that seek to connect

  3. Multiscale Free Energy Simulations: An Efficient Method for Connecting Classical MD Simulations to QM or QM/MM Free Energies Using Non-Boltzmann Bennett Reweighting Schemes.

    PubMed

    König, Gerhard; Hudson, Phillip S; Boresch, Stefan; Woodcock, H Lee

    2014-04-01

    THE RELIABILITY OF FREE ENERGY SIMULATIONS (FES) IS LIMITED BY TWO FACTORS: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Free energy differences are then calculated based on the QM or QM/MM energies using either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmann free energy perturbation (NB-FEP). Both approaches are applied to calculate relative and absolute solvation free energies in explicit and implicit solvent environments. Solvation free energy differences (relative and absolute) between ethane and methanol in explicit solvent are used as the initial test case for QM-NBB. Next, implicit solvent methods are employed in conjunction with both QM-NBB and NB-FEP to compute absolute solvation free energies for 21 compounds. These compounds range from small molecules such as ethane and methanol to fairly large, flexible solutes, such as triacetyl glycerol. Several technical aspects were investigated. Ultimately some best practices are suggested for improving methods that seek to connect

  4. Coarse-grained molecular dynamics simulations of nanopatterning with multivalent inks

    NASA Astrophysics Data System (ADS)

    Cieplak, Marek; Thompson, Damien

    2008-06-01

    A coarse-grained molecular dynamics (MD) model is developed to study the multivalent, or multisite, binding of small functionalized dendrimer molecules to β-cyclodextrin-terminated self-assembled monolayers, the so-called ``molecular printboards'' used to print ``ink'' molecules on surfaces with a high degree of positional control and specificity. Some current and future bionanotechnology applications are in the creation of nanoparticle assemblies, directed protein assembly, platforms for biosensing, and cell:surface attachment. The coarse-grained model allows us to probe up to microsecond timescales and model ink diffusion, crucial for the application of the printboard in, for example, medical diagnostics. Recent all-atom MD simulations identified and quantified the molecular strain limiting the stability of nanopatterns created with small dendrimer inks, and explained the different patterns obtained experimentally with different dendrimer inks. In the present work, the all-atom simulations are ``scaled up'' to longer timescales via coarse graining, without incurring significant additional computational expense, and, crucially, without significant loss in atom-scale detail, the coarse-grained MD simulations yielding properties similar to those obtained from the all-atom simulations. The anchoring of the ink molecules to the monolayer is of multivalent nature and the degree of multivalency shows a sharp dependence on temperature, control of temperature thus providing a further operational ``switch'' for directed molecular assembly. The computational protocol developed can, in principle, be extended to model any multivalent assembly, for example, virus-cell complexation.

  5. 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

  6. 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

  7. An FFT-based method for modeling protein folding and binding under crowding: benchmarking on ellipsoidal and all-atom crowders.

    PubMed

    Qin, Sanbo; Zhou, Huan-Xiang

    2013-10-01

    It is now well recognized that macromolecular crowding can exert significant effects on protein folding and binding stability. In order to calculate such effects in direct simulations of proteins mixed with bystander macromolecules, the latter (referred to as crowders) are usually modeled as spheres and the proteins represented at a coarse-grained level. Our recently developed postprocessing approach allows the proteins to be represented at the all-atom level but, for computational efficiency, has only been implemented for spherical crowders. Modeling crowder molecules in cellular environments and in vitro experiments as spheres may distort their effects on protein stability. Here we present a new method that is capable for treating aspherical crowders. The idea, borrowed from protein-protein docking, is to calculate the excess chemical potential of the proteins in crowded solution by fast Fourier transform (FFT). As the first application, we studied the effects of ellipsoidal crowders on the folding and binding free energies of all-atom proteins, and found, in agreement with previous direct simulations with coarse-grained protein models, that the aspherical crowders exert greater stabilization effects than spherical crowders of the same volume. Moreover, as demonstrated here, the FFT-based method has the important property that its computational cost does not increase strongly even when the level of details in representing the crowders is increased all the way to all-atom, thus significantly accelerating realistic modeling of protein folding and binding in cell-like environments. PMID:24187527

  8. An All-Atom Force Field for Tertiary Structure Prediction of Helical Proteins

    PubMed Central

    Herges, T.; Wenzel, W.

    2004-01-01

    We have developed an all-atom free-energy force field (PFF01) for protein tertiary structure prediction. PFF01 is based on physical interactions and was parameterized using experimental structures of a family of proteins believed to span a wide variety of possible folds. It contains empirical, although sequence-independent terms for hydrogen bonding. Its solvent-accessible surface area solvent model was first fit to transfer energies of small peptides. The parameters of the solvent model were then further optimized to stabilize the native structure of a single protein, the autonomously folding villin headpiece, against competing low-energy decoys. Here we validate the force field for five nonhomologous helical proteins with 20–60 amino acids. For each protein, decoys with 2–3 Å backbone root mean-square deviation and correct experimental Cβ–Cβ distance constraints emerge as those with the lowest energy. PMID:15507688

  9. All-atom homology model of the Escherichia coli 30S ribosomal subunit.

    PubMed

    Tung, Chang-Shung; Joseph, Simpson; Sanbonmatsu, Kevin Y

    2002-10-01

    Understanding the structural basis of ribosomal function requires close comparison between biochemical and structural data. Although a large amount of biochemical data are available for the Escherichia coli ribosome, the structure has not been solved to atomic resolution. Using a new RNA homology procedure, we have modeled the all-atom structure of the E. coli 30S ribosomal subunit. We find that the tertiary structure of the ribosome core, including the A-, P- and E-sites, is highly conserved. The hypervariable regions in our structure, which differ from the structure of the 30S ribosomal subunit from Thermus thermophilus, are consistent with the cryo-EM map of the E. coli ribosome. PMID:12244297

  10. All-atomic generation and noise-quadrature filtering of squeezed vacuum in hot Rb vapor

    NASA Astrophysics Data System (ADS)

    Horrom, Travis; Romanov, Gleb; Novikova, Irina; Mikhailov, Eugeniy E.

    2013-01-01

    With our all-atomic squeezing and filtering setup, we demonstrate control over the noise amplitudes and manipulation of the frequency-dependent squeezing angle of a squeezed vacuum quantum state by passing it through an atomic medium with electromagnetically induced transparency (EIT). We generate low sideband frequency squeezed vacuum using the polarization self-rotation effect in a hot Rb vapor cell, and direct it through a second atomic vapor subject to EIT conditions. We use the frequency-dependent absorption of the EIT window to demonstrate an example of squeeze amplitude attenuation and squeeze angle rotation of the quantum noise quadratures of the squeezed probe. These studies have implications for quantum memory and storage as well as gravitational wave interferometric detectors.

  11. Harold E. Varmus, MD.

    PubMed

    Varmus, H E

    1995-06-01

    On November 19, 1993, the Senate approved the nomination of Harold E. Varmus, MD, as Director of the National Institutes of Health (NIH). Varmus, who received the 1989 Nobel Prize in Medicine, brought unquestioned credentials as a scientist to the NIH. Despite his limited background as an administrator, Varmus has received high marks from most observers for improving the morale of NIH staffers and implementing streamlined procedures in the grant review process. His tenure has not been free of controversy, however. Many clinical researchers have long felt there is a bias in NIH study sections against patient-oriented research. A recent study sponsored by the Division of Research Grants confirmed the lower success rate of patient-oriented research proposals, but the outcome of these findings remains unclear. Faced with mounting political pressure for a balanced budget, and the resultant reduction of funding to many branches of government, Varmus has been a strong voice for non-targeted investigator initiated research. Interviewed in his office in Building One on the NIH campus in Bethesda, Maryland, Varmus discussed the state of patient oriented research, the evolving role of the NIH in supporting science, and just where the money to pay for it should be found. PMID:7614067

  12. A Real-Time All-Atom Structural Search Engine for Proteins

    PubMed Central

    Gonzalez, Gabriel; Hannigan, Brett; DeGrado, William F.

    2014-01-01

    Protein designers use a wide variety of software tools for de novo design, yet their repertoire still lacks a fast and interactive all-atom search engine. To solve this, we have built the Suns program: a real-time, atomic search engine integrated into the PyMOL molecular visualization system. Users build atomic-level structural search queries within PyMOL and receive a stream of search results aligned to their query within a few seconds. This instant feedback cycle enables a new “designability”-inspired approach to protein design where the designer searches for and interactively incorporates native-like fragments from proven protein structures. We demonstrate the use of Suns to interactively build protein motifs, tertiary interactions, and to identify scaffolds compatible with hot-spot residues. The official web site and installer are located at http://www.degradolab.org/suns/ and the source code is hosted at https://github.com/godotgildor/Suns (PyMOL plugin, BSD license), https://github.com/Gabriel439/suns-cmd (command line client, BSD license), and https://github.com/Gabriel439/suns-search (search engine server, GPLv2 license). PMID:25079944

  13. CHARMM Additive All-Atom Force Field for Phosphate and Sulfate Linked to Carbohydrates

    PubMed Central

    Mallajosyula, Sairam S.; Guvench, Olgun; Hatcher, Elizabeth; MacKerell, Alexander D.

    2012-01-01

    Presented is an extension of the CHARMM additive all-atom carbohydrate force field to enable the modeling of phosphate and sulfate linked to carbohydrates. The parameters are developed in a hierarchical fashion using model compounds containing the key atoms in the full carbohydrates. Target data for parameter optimization included full two-dimensional energy surfaces defined by the glycosidic dihedral angle pairs in the phosphate/sulfate model compound analogs of hexopyranose monosaccharide phosphates and sulfates, as determined by quantum mechanical (QM) MP2/cc-pVTZ single point energies on MP2/6-31+G(d) optimized structures. In order to achieve balanced, transferable dihedral parameters for the dihedral angles, surfaces for all possible anomeric and conformational states were included during the parametrization process. In addition, to model physiologically relevant systems both the mono- and di-anionic charged states were studied for the phosphates. This resulted in over 7000 MP2/cc-pVTZ//MP2/6-31G+(d) model compound conformational energies which, supplemented with QM geometries, were the main target data for the parametrization. Parameters were validated against crystals of relevant monosaccharide derivatives obtained from the Cambridge Structural Database (CSD) and larger systems, namely inositol-(tri/tetra/penta) phosphates non-covalently bound to the pleckstrin homology (PH) domain and oligomeric chondroitin sulfate in solution and in complex with cathepsin K protein. PMID:22685386

  14. All-atom force field for the prediction of vapor-liquid equilibria and interfacial properties of HFA134a.

    PubMed

    Peguin, Robson P S; Kamath, Ganesh; Potoff, Jeffrey J; da Rocha, Sandro R P

    2009-01-01

    A new all-atom force field capable of accurately predicting the bulk and interfacial properties of 1,1,1,2-tetrafluoroethane (HFA134a) is reported. Parameterization of several force fields with different initial charge configurations from ab initio calculations was performed using the histogram reweighting method and Monte Carlo simulations in the grand canonical ensemble. The 12-6 Lennard-Jones well depth and diameter for the different HFA134a models were determined by fitting the simulation results to pure-component vapor-equilibrium data. Initial screening of the force fields was achieved by comparing the calculated and experimental bulk properties. The surface tension of pure HFA134a served as an additional screening property to help discriminate an optimum model. The proposed model reproduces the experimental saturated liquid and vapor densities, and the vapor pressure for HFA134a within average errors of 0.7%, 4.4%, and 3.1%, respectively. Critical density, temperature, vapor pressure, normal boiling point, and heat of vaporization at 298 K are also in good agreement with experimental data with errors of 0.2%, 0.1%, 6.2%, 0%, 2.2%, respectively. The calculated surface tension is found to be within the experimental range of 7.7-8.1 mN.m(-1). The dipole moment of the different models was found to significantly affect the prediction of the vapor pressure and surface tension. The ability of the HFA134a models in predicting the interfacial tension against water is also discussed. The results presented here are relevant in the development of technologies where the more environmentally friendly HFA134a is utilized as a substitute to the ozone depleting chlorofluorocarbon propellants. PMID:19086791

  15. CHARMM Additive All-Atom Force Field for Aldopentofuranoses, Methyl-Aldopentofuranosides and Fructofuranose

    PubMed Central

    Hatcher, Elizabeth; Guvench, Olgun; MacKerell, Alexander D.

    2009-01-01

    An additive all-atom empirical force field for aldopentofuranoses, methyl-aldopentofuranosides (Me-aldopentofuranosides) and fructofuranose carbohydrates, compatible with existing CHARMM carbohydrate parameters, is presented. Building on existing parameters transferred from cyclic ethers and hexopyranoses, parameters were further developed using target data for complete furanose carbohydrates as well as O-methyl tetrahydrofuran. The bond and angle equilibrium parameters were adjusted to reproduce target geometries from a survey of furanose crystal structures, and dihedral parameters were fit to over 1700 quantum mechanical (QM) MP2/cc-pVTZ//MP2/6-31G(d) conformational energies. The conformational energies were for a variety of complete furanose monosaccharides, and included two-dimensional ring pucker energy surfaces. Bonded parameter optimization led to the correct description of the ring pucker for a large set of furanose compounds, while furanose-water interaction energies and distances reproduced QM HF/6-31G(d) results for a number of furanose monosaccharides, thereby validating the nonbonded parameters. Crystal lattice unit cell parameters and volumes, aqueous-phase densities, and aqueous NMR ring pucker and exocyclic data were used to validate the parameters in condensed-phase environments. Conformational sampling analysis of the ring pucker and exocyclic group showed excellent agreement with experimental NMR data, demonstrating that the conformational energetics in aqueous solution are accurately described by the optimized force field. Overall, the parameters reproduce available experimental data well and are anticipated to be of utility in future computational studies of carbohydrates, including in the context of proteins, nucleic acids and/or lipids when combined with existing CHARMM biomolecular force fields. PMID:19694450

  16. All-atom 3D structure prediction of transmembrane β-barrel proteins from sequences

    PubMed Central

    Hayat, Sikander; Sander, Chris; Marks, Debora S.

    2015-01-01

    Transmembrane β-barrels (TMBs) carry out major functions in substrate transport and protein biogenesis but experimental determination of their 3D structure is challenging. Encouraged by successful de novo 3D structure prediction of globular and α-helical membrane proteins from sequence alignments alone, we developed an approach to predict the 3D structure of TMBs. The approach combines the maximum-entropy evolutionary coupling method for predicting residue contacts (EVfold) with a machine-learning approach (boctopus2) for predicting β-strands in the barrel. In a blinded test for 19 TMB proteins of known structure that have a sufficient number of diverse homologous sequences available, this combined method (EVfold_bb) predicts hydrogen-bonded residue pairs between adjacent β-strands at an accuracy of ∼70%. This accuracy is sufficient for the generation of all-atom 3D models. In the transmembrane barrel region, the average 3D structure accuracy [template-modeling (TM) score] of top-ranked models is 0.54 (ranging from 0.36 to 0.85), with a higher (44%) number of residue pairs in correct strand–strand registration than in earlier methods (18%). Although the nonbarrel regions are predicted less accurately overall, the evolutionary couplings identify some highly constrained loop residues and, for FecA protein, the barrel including the structure of a plug domain can be accurately modeled (TM score = 0.68). Lower prediction accuracy tends to be associated with insufficient sequence information and we therefore expect increasing numbers of β-barrel families to become accessible to accurate 3D structure prediction as the number of available sequences increases. PMID:25858953

  17. Release notice of MD 9ne and MD25 high fiber quality cotton germplasm lines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    MD 9ne and MD 25 are non-commercial breeding lines of cotton (Gossypium hirsutum L.) released by the USDA-ARS at Stoneville, MS. One parent of MD 9ne was a strain of MD 51ne that had high fiber quality genes introduced from the Species Polycross. The other parent was MD 15. The parents of MD 25 a...

  18. 78 FR 14547 - Praxedes E. Alverez Santiago, M.D., Daniel Perez Brisebois, M.D., Jorge Grillasca Palou, M.D...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-06

    ... Praxedes E. Alverez Santiago, M.D., Daniel Perez Brisebois, M.D., Jorge Grillasca Palou, M.D., Rafael Garcia Nieves, M.D., Francis M. Vazques Roura, M.D., Angel B. Rivera Santos, M.D., Cosme D. Santos Torres, M.D., and Juan L. Vilaro Chardon, M.D.; Analysis of Agreement Containing Consent Order To Aid...

  19. Unraveling the dynamics and structure of functionalized self-assembled monolayers on gold using 2D IR spectroscopy and MD simulations.

    PubMed

    Yan, Chang; Yuan, Rongfeng; Pfalzgraff, William C; Nishida, Jun; Wang, Lu; Markland, Thomas E; Fayer, Michael D

    2016-05-01

    Functionalized self-assembled monolayers (SAMs) are the focus of ongoing investigations because they can be chemically tuned to control their structure and dynamics for a wide variety of applications, including electrochemistry, catalysis, and as models of biological interfaces. Here we combine reflection 2D infrared vibrational echo spectroscopy (R-2D IR) and molecular dynamics simulations to determine the relationship between the structures of functionalized alkanethiol SAMs on gold surfaces and their underlying molecular motions on timescales of tens to hundreds of picoseconds. We find that at higher head group density, the monolayers have more disorder in the alkyl chain packing and faster dynamics. The dynamics of alkanethiol SAMs on gold are much slower than the dynamics of alkylsiloxane SAMs on silica. Using the simulations, we assess how the different molecular motions of the alkyl chain monolayers give rise to the dynamics observed in the experiments. PMID:27044113

  20. Penetration of HIV-1 Tat47–57 into PC/PE Bilayers Assessed by MD Simulation and X-ray Scattering

    PubMed Central

    Neale, Chris; Huang, Kun; García, Angel E.; Tristram-Nagle, Stephanie

    2015-01-01

    The interactions of the basic, cell-penetrating region (Y47GRKKRRQRRR57) of the HIV-1 Tat protein with dioleoylphosphatidylcholine (DOPC) bilayers were previously assessed by comparing experimental X-ray diffuse scattering with atomistic molecular dynamics simulations. Here, we extend this investigation by evaluating the influence of phosphatidylethanolamine (PE) lipids. Using experimental bilayer form factors derivedfrom X-ray diffuse scattering data as a guide, our simulations indicate that Tat peptides localize close to the carbonyl-glycerol group in the headgroup region of bilayers composed of either DOPC or DOPC:DOPE (1:1) lipid. Our results also suggest that Tat peptides may more frequently insert into the hydrophobic core of bilayers composed of PC:PE (1:1) lipids than into bilayers composed entirely of PC lipids. PE lipids may facilitate peptide translocation across a lipid bilayer by stabilizing intermediate states in which hydrated peptides span the bilayer. PMID:26402709

  1. The Molecular Mechanism of Bisphenol A (BPA) as an Endocrine Disruptor by Interacting with Nuclear Receptors: Insights from Molecular Dynamics (MD) Simulations

    PubMed Central

    Li, Lanlan; Wang, Qianqian; Zhang, Yan; Niu, Yuzhen; Yao, Xiaojun; Liu, Huanxiang

    2015-01-01

    Bisphenol A (BPA) can interact with nuclear receptors and affect the normal function of nuclear receptors in very low doses, which causes BPA to be one of the most controversial endocrine disruptors. However, the detailed molecular mechanism about how BPA interferes the normal function of nuclear receptors is still undiscovered. Herein, molecular dynamics simulations were performed to explore the detailed interaction mechanism between BPA with three typical nuclear receptors, including hERα, hERRγ and hPPARγ. The simulation results and calculated binding free energies indicate that BPA can bind to these three nuclear receptors. The binding affinities of BPA were slightly lower than that of E2 to these three receptors. The simulation results proved that the binding process was mainly driven by direct hydrogen bond and hydrophobic interactions. In addition, structural analysis suggested that BPA could interact with these nuclear receptors by mimicking the action of natural hormone and keeping the nuclear receptors in active conformations. The present work provided the structural evidence to recognize BPA as an endocrine disruptor and would be important guidance for seeking safer substitutions of BPA. PMID:25799048

  2. Electronic continuum model for molecular dynamics simulations.

    PubMed

    Leontyev, I V; Stuchebrukhov, A A

    2009-02-28

    A simple model for accounting for electronic polarization in molecular dynamics (MD) simulations is discussed. In this model, called molecular dynamics electronic continuum (MDEC), the electronic polarization is treated explicitly in terms of the electronic continuum (EC) approximation, while the nuclear dynamics is described with a fixed-charge force field. In such a force-field all atomic charges are scaled to reflect the screening effect by the electronic continuum. The MDEC model is rather similar but not equivalent to the standard nonpolarizable force-fields; the differences are discussed. Of our particular interest is the calculation of the electrostatic part of solvation energy using standard nonpolarizable MD simulations. In a low-dielectric environment, such as protein, the standard MD approach produces qualitatively wrong results. The difficulty is in mistreatment of the electronic polarizability. We show how the results can be much improved using the MDEC approach. We also show how the dielectric constant of the medium obtained in a MD simulation with nonpolarizable force-field is related to the static (total) dielectric constant, which includes both the nuclear and electronic relaxation effects. Using the MDEC model, we discuss recent calculations of dielectric constants of alcohols and alkanes, and show that the MDEC results are comparable with those obtained with the polarizable Drude oscillator model. The applicability of the method to calculations of dielectric properties of proteins is discussed. PMID:19256627

  3. Data supporting beta-amyloid dimer structural transitions and protein-lipid interactions on asymmetric lipid bilayer surfaces using MD simulations on experimentally derived NMR protein structures.

    PubMed

    Cheng, Sara Y; Chou, George; Buie, Creighton; Vaughn, Mark W; Compton, Campbell; Cheng, Kwan H

    2016-06-01

    This data article supports the research article entitled "Maximally Asymmetric Transbilayer Distribution of Anionic Lipids Alters the Structure and interaction with Lipids of an Amyloidogenic Protein Dimer Bound to the Membrane Surface" [1]. We describe supporting data on the binding kinetics, time evolution of secondary structure, and residue-contact maps of a surface-absorbed beta-amyloid dimer protein on different membrane surfaces. We further demonstrate the sorting of annular and non-annular regions of the protein/lipid bilayer simulation systems, and the correlation of lipid-number mismatch and surface area per lipid mismatch of asymmetric lipid membranes. PMID:27054174

  4. Comparative MD analysis of the stability of transthyretin providing insight into the fibrillation mechanism.

    PubMed

    Sørensen, Jesper; Hamelberg, Donald; Schiøtt, Birgit; McCammon, J Andrew

    2007-05-01

    Proteins can misfold and aggregate, which is believed to be the cause of a variety of diseases, affecting very diverse organs in the body. Many questions about the nature of aggregation and the proteins that are involved in these events are still left unanswered. One of the proteins that is known to form amyloids is transthyretin (TTR), the secondary transporter of thyroxine, and transporter of retinol-binding protein. Several experimental results have helped to explain this aberrant behavior of TTR; however, structural insights of the amyloidgenic process are still lacking. Therefore, we have used all-atom MD simulation and free energy calculations to study the initial phase of this process. We have calculated the free energy changes of the initial tetramer dissociation under different conditions and in the presence of thyroxine. We show that tetramer formation is indeed only thermodynamically favorable in neutral pH conditions. We find that binding of two thyroxine molecules stabilizes the complex, and that this occurs with negative cooperativity. In addition to the energetic calculations, we have also investigated the dominant motions of the TTR and found that only the dimeric form of the protein could undergo the initial fibril formation. PMID:17315201

  5. Role of the Electrostatic Interactions in the Stabilization of Ionic Liquid Crystals: Insights from Coarse-Grained MD Simulations of an Imidazolium Model.

    PubMed

    Saielli, Giacomo; Wang, Yanting

    2016-09-01

    In order to investigate the role of the electrostatic interactions in stabilizing various phases of ionic liquids, especially smectic ionic liquid crystals, we have employed a coarse-grained model of 1-hexadecyl-3-methylimidazolium nitrate, [C16mim][NO3], to perform molecular dynamics simulations with the partial charges artificially rescaled by a factor from 0.7 to 1.2. The simulated systems have been characterized by means of orientational and translational order parameters and by distribution functions. We have found that increasing the total charge of the ions strongly stabilizes the ionic smectic phase by shifting the clearing point (melting into the isotropic liquid phase) to higher temperatures, while a smaller effect is observed on the stability of the crystal phase. Our results highlight the importance of the electrostatic interactions in promoting the formation of ionic liquid crystals through microphase segregation. Moreover, as the total charge of the model is increased, we observe a transformation from a homogeneous to a nanosegregated isotropic structure typical of ionic liquids. Therefore, a connection can be established between the degree of nanosegregation of ILs and the stability of ILC phases. All the above can be understood by the competition among electrostatic interactions between charged groups (cationic head groups and anions), van der Waals interactions between nonpolar cationic tail groups, and thermal fluctuations. PMID:27486996

  6. The Plasmodium falciparum Malaria M1 Alanyl Aminopeptidase (PfA-M1): Insights of Catalytic Mechanism and Function from MD Simulations

    PubMed Central

    Jones, Peter M.; Robinson, Mark W.; Dalton, John P.; George, Anthony M.

    2011-01-01

    Malaria caused by several species of Plasmodium is major parasitic disease of humans, causing 1–3 million deaths worldwide annually. The widespread resistance of the human parasite to current drug therapies is of major concern making the identification of new drug targets urgent. While the parasite grows and multiplies inside the host erythrocyte it degrades the host cell hemoglobin and utilizes the released amino acids to synthesize its own proteins. The P. falciparum malarial M1 alanyl-aminopeptidase (PfA-M1) is an enzyme involved in the terminal stages of hemoglobin digestion and the generation of an amino acid pool within the parasite. The enzyme has been validated as a potential drug target since inhibitors of the enzyme block parasite growth in vitro and in vivo. In order to gain further understanding of this enzyme, molecular dynamics simulations using data from a recent crystal structure of PfA-M1 were performed. The results elucidate the pentahedral coordination of the catalytic Zn in these metallo-proteases and provide new insights into the roles of this cation and important active site residues in ligand binding and in the hydrolysis of the peptide bond. Based on the data, we propose a two-step catalytic mechanism, in which the conformation of the active site is altered between the Michaelis complex and the transition state. In addition, the simulations identify global changes in the protein in which conformational transitions in the catalytic domain are transmitted at the opening of the N-terminal 8 Å-long channel and at the opening of the 30 Å-long C-terminal internal chamber that facilitates entry of peptides to the active site and exit of released amino acids. The possible implications of these global changes with regard to enzyme function are discussed. PMID:22205955

  7. Computation of relative binding free energy for an inhibitor and its analogs binding with Erk kinase using thermodynamic integration MD simulation.

    PubMed

    Wu, Kuan-Wei; Chen, Po-Chin; Wang, Jun; Sun, Ying-Chieh

    2012-10-01

    In the present study, we carried out thermodynamic integration molecular dynamics simulation for a pair of analogous inhibitors binding with Erk kinase to investigate how computation performs in reproducing the relative binding free energy. The computation with BCC-AM1 charges for ligands gave -1.1 kcal/mol, deviated from experimental value of -2.3 kcal/mol by 1.2 kcal/mol, in good agreement with experimental result. The error of computed value was estimated to be 0.5 kcal/mol. To obtain convergence, switching vdw interaction on and off required approximately 10 times more CPU time than switching charges. Residue-based contributions and hydrogen bonding were analyzed and discussed. Furthermore, subsequent simulation using RESP charge for ligand gave ΔΔG of -1.6 kcal/mol. The computed results are better than the result of -5.6 kcal/mol estimated using PBSA method in a previous study. Based on these results, we further carried out computations to predict ΔΔG for five new analogs, focusing on placing polar and nonpolar functional groups at the meta site of benzene ring shown in the Fig. 1, to see if these ligands have better binding affinity than the above ligands. The computations resulted that a ligand with polar -OH group has better binding affinity than the previous examined ligand by ~2.0 kcal/mol and two other ligands have better affinity by ~1.0 kcal/mol. The predicted better inhibitors of this kind should be of interest to experimentalist for future experimental enzyme and/or cell assays. PMID:22986633

  8. Mechanisms of large Stokes shift and aggregation-enhanced emission of osmapentalyne cations in solution: combined MD simulations and QM/MM calculations.

    PubMed

    Sun, Guang-Xu; Ju, Ming-Gang; Zang, Hang; Zhao, Yi; Liang, WanZhen

    2015-10-01

    Osmapentalyne cations synthesized recently show remarkable optical properties, such as near-infrared emission, unusual large Stokes shift and aggregation-enhanced emission. Here, the mechanisms behind those novel optical behaviors are revealed from the combined molecular dynamics simulations and hybrid quantum mechanics/molecular mechanics calculations. The results demonstrate that the large Stokes shift in the gas phase comes from a photoexcitation-induced deformation of the osmium plane, whereas in solution it corresponds to the variation of osmium ring symmetry. Although the central chromophore ring dominates the absorption and emission processes, the protecting groups PPh3 join the emission. As osmapentalyne cations are aggregated together in solution, the radical distribution functions of their mass-central distances display several peaks immersed in a broad envelope due to different aggregation pathways. However, the chromophore centers are protected by the PPh3 groups, the aggregation structures do not affect the Stokes shift too much, and the calculated aggregate-enhanced emission is consistent with experimental measurements. PMID:26339695

  9. The Binding Mode Prediction and Similar Ligand Potency in the Active Site of Vitamin D Receptor with QM/MM Interaction, MESP, and MD Simulation.

    PubMed

    Selvaraman, Nagamani; Selvam, Saravana Kumar; Muthusamy, Karthikeyan

    2016-08-01

    Non-secosteroidal ligands are well-known vitamin D receptor (VDR) agonists. In this study, we described a combined QM/MM to define the protein-ligand interaction energy a strong positive correlation in both QM-MM interaction energy and binding free energy against the biological activity. The molecular dynamics simulation study was performed, and specific interactions were extensively studied. The molecular docking results and surface analysis shed light on steric and electrostatic complementarities of these non-secosteroidal ligands to VDR. Finally, the drug likeness properties were also calculated and found within the acceptable range. The results show that bulky group substitutions in side chain decrease the VDR activity, whereas a small substitution increased it. Functional analyses of H393A and H301A mutations substantiate their roles in the VDR agonistic and antagonistic activities. Apart from the His393 and His301, two other amino acids in the hinge region viz. Ser233 and Arg270 acted as an electron donor/acceptor specific to the agonist in the distinct ligand potency. The results from this study disclose the binding mechanism of VDR agonists and structural modifications required to improve the selectivity. PMID:26945790

  10. The Nature of Allosteric Inhibition in Glutamate Racemase: discovery and characterization of a cryptic inhibitory pocket using atomistic MD simulations and pKa calculations

    PubMed Central

    Whalen, Katie L.; Tussey, Kenneth B.; Blanke, Steven R.; Spies, M. Ashley

    2011-01-01

    Enzyme inhibition via allostery, in which the ligand binds remotely from the active site, is a poorly understood phenomenon, and represents a significant challenge to structure-based drug design. Dipicolinic acid (DPA), a major component of Bacillus spores, is shown to inhibit glutamate racemase from Bacillus anthracis, a monosubstrate/monoproduct enzyme, in a novel allosteric fashion. Glutamate racemase has long been considered an important drug target for its integral role in bacterial cell wall synthesis. The DPA binding mode was predicted via multiple docking studies and validated via site-directed mutagenesis at the binding locus, while the mechanism of inhibition was elucidated with a combination of Blue Native PAGE, molecular dynamics simulations, free energy and pKa calculations. Inhibition by DPA not only reveals a novel cryptic binding site, but also represents a form of allosteric regulation that exploits the interplay between enzyme conformational changes, fluctuations in the pKa values of buried residues and catalysis. The potential for future drug development is discussed. PMID:21395329

  11. Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications.

    PubMed

    Stockner, Thomas; Mullen, Anna; MacMillan, Fraser

    2015-10-01

    ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented. PMID:26517918

  12. Role of Water in the Puzzling Mechanism of the Final Aromatization Step Promoted by the Human Aromatase Enzyme. Insights from QM/MM MD Simulations.

    PubMed

    Sgrignani, Jacopo; Iannuzzi, Marcella; Magistrato, Alessandra

    2015-10-26

    The enzyme human aromatase (HA) catalyzes the conversion of androgens to estrogens via two hydroxylation reactions and a final unique aromatization step. Despite the great interest of HA as a drug target against breast cancer detailed structural and spectroscopic information on this enzyme became available only in the past few years. As such, the enigmatic mechanism of the final aromatization step is still a matter of debate. Here, we investigated the final step of the HA enzymatic cycle via hybrid quantum-classical (QM/MM) metadynamics and blue-moon ensemble simulations. Our results show that the rate-determining step of the aromatization process is the nucleophilic attack of the distal oxygen of a peroxo-ferric species on the formyl carbon of the enol-19-oxo-androstenedione, which occurs with a free energy barrier (ΔF(#)) of ∼ 16.7 ± 1.9 kcal/mol, in good agreement with experimental data. This reaction is followed by a water mediated 1β-hydrogen abstraction (ΔF(#) = 7.9 ± 0.8 kcal/mol) and by the formation of a hydroxo-ferric moiety. This latter may be finally protonated by a hydrogen delivery channel involving Asp309 and Thr310, both residues pointed out as crucial for HA activity. In the absence of the catalytic water in the active site the substrate does not assume a position suitable to undergo the nucleophilic attack. Our data not only reveal a novel possible mechanism for the aromatization process consistent with some of the spectroscopic and kinetic data available in the literature, complementing current knowledge on the mechanism of this enzyme, but also point out a remarkable influence of the level of theory used on the calculated free energy barriers. The structural information obtained in this study may be used for the rational structure-based drug design of HA inhibitors to be employed in breast cancer therapy. PMID:26381712

  13. Is There Any Preferential Interaction of Ions of Ionic Liquids with DMSO and H2O? A Comparative Study from MD Simulation.

    PubMed

    Zhao, Yuling; Wang, Jianji; Wang, Huiyong; Li, Zhiyong; Liu, Xiaomin; Zhang, Suojiang

    2015-06-01

    Recently, some binary ionic liquid (IL)/cosolvent systems have shown better performance than the pure ILs in fields such as CO2 absorption, catalysis, cellulose dissolution, and electrochemistry. However, interactions of ILs with cosolvents are still not well understood at the molecular level. In this work, H2O and DMSO were chosen as the representative protic and aprotic solvents to study the effect of cosolvent nature on solvation of a series of ILs by molecular dynamics simulations and quantum chemistry calculations. The concept of preferential interaction of ions was proposed to describe the interaction of cosolvent with cation and anion of the ILs. By comparing the interaction energies between IL and different cosolvents, it was found that there were significantly preferential interactions of anions of the ILs with water, but the same was not true for the interactions of cations/anions of the ILs with DMSO. Then, a detailed analysis and comparison of the interactions in IL/cosolvent systems, hydrogen bonds between cations and anions of the ILs, and the structure of the first coordination shells of the cations and the anions were performed to reveal the existing state of ions at different molar ratios of the cosolvent to a given IL. Furthermore, a systematic knowledge for the solvation of ions of the ILs in DMSO was given to understand cellulose dissolution in IL/cosolvent systems. The conclusions drawn from this study may provide new insight into the ionic solvation of ILs in cosolvents, and motivate further studies in the related applications. PMID:25970011

  14. Oil-soluble and water-soluble BTPhens and their europium complexes in octanol/water solutions: interface crossing studied by MD and PMF simulations.

    PubMed

    Benay, G; Wipff, G

    2013-01-31

    Bistriazinyl-phenantroline "BTPhen" ligands L display the remarkable feature to complex trivalent lanthanide and actinide ions, with a marked selectivity for the latter. We report on molecular dynamics studies of tetrasubstituted X(4)BTPhens: L(4+) (X = (+)Et(3)NCH(2)-), L(4-) (X = (-)SO(3)Ph-), and L(0) (X = CyMe(4)) and their complexes with Eu(III) in binary octanol/water solutions. Changes in free energies upon interface crossing are also calculated for typical solutes by potential of mean force PMF simulations. The ligands and their complexes partition, as expected, to either the aqueous or the oil phase, depending on the "solubilizing" group X. Furthermore, most of them are found to be surface active. The water-soluble L(4+) and L(4-) ligands and their (L)Eu(NO(3))(3) complexes adsorb at the aqueous side of the interface, more with L(4-) than with L(4+). The oil soluble ligand L(0) is not surface active in its endo-endo form but adsorbs on the oil side of the interface in its most polar endo-exo form, as well as in its protonated L(0)H(+) and complexed (L(0))Eu(NO(3))(3) states. Furthermore, comparing PMFs of the Eu(III) complexes with and without nitric acid shows that acidifying the aqueous phase has different effects, depending on the ligand charge. In particular, acid promotes the Eu(III) extraction by L(0) via the (L(0))(2)Eu(NO(3))(2+) complex, as observed experimentally. Overall, the results point to the importance of interfacial adsorption for the liquid-liquid extraction of trivalent lanthanide and actinide cations by BTPhens and analogues. PMID:23293892

  15. MD simulations of ligand-bound and ligand-free aptamer: Molecular level insights into the binding and switching mechanism of the add A-riboswitch

    PubMed Central

    Sharma, Monika; Bulusu, Gopalakrishnan; Mitra, Abhijit

    2009-01-01

    Riboswitches are structural cis-acting genetic regulatory elements in 5′ UTRs of mRNAs, consisting of an aptamer domain that regulates the behavior of an expression platform in response to its recognition of, and binding to, specific ligands. While our understanding of the ligand-bound structure of the aptamer domain of the adenine riboswitches is based on crystal structure data and is well characterized, understanding of the structure and dynamics of the ligand-free aptamer is limited to indirect inferences from physicochemical probing experiments. Here we report the results of 15-nsec-long explicit-solvent molecular dynamics simulations of the add A-riboswitch crystal structure (1Y26), both in the adenine-bound (CLOSED) state and in the adenine-free (OPEN) state. Root-mean-square deviation, root-mean-square fluctuation, dynamic cross-correlation, and backbone torsion angle analyses are carried out on the two trajectories. These, along with solvent accessible surface area analysis of the two average structures, are benchmarked against available experimental data and are shown to constitute the basis for obtaining reliable insights into the molecular level details of the binding and switching mechanism. Our analysis reveals the interaction network responsible for, and conformational changes associated with, the communication between the binding pocket and the expression platform. It further highlights the significance of a, hitherto unreported, noncanonical W:H trans base pairing between A73 and A24, in the OPEN state, and also helps us to propose a possibly crucial role of U51 in the context of ligand binding and ligand discrimination. PMID:19625387

  16. High-resolution Structures of Protein-Membrane Complexes by Neutron Reflection and MD Simulation: Membrane Association of the PTEN Tumor Suppressor

    NASA Astrophysics Data System (ADS)

    Lösche, Matthias

    2012-02-01

    phosphatase domains. In the bound state, PTEN's regulatory C-terminal tail is displaced from the membrane and organized on the far side of the protein, ˜ 60 å away from the bilayer surface, in a rather compact structure. The combination of binding studies and neutron reflection allows us to distinguish between PTEN mutant proteins and ultimately may identify the structural features required for membrane binding and activation of PTEN. Molecular dynamics simulations, currently in progress, refine this structural picture further.

  17. Bridging between NMA and Elastic Network Models: Preserving All-Atom Accuracy in Coarse-Grained Models

    PubMed Central

    Na, Hyuntae; Jernigan, Robert L.; Song, Guang

    2015-01-01

    Dynamics can provide deep insights into the functional mechanisms of proteins and protein complexes. For large protein complexes such as GroEL/GroES with more than 8,000 residues, obtaining a fine-grained all-atom description of its normal mode motions can be computationally prohibitive and is often unnecessary. For this reason, coarse-grained models have been used successfully. However, most existing coarse-grained models use extremely simple potentials to represent the interactions within the coarse-grained structures and as a result, the dynamics obtained for the coarse-grained structures may not always be fully realistic. There is a gap between the quality of the dynamics of the coarse-grained structures given by all-atom models and that by coarse-grained models. In this work, we resolve an important question in protein dynamics computations—how can we efficiently construct coarse-grained models whose description of the dynamics of the coarse-grained structures remains as accurate as that given by all-atom models? Our method takes advantage of the sparseness of the Hessian matrix and achieves a high efficiency with a novel iterative matrix projection approach. The result is highly significant since it can provide descriptions of normal mode motions at an all-atom level of accuracy even for the largest biomolecular complexes. The application of our method to GroEL/GroES offers new insights into the mechanism of this biologically important chaperonin, such as that the conformational transitions of this protein complex in its functional cycle are even more strongly connected to the first few lowest frequency modes than with other coarse-grained models. PMID:26473491

  18. Molecular dynamics simulations data of the twenty encoded amino acids in different force fields.

    PubMed

    Vitalini, F; Noé, F; Keller, B G

    2016-06-01

    We present extensive all-atom Molecular Dynamics (MD) simulation data of the twenty encoded amino acids in explicit water, simulated with different force fields. The termini of the amino acids have been capped to ensure that the dynamics of the Φ and ψ torsion angles are analogues to the dynamics within a peptide chain. We use representatives of each of the four major force field families: AMBER ff-99SBILDN [1], AMBER ff-03 [2], OPLS-AA/L [3], CHARMM27 [4] and GROMOS43a1 [5], [6]. Our data represents a library and test bed for method development for MD simulations and for force fields development. Part of the data set has been previously used for comparison of the dynamic properties of force fields (Vitalini et al., 2015) [7] and for the construction of peptide basis functions for the variational approach to molecular kinetics [8]. PMID:27054161

  19. Molecular dynamics simulations data of the twenty encoded amino acids in different force fields

    PubMed Central

    Vitalini, F.; Noé, F.; Keller, B.G.

    2016-01-01

    We present extensive all-atom Molecular Dynamics (MD) simulation data of the twenty encoded amino acids in explicit water, simulated with different force fields. The termini of the amino acids have been capped to ensure that the dynamics of the Φ and ψ torsion angles are analogues to the dynamics within a peptide chain. We use representatives of each of the four major force field families: AMBER ff-99SBILDN [1], AMBER ff-03 [2], OPLS-AA/L [3], CHARMM27 [4] and GROMOS43a1 [5], [6]. Our data represents a library and test bed for method development for MD simulations and for force fields development. Part of the data set has been previously used for comparison of the dynamic properties of force fields (Vitalini et al., 2015) [7] and for the construction of peptide basis functions for the variational approach to molecular kinetics [8]. PMID:27054161

  20. Atomic force microscopy and MD simulations reveal pore-like structures of all-D-enantiomer of Alzheimer's β-amyloid peptide: relevance to the ion channel mechanism of AD pathology.

    PubMed

    Connelly, Laura; Jang, Hyunbum; Arce, Fernando Teran; Capone, Ricardo; Kotler, Samuel A; Ramachandran, Srinivasan; Kagan, Bruce L; Nussinov, Ruth; Lal, Ratnesh

    2012-02-01

    Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length Aβ(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-Aβ(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors. PMID:22217000

  1. Molecular Basis of the Functional Differences between Soluble Human Versus Murine MD-2: Role of Val135 in Transfer of Lipopolysaccharide from CD14 to MD-2.

    PubMed

    Vašl, Jožica; Oblak, Alja; Peternelj, Tina T; Klett, Javier; Martín-Santamaría, Sonsoles; Gioannini, Theresa L; Weiss, Jerrold P; Jerala, Roman

    2016-03-01

    Myeloid differentiation factor 2 (MD-2) is an extracellular protein, associated with the ectodomain of TLR4, that plays a critical role in the recognition of bacterial LPS. Despite high overall structural and functional similarity, human (h) and murine (m) MD-2 exhibit several species-related differences. hMD-2 is capable of binding LPS in the absence of TLR4, whereas mMD-2 supports LPS responsiveness only when mMD-2 and mTLR4 are coexpressed in the same cell. Previously, charged residues at the edge of the LPS binding pocket have been attributed to this difference. In this study, site-directed mutagenesis was used to explore the hydrophobic residues within the MD-2 binding pocket as the source of functional differences between hMD-2 and mMD-2. Whereas decreased hydrophobicity of residues 61 and 63 in the hMD-2 binding pocket retained the characteristics of wild-type hMD-2, a relatively minor change of valine to alanine at position 135 completely abolished the binding of LPS to the hMD-2 mutant. The mutant, however, retained the LPS binding in complex with TLR4 and also cell activation, resulting in a murine-like phenotype. These results were supported by the molecular dynamics simulation. We propose that the residue at position 135 of MD-2 governs the dynamics of the binding pocket and its ability to accommodate lipid A, which is allosterically affected by bound TLR4. PMID:26826249

  2. Interactions between ether phospholipids and cholesterol as determined by scattering and molecular dynamics simulations.

    PubMed

    Pan, Jianjun; Cheng, Xiaolin; Heberle, Frederick A; Mostofian, Barmak; Kučerka, Norbert; Drazba, Paul; Katsaras, John

    2012-12-27

    Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol's molecular interactions with ether lipids as determined using a combination of small-angle neutron and X-ray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data. This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup's phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid-mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules. PMID:23199292

  3. Interactions between Ether Phospholipids and Cholesterol as Determined by Scattering and Molecular Dynamics Simulations

    SciTech Connect

    Pan, Jianjun; Cheng, Xiaolin; Heberle, Frederick A; Mostofian, Barmak; Kucerka, Norbert; Drazba, Paul; Katsaras, John

    2012-01-01

    Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol s molecular interactions with ether lipids as determined using a combination of small-angle neutron and Xray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data. This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup s phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid-mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules.

  4. An optimized MD program for the vector computer cyber 205

    NASA Astrophysics Data System (ADS)

    Brode, Stefan; Ahlrichs, Reinhart

    1986-09-01

    The potential of supercomputers for MD simulation runs is explored for the CYBER 205 vectorcomputer in the treatment of molecular liquids with site-site interaction potentials. Careful vectorization and optimization of remaining scalar codes is shown to reduce the CPU time to 7% as compared to the original code. The advantage of avoiding IO completely by computing time correlation functions in the course of the MD run is demostrated. Special emphasis is given to optimized data structures and data flow in order to minimize start up times and to exploit the hardware features of the CYBER 205.

  5. Toward a Coarse Graining/All Atoms Force Field (CG/AA) from a Multiscale Optimization Method: An Application to the MCM-41 Mesoporous Silicates.

    PubMed

    Ghoufi, A; Morineau, D; Lefort, R; Malfreyt, P

    2010-10-12

    Many interesting physical phenomena occur on length and time scales that are not accessible by atomistic molecular simulations. By introducing a coarse graining of the degrees of freedom, coarse-grained (CG) models allow ther study of larger scale systems for longer times. Coarse-grained force fields have been mostly derived for large molecules, including polymeric materials and proteins. By contrast, there exist no satisfactory CG potentials for mesostructured porous solid materials in the literature. This issue has become critical among a growing number of studies on confinement effects on fluid properties, which require both long time and large scale simulations and the conservation of a sufficient level of atomistic description to account for interfacial phenomena. In this paper, we present a general multiscale procedure to derive a hybrid coarse grained/all atoms force field CG/AA model for mesoporous systems. The method is applied to mesostructured MCM-41 molecular sieves, while the parameters of the mesoscopic interaction potentials are obtained and validated from the computation of the adsorption isotherm of methanol by grand canonical molecular dynamic simulation. PMID:26616783

  6. H5MD: A structured, efficient, and portable file format for molecular data

    NASA Astrophysics Data System (ADS)

    de Buyl, Pierre; Colberg, Peter H.; Höfling, Felix

    2014-06-01

    We propose a new file format named "H5MD" for storing molecular simulation data, such as trajectories of particle positions and velocities, along with thermodynamic observables that are monitored during the course of the simulation. H5MD files are HDF5 (Hierarchical Data Format) files with a specific hierarchy and naming scheme. Thus, H5MD inherits many benefits of HDF5, e.g., structured layout of multi-dimensional datasets, data compression, fast and parallel I/O, and portability across many programming languages and hardware platforms. H5MD files are self-contained, and foster the reproducibility of scientific data and the interchange of data between researchers using different simulation programs and analysis software. In addition, the H5MD specification can serve for other kinds of data (e.g. experimental data) and is extensible to supplemental data, or may be part of an enclosing file structure.

  7. A hybrid MD-DSMC coupling method to investigate flow characteristics of micro-devices

    NASA Astrophysics Data System (ADS)

    Watvisave, D. S.; Puranik, B. P.; Bhandarkar, U. V.

    2015-12-01

    A new methodology is proposed to couple Molecular Dynamics (MD) and Direct Simulation Monte Carlo (DSMC) methods to simulate high Knudsen number (Kn) flows. For this purpose a two-dimensional hybrid MD-DSMC code is developed. In this method gas-surface interactions are modeled using MD, and gas-gas interactions are modeled using DSMC method. Two-way coupling between MD and DSMC is implemented by employing buffer zones for both MD and DSMC regions. Bootstrap sampling and energy minimization algorithms are employed for dynamic coupling of these two methods since MD utilizes real number of molecules during simulation whereas DSMC utilizes a lesser number of simulated molecules. The hybrid methodology combines the advantages of both methods; it has the capability of modeling the gas-surface interaction accurately considering the effect of the presence of neighboring real number of gas molecules, while in the bulk it utilizes DSMC with only the simulated number of molecules thus increasing the computational efficiency significantly compared to pure MD codes. As a result comparatively large domain sizes can be simulated with realistic behavior at the walls. The utility of the hybrid method is demonstrated by simulating high Kn flows through a micro-channel, micro-nozzle and micro-scale shock tube. The effect of partial accommodation of gas molecules with the wall is seen to be captured dynamically with this approach.

  8. CoMD Implementation Suite in Emerging Programming Models

    2014-09-23

    CoMD-Em is a software implementation suite of the CoMD [4] proxy app using different emerging programming models. It is intended to analyze the features and capabilities of novel programming models that could help ensure code and performance portability and scalability across heterogeneous platforms while improving programmer productivity. Another goal is to provide the authors and venders with some meaningful feedback regarding the capabilities and limitations of their models. The actual application is a classical molecularmore » dynamics (MD) simulation using either the Lennard-Jones method (LJ) or the embedded atom method (EAM) for primary particle interaction. The code can be extended to support alternate interaction models. The code is expected ro run on a wide class of heterogeneous hardware configurations like shard/distributed/hybrid memory, GPU's and any other platform supported by the underlying programming model.« less

  9. CoMD Implementation Suite in Emerging Programming Models

    SciTech Connect

    Haque, Riyaz; Reeve, Sam; Juallmes, Luc; Asal, Sameer Abu; Landmehr, Aaron; Gaffer, Sanian; Teodor Bercea, Gheorghe; Rubinstein, Zach

    2014-09-23

    CoMD-Em is a software implementation suite of the CoMD [4] proxy app using different emerging programming models. It is intended to analyze the features and capabilities of novel programming models that could help ensure code and performance portability and scalability across heterogeneous platforms while improving programmer productivity. Another goal is to provide the authors and venders with some meaningful feedback regarding the capabilities and limitations of their models. The actual application is a classical molecular dynamics (MD) simulation using either the Lennard-Jones method (LJ) or the embedded atom method (EAM) for primary particle interaction. The code can be extended to support alternate interaction models. The code is expected ro run on a wide class of heterogeneous hardware configurations like shard/distributed/hybrid memory, GPU's and any other platform supported by the underlying programming model.

  10. All-atom normal-mode analysis reveals an RNA-induced allostery in a bacteriophage coat protein

    NASA Astrophysics Data System (ADS)

    Dykeman, Eric C.; Twarock, Reidun

    2010-03-01

    Assembly of the T=3 bacteriophage MS2 is initiated by the binding of a 19 nucleotide RNA stem loop from within the phage genome to a symmetric coat protein dimer. This binding event effects a folding of the FG loop in one of the protein subunits of the dimer and results in the formation of an asymmetric dimer. Since both the symmetric and asymmetric forms of the dimer are needed for the assembly of the protein container, this allosteric switch plays an important role in the life cycle of the phage. We provide here details of an all-atom normal-mode analysis of this allosteric effect. The results suggest that asymmetric contacts between the A -duplex RNA phosphodiester backbone of the stem loop with the EF loop in one coat protein subunit results in an increased dynamic behavior of its FG loop. The four lowest-frequency modes, which encompass motions predominantly on the FG loops, account for over 90% of the increased dynamic behavior due to a localization of the vibrational pattern on a single FG loop. Finally, we show that an analysis of the allosteric effect using an elastic network model fails to predict this localization effect, highlighting the importance of using an all-atom full force field method for this problem.

  11. GENESIS: a hybrid-parallel and multi-scale molecular dynamics simulator with enhanced sampling algorithms for biomolecular and cellular simulations

    PubMed Central

    Jung, Jaewoon; Mori, Takaharu; Kobayashi, Chigusa; Matsunaga, Yasuhiro; Yoda, Takao; Feig, Michael; Sugita, Yuji

    2015-01-01

    GENESIS (Generalized-Ensemble Simulation System) is a new software package for molecular dynamics (MD) simulations of macromolecules. It has two MD simulators, called ATDYN and SPDYN. ATDYN is parallelized based on an atomic decomposition algorithm for the simulations of all-atom force-field models as well as coarse-grained Go-like models. SPDYN is highly parallelized based on a domain decomposition scheme, allowing large-scale MD simulations on supercomputers. Hybrid schemes combining OpenMP and MPI are used in both simulators to target modern multicore computer architectures. Key advantages of GENESIS are (1) the highly parallel performance of SPDYN for very large biological systems consisting of more than one million atoms and (2) the availability of various REMD algorithms (T-REMD, REUS, multi-dimensional REMD for both all-atom and Go-like models under the NVT, NPT, NPAT, and NPγT ensembles). The former is achieved by a combination of the midpoint cell method and the efficient three-dimensional Fast Fourier Transform algorithm, where the domain decomposition space is shared in real-space and reciprocal-space calculations. Other features in SPDYN, such as avoiding concurrent memory access, reducing communication times, and usage of parallel input/output files, also contribute to the performance. We show the REMD simulation results of a mixed (POPC/DMPC) lipid bilayer as a real application using GENESIS. GENESIS is released as free software under the GPLv2 licence and can be easily modified for the development of new algorithms and molecular models. WIREs Comput Mol Sci 2015, 5:310–323. doi: 10.1002/wcms.1220 PMID:26753008

  12. Molecular dynamics simulation of rotational relaxation in nitrogen: Implications for rotational collision number models

    NASA Astrophysics Data System (ADS)

    Valentini, Paolo; Zhang, Chonglin; Schwartzentruber, Thomas E.

    2012-10-01

    We study the rotational relaxation process in nitrogen using all-atom molecular dynamics (MD) simulations and direct simulation Monte Carlo (DSMC). The intermolecular model used in the MD simulations is shown to (i) reproduce very well the shear viscosity of nitrogen over a wide range of temperatures, (ii) predict the near-equilibrium rotational collision number in good agreement with published trajectory calculations done on ab initio potential energy surfaces, and (iii) produce shock wave profiles in excellent accordance with the experimental measurements. We find that the rotational relaxation process is dependent not only on the near-equilibrium temperature (i.e., when systems relax to equilibrium after a small perturbation), but more importantly on both the magnitude and direction of the initial deviation from the equilibrium state. The comparison between MD and DSMC, based on the Borgnakke-Larsen model, for shock waves (both at low and high temperatures) and one-dimensional expansions shows that a judicious choice of a constant Zrot can produce DSMC results which are in relatively good agreement with MD. However, the selection of the rotational collision number is case-specific, depending not only on the temperature range, but more importantly on the type of flow (compression or expansion), with significant limitations for more complex simulations characterized both by expansion and compression zones. Parker's model, parametrized for nitrogen, overpredicts Zrot for temperatures above about 300 K. It is also unable to describe the dependence of the relaxation process on the direction to equilibrium. Finally, we present a demonstrative cell-based formulation of a rotational relaxation model to illustrate how, by including the key physics obtained from the MD data (dependence of the relaxation process on both the rotational and the translational state of the gas), the agreement between MD and DSMC solutions is drastically improved.

  13. CHARMM General Force Field (CGenFF): A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields

    PubMed Central

    Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; MacKerell, A. D.

    2010-01-01

    The widely used CHARMM additive all-atom force field includes parameters for proteins, nucleic acids, lipids and carbohydrates. In the present paper an extension of the CHARMM force field to drug-like molecules is presented. The resulting CHARMM General Force Field (CGenFF) covers a wide range of chemical groups present in biomolecules and drug-like molecules, including a large number of heterocyclic scaffolds. The parametrization philosophy behind the force field focuses on quality at the expense of transferability, with the implementation concentrating on an extensible force field. Statistics related to the quality of the parametrization with a focus on experimental validation are presented. Additionally, the parametrization procedure, described fully in the present paper in the context of the model systems, pyrrolidine, and 3-phenoxymethylpyrrolidine will allow users to readily extend the force field to chemical groups that are not explicitly covered in the force field as well as add functional groups to and link together molecules already available in the force field. CGenFF thus makes it possible to perform “all-CHARMM” simulations on drug-target interactions thereby extending the utility of CHARMM force fields to medicinally relevant systems. PMID:19575467

  14. [MD-NET--muscular dystrophy network].

    PubMed

    Lochmüller, H; Straub, V

    2007-12-01

    Muscular dystrophies (MD) constitute a group of inherited disorders characterized by progressive weakness of skeletal and sometimes cardiac muscle. MD are rare disorders affecting approximately 26,000 to 40,000 people in Germany based on a pre valence of 1:2000 to 1:3000 (estimate of the Association Française contre les Myopathies, AFM) and a population of 80 million people residing in Germany. More than 30 forms of MD are recognized today caused by different genetic defects. Based on the symptoms of an individual patient the underlying genetic defect cannot be determined, since all MD have the following in common: Muscle fibers are destroyed and become replaced by fatty and fibrous tissue. Various forms of MD are caused by defects of proteins residing in the sarcolemma, the cell membrane of muscle fibers. Other forms are caused by defects of proteins that are associated to the nucleus, to the sarcomer or the cytoplasm. Moreover, there are numerous forms where the exact molecular defect is unknown to date. Even though the underlying defect is known for many MD, the pathogenic process that leads to the decay of musculature is poorly understood. At present, MD cannot be cured. MD are treated by physiotherapy, surgery and medication that may delay progression. Symptomatic therapy such as cardiac pace makers may be life-saving and improve quality of life in many patients. For optimizing research into the MD, a network, the muscular dystrophy network or MD-NET, was initiated and has been supported by the German ministry of education and research (BMBF) since 2003. PMID:18026885

  15. Hemolytic mechanism of dioscin proposed by molecular dynamics simulations.

    PubMed

    Lin, Fu; Wang, Renxiao

    2010-01-01

    Saponins are a class of compounds containing a triterpenoid or steroid core with some attached carbohydrate modules. Many saponins cause hemolysis. However, the hemolytic mechanism of saponins at the molecular level is not yet fully understood. In an attempt to explore this issue, we have studied dioscin-a saponin with high hemolytic activity-through extensive molecular dynamics (MD) simulations. Firstly, all-atom MD simulations of 8 ns duration were conducted to study the stability of the dioscin-cholesterol complex and the cholesterol-cholesterol complex in water and in decane, respectively. MM-GB/SA computations indicate that the dioscin-cholesterol complex is energetically more favorable than the cholesterol-cholesterol complex in a non-polar environment. Next, several coarse-grained MD simulations of 400 ns duration were conducted to directly observe the distribution of multiple dioscin molecules on a DPPC-POPC-PSM-CHOL lipid bilayer. Our results indicate that dioscin can penetrate into the lipid bilayer, accumulate in the lipid raft micro-domain, and then bind cholesterol. This leads to the destabilization of lipid raft and consequent membrane curvature, which may eventually result in the hemolysis of red cells. This possible mechanism of hemolysis can well explain some experimental observations on hemolysis. PMID:19513766

  16. C-type related order in the defective fluorites La2Ce2O7 and Nd2Ce2O7 studied by neutron scattering and ab initio MD simulations.

    PubMed

    Kalland, Liv-Elisif; Norberg, Stefan T; Kyrklund, Jakob; Hull, Stephen; Eriksson, Sten G; Norby, Truls; Mohn, Chris E; Knee, Christopher S

    2016-09-14

    This work presents a structural investigation of La2-xNdxCe2O7 (x = 0.0, 0.5, 1.0, 1.5, 2.0) using X-ray powder diffraction and total scattering neutron powder diffraction, analysed using Rietveld and the reverse Monte Carlo method (RMC). Ab initio molecular dynamics (MD) modelling is also performed for further investigations of the local order. The main intensities in the neutron diffraction data for the La2-xNdxCe2O7 series correspond to the fluorite structure. However, additional C-type superlattice peaks are visible for x > 0 and increase in intensity with increasing x. The Nd-containing compositions (x > 0) are best fitted with Rietveld analysis by using a combination of oxygen deficient fluorite and oxygen excess C-type structures. No indications of cation order are found in the RMC or Rietveld analysis, and the absence of cation order is supported by the MD modelling. We argue that the superlattice peaks originate from oxygen vacancy ordering and associated shift in the cation position away from the ideal fluorite site similar to that in the C-type structure, which is seen from the Rietveld refinements and the observed ordering in the MD modelling. The vacancies favour alignments in the 〈110〉, 〈111〉 and especially the 〈210〉 direction. Moreover, we find that such ordering might also be found to a small extent in La2Ce2O7, explaining the discernible modulated background between the fluorite peaks. The observed overlap of the main Bragg peaks between the fluorite and C-type phase supports the co-existence of vacancy ordered and more disordered domains. This is further supported by the observed similarity of the radial distribution functions as modelled with MD. The increase in long range oxygen vacancy order with increasing Nd-content in La2-xNdxCe2O7 corresponds well with the lower oxide ion conductivity in Nd2Ce2O7 compared to La2Ce2O7 reported earlier. PMID:27526388

  17. The Molecular Structure of a Phosphatidylserine Bilayer Determined by Scattering and Molecular Dynamics Simulations

    SciTech Connect

    Pan, Jianjun; Cheng, Xiaolin; Monticelli, Luca; Heberle, Frederick A; Kucerka, Norbert; Tieleman, D. Peter; Katsaras, John

    2014-01-01

    Phosphatidylserine (PS) lipids play essential roles in biological processes, including enzyme activation and apoptosis. We report on the molecular structure and atomic scale interactions of a fluid bilayer composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS). A scattering density profile model, aided by molecular dynamics (MD) simulations, was developed to jointly refine different contrast small-angle neutron and X-ray scattering data, which yielded a lipid area of 62.7 A2 at 25 C. MD simulations with POPS lipid area constrained at different values were also performed using all-atom and aliphatic united-atom models. The optimal simulated bilayer was obtained using a model-free comparison approach. Examination of the simulated bilayer, which agrees best with the experimental scattering data, reveals a preferential interaction between Na+ ions and the terminal serine and phosphate moieties. Long-range inter-lipid interactions were identified, primarily between the positively charged ammonium, and the negatively charged carboxylic and phosphate oxygens. The area compressibility modulus KA of the POPS bilayer was derived by quantifying lipid area as a function of surface tension from area-constrained MD simulations. It was found that POPS bilayers possess a much larger KA than that of neutral phosphatidylcholine lipid bilayers. We propose that the unique molecular features of POPS bilayers may play an important role in certain physiological functions.

  18. Registration of MD25-26ne, MD25-27, and MD25-87 germplasm lines of cotton with superior yield, fiber quality, and pest resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Three non-commercial cotton (Gossypium hirsutum L.) lines which were released by the USDA-ARS are MD25-26ne (PI 666042), MD25-27 (PI 666043), and MD25-87 (PI 666044). The three lines are reselections out of MD25 (Reg. No GP-929; PI 659505). The objective of this research was to select lines that h...

  19. MD-11 PCA - landing at DFRC

    NASA Technical Reports Server (NTRS)

    1995-01-01

    On August 29, 1995, aided by NASA-developed propulsion controlled aircraft (PCA) system, a McDonnell-Douglas MD-11 made the first-ever, safe landings of an actual transport aircraft using only engine power for control. Later, on November 30, 1995, improved software enabled a McDonnell-Douglas MD-11 to make a final landing at Edwards without the need for the pilot to manipulate the flight controls while using only engine power for control.

  20. Error and efficiency of replica exchange molecular dynamics simulations

    PubMed Central

    Rosta, Edina; Hummer, Gerhard

    2009-01-01

    We derive simple analytical expressions for the error and computational efficiency of replica exchange molecular dynamics (REMD) simulations (and by analogy replica exchange Monte Carlo simulations). The theory applies to the important case of systems whose dynamics at long times is dominated by the slow interconversion between two metastable states. As a specific example, we consider the folding and unfolding of a protein. The efficiency is defined as the rate with which the error in an estimated equilibrium property, as measured by the variance of the estimator over repeated simulations, decreases with simulation time. For two-state systems, this rate is in general independent of the particular property. Our main result is that, with comparable computational resources used, the relative efficiency of REMD and molecular dynamics (MD) simulations is given by the ratio of the number of transitions between the two states averaged over all replicas at the different temperatures, and the number of transitions at the single temperature of the MD run. This formula applies if replica exchange is frequent, as compared to the transition times. High efficiency of REMD is thus achieved by including replica temperatures in which the frequency of transitions is higher than that at the temperature of interest. In tests of the expressions for the error in the estimator, computational efficiency, and the rate of equilibration we find quantitative agreement with the results both from kinetic models of REMD and from actual all-atom simulations of the folding of a peptide in water. PMID:19894977

  1. Error and efficiency of replica exchange molecular dynamics simulations.

    PubMed

    Rosta, Edina; Hummer, Gerhard

    2009-10-28

    We derive simple analytical expressions for the error and computational efficiency of replica exchange molecular dynamics (REMD) simulations (and by analogy replica exchange Monte Carlo simulations). The theory applies to the important case of systems whose dynamics at long times is dominated by the slow interconversion between two metastable states. As a specific example, we consider the folding and unfolding of a protein. The efficiency is defined as the rate with which the error in an estimated equilibrium property, as measured by the variance of the estimator over repeated simulations, decreases with simulation time. For two-state systems, this rate is in general independent of the particular property. Our main result is that, with comparable computational resources used, the relative efficiency of REMD and molecular dynamics (MD) simulations is given by the ratio of the number of transitions between the two states averaged over all replicas at the different temperatures, and the number of transitions at the single temperature of the MD run. This formula applies if replica exchange is frequent, as compared to the transition times. High efficiency of REMD is thus achieved by including replica temperatures in which the frequency of transitions is higher than that at the temperature of interest. In tests of the expressions for the error in the estimator, computational efficiency, and the rate of equilibration we find quantitative agreement with the results both from kinetic models of REMD and from actual all-atom simulations of the folding of a peptide in water. PMID:19894977

  2. Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics

    PubMed Central

    Kwon, Taekyung; Harris, Andrew L.; Rossi, Angelo

    2011-01-01

    The recently published crystal structure of the Cx26 gap junction channel provides a unique opportunity for elucidation of the structure of the conductive connexin pore and the molecular determinants of its ion permeation properties (conductance, current–voltage [I-V] relations, and charge selectivity). However, the crystal structure was incomplete, most notably lacking the coordinates of the N-terminal methionine residue, which resides within the pore, and also lacking two cytosolic domains. To allow computational studies for comparison with the known channel properties, we completed the structure. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) simulations of the completed and the published Cx26 hemichannel crystal structure indicate that the pore is too narrow to permit significant ion flux. The GCMC/BD simulations predict marked inward current rectification and almost perfect anion selectivity, both inconsistent with known channel properties. The completed structure was refined by all-atom molecular dynamics (MD) simulations (220 ns total) in an explicit solvent and POPC membrane system. These MD simulations produced an equilibrated structure with a larger minimal pore diameter, which decreased the height of the permeation barrier formed by the N terminus. GCMC/BD simulations of the MD-equilibrated structure yielded more appropriate single-channel conductance and less anion/cation selectivity. However, the simulations much more closely matched experimentally determined I-V relations when the charge effects of specific co- and posttranslational modifications of Cx26 previously identified by mass spectrometry were incorporated. We conclude that the average equilibrated structure obtained after MD simulations more closely represents the open Cx26 hemichannel structure than does the crystal structure, and that co- and posttranslational modifications of Cx26 hemichannels are likely to play an important physiological role by defining the conductance and ion

  3. VIEW IN OPPOSITE DIRECTION AS MD1351 AND MD1352. RAW MATERIAL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW IN OPPOSITE DIRECTION AS MD-135-1 AND MD-135-2. RAW MATERIAL CONVEYOR AT LEFT DEPOSITS SHELL INTO MILLING MACHINE AT LOWER LEFT. ENGINE IS AT LOWER RIGHT AND RADIATOR AT LOWER CENTER. ROLLER SORTER IS AT TOP OF CONVEYOR. - F. & H. Benning Company Oyster Mill, 14430 Solomons Island Road (moved from 1014 Benning Road, Galesville, Anne Arundel County, Maryland), Solomons, Calvert County, MD

  4. Near-Collision Attacks on MD4: Applied to MD4-Based Protocols

    NASA Astrophysics Data System (ADS)

    Wang, Lei; Ohta, Kazuo; Kunihiro, Noboru

    The most widely used hash functions from MD4 family have been broken, which lead to a public competition on designing new hash functions held by NIST. This paper focuses on one concept called near-collision resistance: computationally difficult to find a pair of messages with hash values differing in only few bits, which new hash functions should satisfy. In this paper, we will give a model of near-collisions on MD4, and apply it to attack protocols including HMAC/NMAC-MD4 and MD4(Password||Challenge). Our new outer-key recovery attacks on HMAC/NMAC-MD4 has a complexity of 272 online queries and 277 MD4 computations, while previous result was 288 online queries and 295 MD4 computations. Our attack on MD4(Password||Challenge) can recover 16 password characters with a complexity of 237 online queries and 221 MD4 computations, which is the first approach to attack such protocols.

  5. 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

    2014-05-01

    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. PMID:24638223

  6. Self-assembling dipeptides: conformational sampling in solvent-free coarse-grained simulation.

    PubMed

    Villa, Alessandra; Peter, Christine; van der Vegt, Nico F A

    2009-03-28

    We discuss the development of a coarse-grained (CG) model for molecular dynamics (MD) simulation of a hydrophobic dipeptide, diphenylalanine, in aqueous solution. The peptide backbone is described with two CG beads per amino acid, the side groups and charged end groups are each described with one CG bead. In the derivation of interaction functions between CG beads we follow a bottom-up strategy where we devise potentials such that the resulting CG simulation reproduces the conformational sampling and the intermolecular interactions observed in an atomistic simulation of the same peptide. In the CG model, conformational flexibility of the peptide is accounted for through a set of intra-molecular (bonded) potentials. The approach followed to obtain the bonded potentials is discussed in detail. The CG potentials for nonbonded interactions are based on potentials of mean force obtained by atomistic simulations in aqueous solution. Following this approach, solvent mediation effects are included in the effective bead-bead nonbonded interactions and computationally very efficient (solvent-free) simulations of self-assembly processes can be performed. We show that the conformational properties of the all-atom dipeptide in explicit solvent can be accurately reproduced with the CG model. Moreover, preliminary simulations of peptide self-assembly performed with the CG model illustrate good agreement with results obtained from all-atom, explicit solvent simulations. PMID:19280018

  7. 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.

  8. Functional Domain Motions in Proteins on the 1 100 ns Timescale: Comparison of Neutron Spin-Echo Spectroscopy of Phosphoglycerate Kinase with Molecular-Dynamics Simulation

    SciTech Connect

    Smolin, Nikolai; Biehl, R; Kneller, Gerald; Richter, Dieter O; Smith, Jeremy C

    2011-01-01

    Protein function often requires large-scale domain motion. An exciting new development in the experimental characterization of domain motions in proteins is the application of neutron spin-echo spectroscopy (NSE). NSE directly probes coherent (i.e., pair correlated) scattering on the 1 100 ns timescale. Here, we report on all-atom molecular-dynamics (MD) simulation of a protein, phosphoglycerate kinase, from which we calculate small-angle neutron scattering (SANS) and NSE scattering properties. The simulation-derived and experimental-solution SANS results are in excellent agreement. The contributions of translational and rotational whole-molecule diffusion to the simulation-derived NSE and potential problems in their estimation are examined. Principal component analysis identifies types of domain motion that dominate the internal motion's contribution to the NSE signal, with the largest being classic hinge bending. The associated free-energy profiles are quasiharmonic and the frictional properties correspond to highly overdamped motion. The amplitudes of the motions derived by MD are smaller than those derived from the experimental analysis, and possible reasons for this difference are discussed. The MD results confirm that a significant component of the NSE arises from internal dynamics. They also demonstrate that the combination of NSE with MD is potentially useful for determining the forms, potentials of mean force, and time dependence of functional domain motions in proteins.

  9. Registration of cotton germplasm line md 10-5

    Technology Transfer Automated Retrieval System (TEKTRAN)

    MD 10-5 (Reg. No. ______, PI 675077) is a noncommercial breeding line of cotton (Gossypium hirsutum L.) released by the USDA-ARS at Stoneville, MS in 2015. MD 10-5 was selected in F4 progenies from a cross between MD 15 (PI 642769) and JJ 1145ne. MD 10-5 has a desirable combination between lint yi...

  10. Significant reduction in errors associated with nonbonded contacts in protein crystal structures: automated all-atom refinement with PrimeX

    SciTech Connect

    Bell, Jeffrey A.; Ho, Kenneth L.; Farid, Ramy

    2012-08-01

    All-atom models derived from moderate-resolution protein crystal structures contain a high frequency of close nonbonded contacts, independent of the major refinement program used for structure determination. All-atom refinement with PrimeX corrects many of these problematic interactions, producing models that are better suited for use in computational chemistry and related applications. All-atom models are essential for many applications in molecular modeling and computational chemistry. Nonbonded atomic contacts much closer than the sum of the van der Waals radii of the two atoms (clashes) are commonly observed in such models derived from protein crystal structures. A set of 94 recently deposited protein structures in the resolution range 1.5–2.8 Å were analyzed for clashes by the addition of all H atoms to the models followed by optimization and energy minimization of the positions of just these H atoms. The results were compared with the same set of structures after automated all-atom refinement with PrimeX and with nonbonded contacts in protein crystal structures at a resolution equal to or better than 0.9 Å. The additional PrimeX refinement produced structures with reasonable summary geometric statistics and similar R{sub free} values to the original structures. The frequency of clashes at less than 0.8 times the sum of van der Waals radii was reduced over fourfold compared with that found in the original structures, to a level approaching that found in the ultrahigh-resolution structures. Moreover, severe clashes at less than or equal to 0.7 times the sum of atomic radii were reduced 15-fold. All-atom refinement with PrimeX produced improved crystal structure models with respect to nonbonded contacts and yielded changes in structural details that dramatically impacted on the interpretation of some protein–ligand interactions.

  11. Recovering position-dependent diffusion from biased molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Ljubetič, Ajasja; Urbančič, Iztok; Štrancar, Janez

    2014-02-01

    All atom molecular dynamics (MD) models provide valuable insight into the dynamics of biophysical systems, but are limited in size or length by the high computational demands. The latter can be reduced by simulating long term diffusive dynamics (also known as Langevin dynamics or Brownian motion) of the most interesting and important user-defined parts of the studied system, termed collective variables (colvars). A few hundred nanosecond-long biased MD trajectory can therefore be extended to millisecond lengths in the colvars subspace at a very small additional computational cost. In this work, we develop a method for determining multidimensional anisotropic position- and timescale-dependent diffusion coefficients (D) by analysing the changes of colvars in an existing MD trajectory. As a test case, we obtained D for dihedral angles of the alanine dipeptide. An open source Mathematica® package, capable of determining and visualizing D in one or two dimensions, is available at https://github.com/lbf-ijs/DiffusiveDynamics. Given known free energy and D, the package can also generate diffusive trajectories.

  12. Recovering position-dependent diffusion from biased molecular dynamics simulations

    SciTech Connect

    Ljubetič, Ajasja; Urbančič, Iztok; Štrancar, Janez

    2014-02-28

    All atom molecular dynamics (MD) models provide valuable insight into the dynamics of biophysical systems, but are limited in size or length by the high computational demands. The latter can be reduced by simulating long term diffusive dynamics (also known as Langevin dynamics or Brownian motion) of the most interesting and important user-defined parts of the studied system, termed collective variables (colvars). A few hundred nanosecond-long biased MD trajectory can therefore be extended to millisecond lengths in the colvars subspace at a very small additional computational cost. In this work, we develop a method for determining multidimensional anisotropic position- and timescale-dependent diffusion coefficients (D) by analysing the changes of colvars in an existing MD trajectory. As a test case, we obtained D for dihedral angles of the alanine dipeptide. An open source Mathematica{sup ®} package, capable of determining and visualizing D in one or two dimensions, is available at https://github.com/lbf-ijs/DiffusiveDynamics . Given known free energy and D, the package can also generate diffusive trajectories.

  13. Recovering position-dependent diffusion from biased molecular dynamics simulations.

    PubMed

    Ljubetič, Ajasja; Urbančič, Iztok; Štrancar, Janez

    2014-02-28

    All atom molecular dynamics (MD) models provide valuable insight into the dynamics of biophysical systems, but are limited in size or length by the high computational demands. The latter can be reduced by simulating long term diffusive dynamics (also known as Langevin dynamics or Brownian motion) of the most interesting and important user-defined parts of the studied system, termed collective variables (colvars). A few hundred nanosecond-long biased MD trajectory can therefore be extended to millisecond lengths in the colvars subspace at a very small additional computational cost. In this work, we develop a method for determining multidimensional anisotropic position- and timescale-dependent diffusion coefficients (D) by analysing the changes of colvars in an existing MD trajectory. As a test case, we obtained D for dihedral angles of the alanine dipeptide. An open source Mathematica(®) package, capable of determining and visualizing D in one or two dimensions, is available at https://github.com/lbf-ijs/DiffusiveDynamics. Given known free energy and D, the package can also generate diffusive trajectories. PMID:24588150

  14. Folding simulations of gramicidin A into the β-helix conformations: Simulated annealing molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Mori, Takaharu; Okamoto, Yuko

    2009-10-01

    Gramicidin A is a linear hydrophobic 15-residue peptide which consists of alternating D- and L-amino acids and forms a unique tertiary structure, called the β6.3-helix, to act as a cation-selective ion channel in the natural conditions. In order to investigate the intrinsic ability of the gramicidin A monomer to form secondary structures, we performed the folding simulation of gramicidin A using a simulated annealing molecular dynamics (MD) method in vacuum mimicking the low-dielectric, homogeneous membrane environment. The initial conformation was a fully extended one. From the 200 different MD runs, we obtained a right-handed β4.4-helix as the lowest-potential-energy structure, and left-handed β4.4-helix, right-handed and left-handed β6.3-helix as local-minimum energy states. These results are in accord with those of the experiments of gramicidin A in homogeneous organic solvent. Our simulations showed a slight right-hand sense in the lower-energy conformations and a quite β-sheet-forming tendency throughout almost the entire sequence. In order to examine the stability of the obtained right-handed β6.3-helix and β4.4-helix structures in more realistic membrane environment, we have also performed all-atom MD simulations in explicit water, ion, and lipid molecules, starting from these β-helix structures. The results suggested that β6.3-helix is more stable than β4.4-helix in the inhomogeneous, explicit membrane environment, where the pore water and the hydrogen bonds between Trp side-chains and lipid-head groups have a role to further stabilize the β6.3-helix conformation.

  15. Folding simulations of gramicidin A into the beta-helix conformations: Simulated annealing molecular dynamics study.

    PubMed

    Mori, Takaharu; Okamoto, Yuko

    2009-10-28

    Gramicidin A is a linear hydrophobic 15-residue peptide which consists of alternating D- and L-amino acids and forms a unique tertiary structure, called the beta(6.3)-helix, to act as a cation-selective ion channel in the natural conditions. In order to investigate the intrinsic ability of the gramicidin A monomer to form secondary structures, we performed the folding simulation of gramicidin A using a simulated annealing molecular dynamics (MD) method in vacuum mimicking the low-dielectric, homogeneous membrane environment. The initial conformation was a fully extended one. From the 200 different MD runs, we obtained a right-handed beta(4.4)-helix as the lowest-potential-energy structure, and left-handed beta(4.4)-helix, right-handed and left-handed beta(6.3)-helix as local-minimum energy states. These results are in accord with those of the experiments of gramicidin A in homogeneous organic solvent. Our simulations showed a slight right-hand sense in the lower-energy conformations and a quite beta-sheet-forming tendency throughout almost the entire sequence. In order to examine the stability of the obtained right-handed beta(6.3)-helix and beta(4.4)-helix structures in more realistic membrane environment, we have also performed all-atom MD simulations in explicit water, ion, and lipid molecules, starting from these beta-helix structures. The results suggested that beta(6.3)-helix is more stable than beta(4.4)-helix in the inhomogeneous, explicit membrane environment, where the pore water and the hydrogen bonds between Trp side-chains and lipid-head groups have a role to further stabilize the beta(6.3)-helix conformation. PMID:19894978

  16. CHARMM All-Atom Additive Force Field for Sphingomyelin: Elucidation of Hydrogen Bonding and of Positive Curvature

    PubMed Central

    Venable, Richard M.; Sodt, Alexander J.; Rogaski, Brent; Rui, Huan; Hatcher, Elizabeth; MacKerell, Alexander D.; Pastor, Richard W.; Klauda, Jeffery B.

    2014-01-01

    The C36 CHARMM lipid force field has been extended to include sphingolipids, via a combination of high-level quantum mechanical calculations on small molecule fragments, and validation by extensive molecular dynamics simulations on N-palmitoyl and N-stearoyl sphingomyelin. NMR data on these two molecules from several studies in bilayers and micelles played a strong role in the development and testing of the force field parameters. Most previous force fields for sphingomyelins were developed before the availability of the detailed NMR data and relied on x-ray diffraction of bilayers alone for the validation; these are shown to be too dense in the bilayer plane based on published chain order parameter data from simulations and experiments. The present simulations reveal O-H:::O-P intralipid hydrogen bonding occurs 99% of the time, and interlipid N-H:::O=C (26-29%, depending on the lipid) and N-H:::O-H (17–19%). The interlipid hydrogen bonds are long lived, showing decay times of 50 ns, and forming strings of lipids, and leading to reorientational correlation time of nearly 100 ns. The spontaneous radius of curvature for pure N-palmitoyl sphingomyelin bilayers is estimated to be 43–100 Å, depending on the assumptions made in assigning a bending constant; this unusual positive curvature for a two-tailed neutral lipid is likely associated with hydrogen bond networks involving the NH of the sphingosine group. PMID:24988348

  17. The Multidimensional Curriculum Model (MdCM)

    ERIC Educational Resources Information Center

    Vidergor, Hava E.

    2010-01-01

    The multidimensional Curriculum Model (MdCM) helps teachers to better prepare gifted and able students for our changing world, acquiring much needed skills. It is influenced by general learning theory of constructivism, notions of preparing students for 21st century, Teaching the Future Model, and current comprehensive curriculum models for…

  18. Howard Parnes, MD | Division of Cancer Prevention

    Cancer.gov

    Dr. Howard Parnes received a BA from Cornell University in 1977 and an MD from the University of Medicine and Dentistry of New Jersey in 1981. He trained in internal medicine at the Johns Hopkins Bayview Medical Center from 1981 to 1984 followed by a medical oncology fellowship at the University of Maryland Cancer Center (UMCC) from 1984 to 1987. |

  19. 78 FR 2707 - Maryland Disaster # MD-00026

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-14

    ... From the Federal Register Online via the Government Publishing Office SMALL BUSINESS ADMINISTRATION Maryland Disaster MD-00026 AGENCY: U.S. Small Business Administration. ACTION: Notice. SUMMARY... Deadline Date: 10/02/2013. ADDRESSES: Submit completed loan applications to: U.S. Small...

  20. MD-11 PCA - Research flight team photo

    NASA Technical Reports Server (NTRS)

    1995-01-01

    On Aug. 30, 1995, a the McDonnell Douglas MD-11 transport aircraft landed equipped with a computer-assisted engine control system that has the potential to increase flight safety. In landings at NASA Dryden Flight Research Center, Edwards, California, on August 29 and 30, the aircraft demonstrated software used in the aircraft's flight control computer that essentially landed the MD-11 without a need for the pilot to manipulate the flight controls significantly. In partnership with McDonnell Douglas Aerospace (MDA), with Pratt & Whitney and Honeywell helping to design the software, NASA developed this propulsion-controlled aircraft (PCA) system following a series of incidents in which hydraulic failures resulted in the loss of flight controls. This new system enables a pilot to operate and land the aircraft safely when its normal, hydraulically-activated control surfaces are disabled. This August 29, 1995, photo shows the MD-11 team. Back row, left to right: Tim Dingen, MDA pilot; John Miller, MD-11 Chief pilot (MDA); Wayne Anselmo, MD-11 Flight Test Engineer (MDA); Gordon Fullerton, PCA Project pilot; Bill Burcham, PCA Chief Engineer; Rudey Duran, PCA Controls Engineer (MDA); John Feather, PCA Controls Engineer (MDA); Daryl Townsend, Crew Chief; Henry Hernandez, aircraft mechanic; Bob Baron, PCA Project Manager; Don Hermann, aircraft mechanic; Jerry Cousins, aircraft mechanic; Eric Petersen, PCA Manager (Honeywell); Trindel Maine, PCA Data Engineer; Jeff Kahler, PCA Software Engineer (Honeywell); Steve Goldthorpe, PCA Controls Engineer (MDA). Front row, left to right: Teresa Hass, Senior Project Management Analyst; Hollie Allingham (Aguilera), Senior Project Management Analyst; Taher Zeglum, PCA Data Engineer (MDA); Drew Pappas, PCA Project Manager (MDA); John Burken, PCA Control Engineer.

  1. All-atom structures and calcium binding sites of the bacterial photosynthetic LH1-RC core complex from Thermochromatium tepidum.

    PubMed

    Khrenova, Maria G; Nemukhin, Alexander V; Grigorenko, Bella L; Wang, Peng; Zhang, Jian-Ping

    2014-06-01

    Computationally derived structures of the photosynthetic core complex composed of the light-harvesting (LH) system LH1 and the reaction center (RC) from a thermophilic purple sulfur bacterium Thermochromatium tepidum are reported providing first models of the LH1 system at atomic resolution. We used the known primary structure of α and β polypeptides from this particular LH1 complex and the related bacterial LH templates to design the LH1 torus composed of 16 αβ subunits trapping bacteriochlorophyll (BChl-a) dimers and carotenoid molecules. The macromolecule of RC was placed in the center of the ring and the LH1-RC complex was inserted inside the lipid bilayer to simulate the membrane environment. Since thermal stability of the LH1-RC complex is linked to Ca(2+) binding by the complex, location of trapping sites of calcium ions in the LH1 polypeptides is examined by using molecular dynamics simulations of the entire system solvated in water with CaCl2 molecules in the system. The newly predicted Ca(2+) trapping sites can be responsible for attractive interaction of neighboring αβ subunits of LH1 with relevance to stability of the calcium-bound LH1-RC complex. PMID:24852455

  2. Significant reduction in errors associated with nonbonded contacts in protein crystal structures: automated all-atom refinement with PrimeX.

    PubMed

    Bell, Jeffrey A; Ho, Kenneth L; Farid, Ramy

    2012-08-01

    All-atom models are essential for many applications in molecular modeling and computational chemistry. Nonbonded atomic contacts much closer than the sum of the van der Waals radii of the two atoms (clashes) are commonly observed in such models derived from protein crystal structures. A set of 94 recently deposited protein structures in the resolution range 1.5-2.8 Å were analyzed for clashes by the addition of all H atoms to the models followed by optimization and energy minimization of the positions of just these H atoms. The results were compared with the same set of structures after automated all-atom refinement with PrimeX and with nonbonded contacts in protein crystal structures at a resolution equal to or better than 0.9 Å. The additional PrimeX refinement produced structures with reasonable summary geometric statistics and similar R(free) values to the original structures. The frequency of clashes at less than 0.8 times the sum of van der Waals radii was reduced over fourfold compared with that found in the original structures, to a level approaching that found in the ultrahigh-resolution structures. Moreover, severe clashes at less than or equal to 0.7 times the sum of atomic radii were reduced 15-fold. All-atom refinement with PrimeX produced improved crystal structure models with respect to nonbonded contacts and yielded changes in structural details that dramatically impacted on the interpretation of some protein-ligand interactions. PMID:22868759

  3. Practical Password Recovery Attacks on MD4 Based Prefix and Hybrid Authentication Protocols

    NASA Astrophysics Data System (ADS)

    Sasaki, Yu; Wang, Lei; Ohta, Kazuo; Aoki, Kazumaro; Kunihiro, Noboru

    In this paper, we present practical password recovery attacks against two challenge and response authentication protocols using MD4. For attacks on protocols, the number of queries is one of the most important factors because the opportunity where an attacker can ask queries is very limited in real protocols. When responses are computed as MD4(Password||Challenge), which is called prefix approach, previous work needs to ask 237 queries to recover a password. Asking 237 queries in real protocols is almost impossible. In our attack, to recover up to 8-octet passwords, we only need 1 time the amount of eavesdropping, 17 queries, and 234 MD4 off-line computations. To recover up to 12-octet passwords, we only need 210 times the amount of eavesdropping, 210 queries, and 241 off-line MD4 computations. When responses are computed as MD4(Password||Challenge||Password), which is called hybrid approach, previous work needs to ask 263 queries, while in our attack, up to 8-octet passwords are practically recovered by 28 times the amount of eavesdropping, 28 queries, and 239 off-line MD4 computations. Our idea is guessing a part of passwords so that we can simulate values of intermediate chaining variables from observed hash values. This enables us to use a short local collision that occurs with a very high probability, and thus the number of queries becomes practical.

  4. Angular Effects on F+ Etching SiC: MD Study

    NASA Astrophysics Data System (ADS)

    Chen, Xu; Tian, Shuping; He, Pingni; Zhao, Chengli; Sun, Weizhong; Zhang, Junyuan; Chen, Feng; Gou, Fujun

    2012-12-01

    Molecular dynamics (MD) simulations were performed to investigate F+ continuously bombarding SiC surfaces with energies of 100 eV at different incident angles at 300 K. The simulated results show that the steady-state uptake of F atoms increases with increasing incident angle. With the steady-state etching established, a Si-C-F reactive layer is formed. It is found that the etching yield of Si is greater than that of C. In the F-containing reaction layer, the SiF species is dominant with incident angles less than 30°. For all incident angles, the CF species is dominant over CF2 and CF3.

  5. Toxic wastes discovered in Cecil County, MD

    SciTech Connect

    Not Available

    1994-01-01

    This report focuses on the clean-up activities following toxic waste contamination in Cecil County, MD. The potentially hazardous leakage from waste containers buried in a quarry was addressed before it was turned into a civil emergency of the magnitude of Love Canal. US Superfund is a federal government trust fund largely comprised of taxes on the chemical and petrochemical industries. Local governments share in the cost of removing the waste and other aspects of emergency management.

  6. Toxic wastes discovered in Cecil County, MD

    SciTech Connect

    1994-12-31

    This report focuses on the clean-up activities following toxic waste contamination in Cecil County, MD. The potentially hazardous leakage from waste containers buried in a quarry was addressed before it was turned into a civil emergency of the magnitude of Love Canal. US Superfund is a federal government trust fund largely comprised of taxes on the chemical and petrochemical industries. Local governments share in the cost of removing the waste and other aspects of emergency management.

  7. Eva Szabo, MD | Division of Cancer Prevention

    Cancer.gov

    Dr. Eva Szabo is Chief of the Lung and Upper Aerodigestive Cancer Research Group at the NCI Division of Cancer Prevention. She graduated from Yale University with a BS in Molecular Biophysics and Biochemistry, received her MD from Duke University, and completed her internal medicine residency at Bellevue-NYU Medical Center. After completing her medical oncology fellowship at the National Cancer Institute, Dr. Szabo led a laboratory effort studying lung cancer biology. |

  8. Simulating the Distance Distribution between Spin-Labels Attached to Proteins

    PubMed Central

    2016-01-01

    EPR/DEER spectroscopy is playing an increasingly important role in the characterization of the conformational states of proteins. In this study, force field parameters for the bifunctional spin-label (RX) used in EPR/DEER are parametrized and tested with molecular dynamics (MD) simulations. The dihedral angles connecting the Cα atom of the backbone to the nitroxide ring moiety of the RX spin-label attached to i and i + 4 positions in a polyalanine α-helix agree very well with those observed in the X-ray crystallography. Both RXi,i+4 and RXi,i+3 are more rigid than the monofunctional spin-label (R1) commonly used in EPR/DEER, while RXi,i+4 is more rigid and causes less distortion in a protein backbone than RXi,i+3. Simplified dummy spin-label models with a single effective particle representing the RXi,i+3 and RXi,i+4 are also developed and parametrized from the all-atom simulations. MD simulations with dummy spin-labels (MDDS) provide distance distributions that can be directly compared to distance distributions obtained from EPR/DEER to rapidly assess if a hypothetical three-dimensional (3D) structural model is consistent with experiment. The dummy spin-labels can also be used in the restrained-ensemble MD (re-MD) simulations to carry out structural refinement of 3D models. Applications of this methodology to T4 lysozyme, KCNE1, and LeuT are shown to provide important insights about their conformational dynamics. PMID:25645890

  9. Susquehanna River Bridge. Havre de Grace, Hareford Co., MD. Sec. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Susquehanna River Bridge. Havre de Grace, Hareford Co., MD. Sec. 1201, MP 60.07. - Northeast Railroad Corridor, Amtrak route between District of Columbia/Maryland state line & Maryland/Delaware state line, Baltimore, Independent City, MD

  10. Juniata Street Culvert. Havre de Grace, Hareford Co., MD. Sec. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Juniata Street Culvert. Havre de Grace, Hareford Co., MD. Sec. 1201, MP 60.77. - Northeast Railroad Corridor, Amtrak route between District of Columbia/Maryland state line & Maryland/Delaware state line, Baltimore, Independent City, MD

  11. Local Legends of Medicine: Janelle Goetcheus, M.D.

    MedlinePlus

    ... Issues Local Legends of Medicine: Janelle Goetcheus, M.D. Past Issues / Spring 2007 Table of Contents For ... and photos by Christopher Klose Janelle Goetcheus, M.D., Caring for and about Washington, DC's Homeless "The ...

  12. Remains of abutments for Bridge No. 1575 at MD Rt. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Remains of abutments for Bridge No. 1575 at MD Rt. 51 in Spring Gap, Maryland, looking northeast. (Compare with HAER MD-115 photos taken 1988). - Western Maryland Railway, Cumberland Extension, Pearre to North Branch, from WM milepost 125 to 160, Pearre, Washington County, MD

  13. 75 FR 81125 - Drawbridge Operation Regulation; Sassafras River, Georgetown, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-27

    ... SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulation; Sassafras River, Georgetown, MD... of the Sassafras River (Route 213) Bridge, mile 10.0, in Georgetown, MD. The deviation is necessary... Sassafras River Bridge (Route 213), at mile 10.0, in Georgetown, MD has a vertical clearance in the...

  14. Analysis of solvation structure and thermodynamics of methane in water by reference interaction site model theory using an all-atom model

    NASA Astrophysics Data System (ADS)

    Cui, Qizhi; Smith, Vedene H.

    2000-12-01

    An all-atom molecular model and optimized site-site pair potential parameters are employed for methane solute. By use of the reference interaction site model theory, the methane hydration structure is analyzed at the atomic level and its hydration free energies, energies, enthalpies, and entropies for four different thermodynamic states: temperature T=283.15, 298.15, 313.15, 328.15 K and the corresponding bulk water density ρ=0.9997, 0.9970, 0.9922, 0.9875 g cm-3 are calculated. Our calculated thermodynamic properties are in rather good agreement with experiments.

  15. Discovery of /sup 260/Md and the decay properties of /sup 258/Fm, /sup 258m,g/Md, and /sup 259/Md

    SciTech Connect

    Lougheed, R.W.; Hulet, E.K.; Dougan, R.J.; Wild, J.F.; Dupzyk, R.J.; Henderson, C.M.; Moody, K.J.; Hahn, R.L.; Suemmerer, K.; Bethune, G.

    1985-08-01

    We have discovered a new neutron-rich isotope, /sup 260/Md, from /sup 18/O and /sup 22/Ne bombardments of /sup 254/Es. We observed a spontaneous-fission (SF) activity with a 32-day half-life in electromagnetically separated mass-260 fractions from these bombardments and we have measured the mass and kinetic energy distributions of this SF activity. The mass distribution was symmetric with the principal energy peak at 234-MeV total kinetic energy (TKE), similar to previous observations for heavy Fm isotopes. Surprisingly, we also observed a smaller symmetric component with 195-MeV TKE. We interpret these two peaks in the TKE distribution as arising from two types of fission in the same nucleus, or bimodal fission. The observed fission activity may be either from the SF decay of /sup 260/Md or /sup 260/Fm which would arise from electron capture (EC) decay of /sup 260/Md. We have eliminated the possible ..beta../sup -/ decay of /sup 260/Md by measuring ..beta../sup -/-SF time correlations for the decay of /sup 260/Md and we plan to determine if /sup 260/Md decays by EC by measuring time correlations between Fm x-rays and SF events. We also measured properties for heavy Fm and Md isotopes which include: (1) more accurate cross sections for the neutron-rich Md isotopes which we use to predict the production rates of yet undiscovered nuclides; (2) improved half-live measurements for /sup 258m,g/Md and /sup 259/Md; (3) confirmation of the EC decay of /sup 258m/Md by measuring Fm x-rays preceding the SF decay of /sup 258/Fm; and (4) very substantially improved mass and TKE distributions for the SF decay of /sup 258/Fm and /sup 259/Md.

  16. Computation of shear viscosity of colloidal suspensions by SRD-MD

    SciTech Connect

    Laganapan, A. M. K.; Videcoq, A. Bienia, M.; Ala-Nissila, T.; Bochicchio, D.; Ferrando, R.

    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.

  17. Counter-ion binding and mobility in the presence of hydrophobic polyions – combining molecular dynamics simulations and NMR

    NASA Astrophysics Data System (ADS)

    Druchok, Maksym; Malikova, Natalie; Rollet, Anne-Laure; Vlachy, Vojko

    2016-06-01

    Counter-ion binding and mobility in aqueous solutions of partially hydrophobic ionene oligoions is studied here by a combination of all-atomic molecular dynamics (MD) simulations and NMR (19F and 81Br nuclei) measurements. We present results for 12, 12-ionenes in the presence of different halide ions (F-, Cl-, Br- and I-), as well as their mixtures; the latter allowing us to probe counter-ion selectivity of these oligoions. We consolidate both structural and dynamic information, in particular simulated radial distribution functions and average residence times of counter-ions in the vicinity of ionenes and NMR data in the form of counter-ion chemical shift and self-diffusion coefficients. On one hand, previously reported enthalpy of dilution and mixing measurements show a reverse counter-ion sequence for 12, 12-ionenes with respect to their less hydrophobic 3, 3- and 6, 6- analogues. On the other hand, the current MD and NMR data, reflecting the counter-ion binding tendencies to the ionene chain, give evidence for the same ordering as that observed by MD for 3, 3-ionenes. This is not seen as a contradiction and can be rationalized on the basis of increasing chain hydrophobicity, which has different consequences for enthalpy and ion-binding. The latter is reflecting free energy changes and as such includes both enthalpic and entropic contributions.

  18. Identification of a novel transcript of human MD2 gene.

    PubMed

    Shen, Chen; Shen, A-Dong

    2016-09-15

    Myeloid differentiation protein 2 (MD2) regulates bacterial lipopolysaccharide (LPS) triggered anti-bacterial immune response as a broker between LPS and Toll-like receptor 4 (TLR4). In this study, we identified a novel naturally occurring spliceosome of human MD2, termed as MD2-T3. This transcript lacked two exons of MD2 gene. By protein structure analysis and literature review, we predicted that MD2-T3 isoform might execute regulatory biological effects such as limiting LPS-triggered TLR4 signaling. PMID:27317890

  19. Insights into the structural basis of 3,5-diaminoindazoles as CDK2 inhibitors: prediction of binding modes and potency by QM-MM interaction, MESP and MD simulation.

    PubMed

    Tripathi, Sunil Kumar; Singh, Sanjeev Kumar

    2014-08-01

    The novel 3,5-diaminoindazole derivatives are well-known as potent and anti-proliferative cyclin-dependent kinase 2 inhibitors. We report a combined quantum mechanics/molecular mechanics study to determine the protein-ligand interaction energy, and some quantum chemical descriptors to successfully rank these inhibitors. The results in this work show that the QM-MM interaction energy is strongly correlated to the biological activity and can be used as a predictor, which was further validated by Spearman's rank correlation coefficient. An exhaustive analysis of the protein-ligand structures obtained from molecular dynamics simulations shows specific interactions within the active site. Furthermore, the docking study was supported by electronic property analysis using density functional theory at the B3LYP/3-21*G level. The results obtained from molecular docking and surface analysis shed some insight on steric and electronic complementarities of these molecules to CDK2. Aqueous solvation energy values give an indication of the solubility and can be used as a guide for the pharmacokinetic optimization of these molecules. Furthermore, ADME/T properties calculated are in the desirable range, so these compounds are predicted to be drug like with low toxicity potential. Overall, the approach was successful in the cases considered, and it could be useful for the design of inhibitors in the lead optimization phase of drug discovery against CDK2. PMID:24909777

  20. Analysis of solvation structure and thermodynamics of ethane and propane in water by reference interaction site model theory using all-atom models

    NASA Astrophysics Data System (ADS)

    Cui, Qizhi; Smith, Vedene H.

    2001-08-01

    Following our previous paper on methane [Cui and Smith, J. Chem. Phys. 113, 10240 (2000)], we study the solvation structures and thermodynamics of ethane and propane in water at the infinite dilution limit by using the hypernetted chain closure reference interaction site model (HNC-RISM) theory with all-atom representations for solute molecules. At four thermodynamic states: temperature T=283.15, 298.15, 313.15, 328.15 K and the corresponding bulk water density ρ=0.9997, 0.9970, 0.9922, 0.9875 g cm-3, all the atomic solute-solvent radial distribution functions are obtained, and the corresponding running coordination numbers and the hydration free energies, energies, enthalpies, and entropies are calculated with the radial distribution functions as input. The hydration structures of ethane and propane are presented and analyzed at the atomic level in terms of the atomic solute-solvent radial distribution functions. With the optimized nonbonded potential parameters based on the CHARMM96 all-atom model for alkanes [Yin and Mackerell, J. Comput. Chem. 19, 334 (1998)], the ethane and propane hydration thermodynamic properties predicted by the HNC-RISM theory are improved in the specified temperature range (10-55 °C).

  1. Dawbeney Turbervile, MD (1612-1696).

    PubMed

    Simunovic, Matthew P

    2012-03-01

    The year 2012 marks the quatercentenary of the birth of Dawbeney Turbervile,MD(1612-1696), one-time Royalist soldier and later ophthalmologist to England’s Princess Anne, the diarist Samuel Pepys, the natural philosopher Robert Boyle, and the astronomer Walter Pope. Turbervile is remarkable for many reasons: He specialized at a time when generalization was prized; though he was a qualified physician, he also practiced the trade of surgery. Furthermore, he provided in his communications with the Royal Society early descriptions of achromatopsia, ocular foreign body removal with a magnet, and tic doloreaux. He is a forebear worth remembering PMID:22411681

  2. 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

  3. 76 FR 41662 - Airworthiness Directives; MD Helicopters, Inc. Model MD900 Helicopters

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-15

    ... Executive Order 12866, (2) Is not a ``significant rule'' under DOT Regulatory Policies and Procedures (44 FR.... 39.13 by removing airworthiness directive (AD) 2010-18-52, Amendment 39-16515 (75 FR 69862, November... the flex beam bolt hole locations during maintenance on two MDHI Model MD900 helicopters. Since...

  4. 75 FR 69862 - Airworthiness Directives; MD Helicopters, Inc. Model MD900 Helicopters

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-16

    ... Privacy Act Statement in the Federal Register published on April 11, 2000 (65 FR 19477-78). Regulatory... Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and 3. Will not have a significant... beam bolt hole locations during maintenance on two MDHI Model MD900 helicopters. The actions...

  5. Shock-induced poration, cholesterol flip-flop and small interfering RNA transfection in a phospholipid membrane: Multimillion atom, microsecond molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Choubey, Amit

    performing a 15 mus all-atom MD simulation of a DPPC-CHOL bilayer. We find that the CHOL flip-flop rates are on the sub microsecond timescale. These results are verified by performing various independent parallel replica (PR) simulations. Our PR simulations provide significant boost in sampling of the flip-flop events. We observe that the CHOL flip-flop can induce membrane order, regulate membrane-bending energy, and facilitate membrane relaxation. The rapid flip-flop rates reported here have important implications for the role of CHOL in mechanical properties of cell membranes, formation of domains, and maintaining CHOL concentration asymmetry in plasma membrane. Our PR approach can reach submillisecond time scales and bridge the gap between MD simulations and Nuclear Magnetic Resonance (NMR) experiments on CHOL flip-flop dynamics in membranes. The last project deals with transfection barriers encountered by a bare small interfering RNA (siRNA) in a phospholipid bilayer. SiRNA molecules play a pivotal role in therapeutic applications. A key limitation to the widespread implementation of siRNA-based therapeutics is the difficulty of delivering siRNA-based drugs to cells. We have examined structural and mechanical barriers to siRNA passage across a phospholipid bilayer using all-atom MD simulations. We find that the electrostatic interaction between the anionic siRNA and head groups of phospholipid molecules induces a phase transformation from the liquid crystalline to ripple phase. Steered MD simulations reveal that the siRNA transfection through the ripple phase requires a force of ˜ 1.5 nN.

  6. Ab Initio ONIOM-Molecular Dynamics (MD) Study on the Deamination Reaction by Cytidine Deaminase

    SciTech Connect

    Matsubara, Toshiaki; Dupuis, Michel; Aida, Misako

    2007-08-23

    We applied the ONIOM-molecular dynamics (MD) method to the hydrolytic deamination of cytidine by cytidine deaminase, which is an essential step of the activation process of the anticancer drug inside the human body. The direct MD simulations were performed for the realistic model of cytidine deaminase calculating the energy and its gradient by the ab initio ONIOM method on the fly. The ONIOM-MD calculations including the thermal motion show that the neighboring amino acid residue is an important factor of the environmental effects and significantly affects not only the geometry and energy of the substrate trapped in the pocket of the active site but also the elementary step of the catalytic reaction. We successfully simulate the second half of the catalytic cycle, which has been considered to involve the rate-determining step, and reveal that the rate-determing step is the release of the NH3 molecule. 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.

  7. Benjamin Rush, MD: assassin or beloved healer?

    PubMed

    North, R L

    2000-01-01

    Benjamin Rush, MD (1745-1813), was not only the most well known physician in 18th-century America, he was also a patriot, philosopher, author, lecturer, fervent evangelist, politician, and dedicated social reformer. He was unshakable in his convictions, as well as self-righteous, caustic, satirical, humorless, and polemical. Unquestionably brilliant, he graduated from what later became Princeton University at age 14. He translated Hippocrates' Aphorisms from the Greek at age 17. He wrote the first textbook of chemistry to be published in America. He was by all accounts a devoted, if highly paternalistic, medical practitioner, who cared deeply for his patients' welfare. His principles or theories and his championship of extreme purging and bleeding ("depletion therapy") have engendered 200 years of controversy and debate that continue today. The contradiction in his character is particularly well illustrated by his behavior during the Philadelphia yellow fever epidemic of 1793, as is briefly examined in this essay. PMID:16389324

  8. Ashley W. Oughterson, MD: Surgeon, Soldier, Leader

    PubMed Central

    Kunstman, John W.; Longo, Walter E.

    2015-01-01

    Ashley W. Oughterson, MD, (1895-1956) was a longtime faculty surgeon at Yale University. He performed some of the earliest pancreatic resections in the United States. During World War II, Colonel Oughterson was the primary “Surgical Consultant” in the South Pacific and present at nearly every major battle. His meticulously kept diary is regarded as the foremost source detailing wartime surgical care. Colonel Oughterson led the initial Army team to survey Hiroshima and Nagasaki following the nuclear attacks. Thoughout his academic career at Yale, Oughterson was a key leader in several medical and surgical societies. As scientific director of the American Cancer Society, Oughterson lectured widely and guided research priorities in oncology following World War II. Oughterson also authored numerous benchmark papers in surgical oncology that continue to be cited today. These extensive contributions are examined here and demonstrate the wide-ranging impact Oughterson exerted during a formative period of American surgery. PMID:26029018

  9. MD-11 PCA - First Landing at Edwards

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This McDonnell Douglas MD-11 transport aircraft approaches its first landing under engine power only on Aug. 29, 1995, at NASA's Dryden Flight Research Center, Edwards, California. The milestone flight, flown by NASA research pilot and former astronaut Gordon Fullerton, was part of a NASA project to develop a computer-assisted engine control system that enables a pilot to land a plane safely when its normal control surfaces are disabled. The Propulsion-Controlled Aircraft (PCA) system uses standard autopilot controls already present in the cockpit, together with the new programming in the aircraft's flight control computers. The PCA concept is simple--for pitch control, the program increases thrust to climb and reduces thrust to descend. To turn right, the autopilot increases the left engine thrust while decreasing the right engine thrust. The initial Propulsion-Controlled Aircraft studies by NASA were carried out at Dryden with a modified twin-engine F-15 research aircraft.

  10. MD-11 PCA - Research flight team egress

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This McDonnell Douglas MD-11 has parked on the flightline at NASA's Dryden Flight Research Center, Edwards, California, following its completion of the first and second landings ever performed by a transport aircraft under engine power only (on Aug. 29, 1995). The milestone flight, with NASA research pilot and former astronaut Gordon Fullerton at the controls, was part of a NASA project to develop a computer-assisted engine control system that enables a pilot to land a plane safely when its normal control surfaces are disabled. Coming down the steps from the aircraft are Gordon Fullerton (in front), followed by Bill Burcham, Propulsion Controlled Aircraft (PCA) project engineer at Dryden; NASA Dryden controls engineer John Burken; John Feather of McDonnell Douglas; and Drew Pappas, McDonnell Douglas' project manager for PCA.

  11. MD-11 PCA - First Landing at Edwards

    NASA Technical Reports Server (NTRS)

    1995-01-01

    This McDonnell Douglas MD-11 approaches the first landing ever of a transport aircraft under engine power only on Aug. 29, 1995, at NASA's Dryden Flight Research Center, Edwards, California. The milestone flight, flown by NASA research pilot and former astronaut Gordon Fullerton, was part of a NASA project to develop a computer-assisted engine control system that enables a pilot to land a plane safely when it normal control surfaces are disabled. The Propulsion-Controlled Aircraft (PCA) system uses standard autopilot controls already present in the cockpit, together with the new programming in the aircraft's flight control computers. The PCA concept is simple--for pitch control, the program increases thrust to climb and reduces thrust to descend. To turn right, the autopilot increases the left engine thrust while decreasing the right engine thrust. The initial Propulsion-Controlled Aircraft studies by NASA were carried out at Dryden with a modified twin-engine F-15 research aircraft.

  12. Dynamics of Lipids, Cholesterol, and Transmembrane α-Helices from Microsecond Molecular Dynamics Simulations

    PubMed Central

    2015-01-01

    Extensive all-atom molecular dynamics (∼24 μs total) allowed exploration of configurational space and calculation of lateral diffusion coefficients of the components of a protein-embedded, cholesterol-containing model bilayer. The three model membranes are composed of an ∼50/50 (by mole) dipalmitoylphosphatidylcholine (DPPC)/cholesterol bilayer and contained an α-helical transmembrane protein (HIV-1 gp41 TM). Despite the high concentration of cholesterol, normal Brownian motion was observed and the calculated diffusion coefficients (on the order of 10–9 cm2/s) are consistent with experiments. Diffusion is sensitive to a variety of parameters, and a temperature difference of ∼4 K from thermostat artifacts resulted in 2–10-fold differences in diffusion coefficients and significant differences in lipid order, membrane thickness, and unit cell area. Also, the specific peptide sequence likely underlies the consistently observed faster diffusion in one leaflet. Although the simulations here present molecular dynamics (MD) an order of magnitude longer than those from previous studies, the three systems did not approach ergodicity. The distributions of cholesterol and DPPC around the peptides changed on the microsecond time scale, but not significantly enough to thoroughly explore configurational space. These simulations support conclusions of other recent microsecond MD in that even longer time scales are needed for equilibration of model membranes and simulations of more realistic cellular or viral bilayers. PMID:25380392

  13. Hybrid Atomistic and Coarse-Grained Molecular Dynamics Simulations of Polyethylene Glycol (PEG) in Explicit Water.

    PubMed

    Stanzione, Francesca; Jayaraman, Arthi

    2016-05-01

    In-silico design of polymeric biomaterials requires molecular dynamics (MD) simulations that retain essential atomistic/molecular details (e.g., explicit water around the biofunctional macromolecule) while simultaneously achieving large length and time scales pertinent to macroscale function. Such large-scale atomistically detailed macromolecular MD simulations with explicit solvent representation are computationally expensive. One way to overcome this limitation is to use an adaptive resolution scheme (AdResS) in which the explicit solvent molecules dynamically adopt either atomistic or coarse-grained resolution depending on their location (e.g., near or far from the macromolecule) in the system. In this study we present the feasibility and the limitations of AdResS methodology for studying polyethylene glycol (PEG) in adaptive resolution water, for varying PEG length and architecture. We first validate the AdResS methodology for such systems, by comparing PEG and solvent structure with that from all-atom simulations. We elucidate the role of the atomistic zone size and the need for calculating thermodynamic force correction within this AdResS approach to correctly reproduce the structure of PEG and water. Lastly, by varying the PEG length and architecture, we study the hydration of PEG, and the effect of PEG architectures on the structural properties of water. Changing the architecture of PEG from linear to multiarm star, we observe reduction in the solvent accessible surface area of the PEG, and an increase in the order of water molecules in the hydration shells. PMID:27108869

  14. Simulation of Ionic Aggregation and Ion Dynamics in Model Ionomers

    NASA Astrophysics Data System (ADS)

    Frischknecht, Amalie L.

    2012-02-01

    Ionomers, polymers containing a small fraction of covalently bound ionic groups, are of interest as possible electrolytes in batteries. A single-ion conducting polymer electrolyte would be safer and have higher efficiency than the currently-used liquid electrolytes. However, to date ionomeric materials do not have sufficiently high conductivities for practical application. This is most likely because the ions tend to form aggregates, leading to slow ion transport. A key question is therefore how molecular structure affects the ionic aggregation and ion dynamics. To probe these structure-property relationships, we have performed molecular simulations of a set of recently synthesized poly(ethylene-co-acrylic acid) copolymers and ionomers, with a focus on the morphology of the ionic aggregates. The ionomers have a precise, constant spacing of charged groups, making them ideal for direct comparisons with simulations. Ab initio calculations give insight into the expected coordination of cations with fragments of the ionomers. All-atom molecular dynamics (MD) simulations of the ionomer melt show aggregation of the ionic groups into extended string-like clusters. An extensive set of coarse-grained molecular dynamics simulations extend the results to longer times and larger length scales. The structure factors calculated from the MD simulations compare favorably with x-ray scattering data. Furthermore, the simulations give a detailed picture of the sizes, shapes, and composition of the ionic aggregates, and how they depend on polymer architecture. Implications for ion transport will be discussed. [Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

  15. Theoretical Study of Shocked Formic Acid: Born-Oppenheimer MD Calculations of the Shock Hugoniot and Early-Stage Chemistry.

    PubMed

    Rice, Betsy M; Byrd, Edward F C

    2016-03-01

    Quantum and classical molecular dynamics simulations are used to explore whether chemical reactivity of shocked formic acid occurs at pressures greater than 15 GPa, a question arising from results of different shock compression experiments. The classical molecular dynamics simulations were performed using a quantum-based nonreactive pair additive interaction potential whereas the full resolution quantum mechanical molecular dynamics simulations allow chemical reactions. Although the shock Hugoniot curve calculated using nonreactive classical MD for formic acid is in reasonable agreement with one set of experimental results, shock Hugoniot points calculated using Born-Oppenheimer MD at 30 GPa are in agreement with the set of experimental data that suggests chemical reactivity at these elevated temperatures and pressures. Examination of atomic positions throughout the Born-Oppenheimer MD trajectories clearly indicates extensive and complex chemical reaction, chiefly involving hydrogen-atom transfer and intermolecular complexation. PMID:26654191

  16. Wettability of graphitic-carbon and silicon surfaces: MD modeling and theoretical analysis

    SciTech Connect

    Ramos-Alvarado, Bladimir; Kumar, Satish; Peterson, G. P.

    2015-07-28

    The wettability of graphitic carbon and silicon surfaces was numerically and theoretically investigated. A multi-response method has been developed for the analysis of conventional molecular dynamics (MD) simulations of droplets wettability. The contact angle and indicators of the quality of the computations are tracked as a function of the data sets analyzed over time. This method of analysis allows accurate calculations of the contact angle obtained from the MD simulations. Analytical models were also developed for the calculation of the work of adhesion using the mean-field theory, accounting for the interfacial entropy changes. A calibration method is proposed to provide better predictions of the respective contact angles under different solid-liquid interaction potentials. Estimations of the binding energy between a water monomer and graphite match those previously reported. In addition, a breakdown in the relationship between the binding energy and the contact angle was observed. The macroscopic contact angles obtained from the MD simulations were found to match those predicted by the mean-field model for graphite under different wettability conditions, as well as the contact angles of Si(100) and Si(111) surfaces. Finally, an assessment of the effect of the Lennard-Jones cutoff radius was conducted to provide guidelines for future comparisons between numerical simulations and analytical models of wettability.

  17. 77 FR 42459 - Airworthiness Directives; MD Helicopters, Inc. (MDHI) Helicopters

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-19

    ... (expiration date). For the MDHI Model MD900 helicopters, AD 2006-18-01 (71 FR 51095, August 29, 2006) already... Policies and Procedures (44 FR 11034, February 26, 1979); 3. Will not affect intrastate aviation in Alaska... the MDHI Model MD900 helicopters, AD 2006-18-01 (71 FR 51095, August 29, 2006) contains additional...

  18. 77 FR 24838 - Safety Zone; Magothy River, Sillery Bay, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-26

    ... ``Safety Zone; Magothy River, Sillery Bay, MD'' in the Federal Register (77 FR 11423). We received no... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; Magothy River, Sillery Bay, MD AGENCY... waters of the Magothy River, in Sillery Bay, Maryland. This safety zone is necessary to provide for...

  19. 76 FR 51887 - Safety Zone; Patuxent River, Patuxent River, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-19

    ...) entitled ``Safety Zone; Patuxent River, Patuxent River, MD'' in the Federal Register (76 FR 36447). We... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; Patuxent River, Patuxent River, MD AGENCY... safety zone during the ``NAS Patuxent River Air Expo '11,'' which consists of aerial...

  20. 78 FR 35773 - Airworthiness Directives; MD Helicopters, Inc. (MDHI), Helicopters

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-14

    ... the MDHI Model MD900 helicopters with certain main rotor blade (MRB) retention bolts (bolts) installed...'' under the DOT Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); 3. Will not affect... MD 900 helicopters with a main rotor blade retention bolt (bolt), part number (P/N)...

  1. MD-11 PCA - First Landing at Edwards

    NASA Technical Reports Server (NTRS)

    1995-01-01

    A transport aircraft lands for the first time under engine power only, as this McDonnell Douglas MD-11 touches down at 11:38 a.m., Aug. 29, 1995, at NASA's Dryden Flight Research Center, Edwards, California. The milestone flight, flown by NASA research pilot and former astronaut Gordon Fullerton, was part of a NASA project to develop a computer-assisted engine control system that enables a pilot to land a plane safely when its normal control surfaces are disabled. The propulsion-Controlled Aircraft (PCA) system uses standard autopilot controls already present in the cockpit, together with the new programming in the aircraft's flight control computers. The PCA concept is simple--for pitch control, the program increases thrust to climb and reduces thrust to descend. To turn right, the autopilot increases the left engine thrust while decreasing the right engine thrust. The initial Propulsion-Controlled Aircraft studies by NASA were carried out at Dryden with a modified twin-engine F-15 research aircraft.

  2. MD-11 PCA - First Landing at Edwards

    NASA Technical Reports Server (NTRS)

    1995-01-01

    A transport aircraft lands for the first time under engine power only, as this McDonnell Douglas MD-11 touches down at 11:38 a.m., Aug. 29, 1995, at NASA's Dryden Flight Research Center, Edwards, California. The milestone flight, flown by NASA research pilot and former astronaut Gordon Fullerton, was part of a NASA project to develop a computer-assisted engine control system that enables a pilot to land a plane safely when its normal control surfaces are disabled. The Propulsion-Controlled Aircraft (PCA) system uses standard autopilot controls already present in the cockpit, together with the new programming in the aircraft's flight control computers. The PCA concept is simple--for pitch control, the program increases thrust to climb and reduces thrust to descend. To turn right, the autopilot increases the left engine thrust while decreasing the right engine thrust. The initial Propulsion-Controlled Aircraft studies by NASA were carried out at Dryden with a modified twin-engine F-15 research aircraft.

  3. C6 Coefficients and Dipole Polarizabilities for All Atoms and Many Ions in Rows 1-6 of the Periodic Table.

    PubMed

    Gould, Tim; Bučko, Tomáš

    2016-08-01

    Using time-dependent density functional theory (TDDFT) with exchange kernels, we calculate and test imaginary frequency-dependent dipole polarizabilities for all atoms and many ions in rows 1-6 of the periodic table. These are then integrated over frequency to produce C6 coefficients. Results are presented under different models: straight TDDFT calculations using two different kernels; "benchmark" TDDFT calculations corrected by more accurate quantum chemical and experimental data; and "benchmark" TDDFT with frozen orbital anions. Parametrizations are presented for 411+ atoms and ions, allowing results to be easily used by other researchers. A curious relationship, C6,XY ∝ [αX(0)αY(0)](0.73), is found between C6 coefficients and static polarizabilities α(0). The relationship C6,XY = 2C6,XC6,Y/[(αX/αY)C6,Y + (αY/αX)C6,X] is tested and found to work well (<5% errors) in ∼80% of the cases, but can break down badly (>30% errors) in a small fraction of cases. PMID:27304856

  4. Steric effects on intramolecular reactivity in cyclic dipeptides: Conformational analysis validated by a combined MD/DFT approach

    NASA Astrophysics Data System (ADS)

    Lewandowska, A.; Carmichael, I.; Hörner, G.; Hug, G. L.; Marciniak, B.

    2011-08-01

    The present Molecular Dynamics (MD) simulation study addresses the geometric requirements of close-contact formation in short peptides. This process, that is probed herein by intramolecular H-atom transfer, initiated by triplet-excited ketones, demands close contact between the H-donating and H-accepting moieties. Thus, any deduction about the compound's reactivity based just on MD simulations, requires independent verification of the computed conformational preferences. In this study, a procedure was developed using diketopiperazine-linked benzophenone/tyrosine dyads. Specifically, it involves a comparison of the dyads' experimental 3J(H α-H β(a/b)) spin-spin coupling constants with the theoretical values obtained by weighting DFT-computed spin-spin coupling constants with the MD-computed probability distributions for the dyads' configurations.

  5. Molecular dynamics simulation on adsorption of pyrene-polyethylene onto ultrathin single-walled carbon nanotube

    NASA Astrophysics Data System (ADS)

    Cai, Lu; Lv, Wenzhen; Zhu, Hong; Xu, Qun

    2016-07-01

    The mechanism of the adsorption of pyrene-polyethylene (Py-PE) onto ultrathin single-walled carbon nanotube (SWNT) was studied by using all-atom molecular dynamics (MD) simulations. We found that solvent polarity and pyrene group are two critical factors in the Py-PE decoration on ultrathin SWNT. Combined MD simulations with free energy calculations, our results indicate that larger solvent polarity can decrease the contribution of conformation entropy, but contributes little to the interaction energy, moreover, larger SWNT diameter can decrease the contribution of conformation entropy but lead to the increasing of the interaction energy. In polar organic solvent (N, N-Dimethylacetamide), the pyrene group plays a key role in the adsorption of Py-PE onto ultrathin SWNT, not only facilitates the spontaneous adsorption of Py-PE onto ultrathin SWNT, but also helps to form compact structure between themselves in the final adsorption states. While in aqueous solution, pyrene group no longer works as an anchor, but still affects a lot to the final adsorption conformation. Our present work provides detailed theoretical clue to understand the noncovalent interaction between aromatic segment appended polymer and ultrathin SWNT, and helps to explore the potential application of ultrathin SWNT in the fields of hybrid material, biomedical and electronic materials.

  6. Combined Molecular Dynamics Simulations and Experimental Studies of the Structure and Dynamics of Poly-Amido-Saccharides.

    PubMed

    Chin, Stacy L; Lu, Qing; Dane, Eric L; Dominguez, Laura; McKnight, Christopher J; Straub, John E; Grinstaff, Mark W

    2016-05-25

    Poly-amido-saccharides (PAS) are carbohydrate-based, enantiopure synthetic polymers in which sugar repeat units are joined by amide linkages. This unique and relatively rigid pyranose backbone contributes to their defined helical secondary structure and remarkable chemical properties. Glucose- (glc-) and galactose- (gal-) PAS 10-mer structures are synthesized and investigated with molecular dynamics (MD) simulations and experimental measurements. Quantum mechanical DFT energy minimization calculations, as well as experimental observables including circular dichroism, (1)H,(13)C-HSQC, and (1)H,(1)H-NOESY 2D-NMR studies, validated the all-atom simulation models produced using a modified CHARMM force field. Water radial distribution functions show distinct differences in the glc- and gal-PAS systems that correlate well with observed differences in solubility between gal-PASs and glc-PASs. The computational analysis and MD simulations are in good agreement with experimental results, validating the proposed models as reliable representations of novel glc- and gal-PASs. PMID:27119983

  7. MD-Logic Artificial Pancreas System

    PubMed Central

    Atlas, Eran; Nimri, Revital; Miller, Shahar; Grunberg, Eli A.; Phillip, Moshe

    2010-01-01

    OBJECTIVE Current state-of-the-art artificial pancreas systems are either based on traditional linear control theory or rely on mathematical models of glucose-insulin dynamics. Blood glucose control using these methods is limited due to the complexity of the biological system. The aim of this study was to describe the principles and clinical performance of the novel MD-Logic Artificial Pancreas (MDLAP) System. RESEARCH DESIGN AND METHODS The MDLAP applies fuzzy logic theory to imitate lines of reasoning of diabetes caregivers. It uses a combination of control-to-range and control-to-target strategies to automatically regulate individual glucose levels. Feasibility clinical studies were conducted in seven adults with type 1 diabetes (aged 19–30 years, mean diabetes duration 10 ± 4 years, mean A1C 6.6 ± 0.7%). All underwent 14 full, closed-loop control sessions of 8 h (fasting and meal challenge conditions) and 24 h. RESULTS The mean peak postprandial (overall sessions) glucose level was 224 ± 22 mg/dl. Postprandial glucose levels returned to <180 mg/dl within 2.6 ± 0.6 h and remained stable in the normal range for at least 1 h. During 24-h closed-loop control, 73% of the sensor values ranged between 70 and 180 mg/dl, 27% were >180 mg/dl, and none were <70 mg/dl. There were no events of symptomatic hypoglycemia during any of the trials. CONCLUSIONS The MDLAP system is a promising tool for individualized glucose control in patients with type 1 diabetes. It is designed to minimize high glucose peaks while preventing hypoglycemia. Further studies are planned in the broad population under daily-life conditions. PMID:20150292

  8. MD-PhD training: looking back and looking forward.

    PubMed

    Bonham, Ann C

    2014-01-01

    MD-PhD programs provide rigorous, integrated training for physician-scientists, enabling them to frame scientific questions in unique ways and to apply clinical insight to fundamental science. Few would question the influential contributions of MD-PhD physician-scientists in advancing medical science. In this issue of Academic Medicine, Jeffe et al affirm high levels of excellence in educational outcomes from MD-PhD training programs at U.S. MD-granting medical schools, especially programs that receive funding from the NIH Medical Scientist Training Program (MSTP). The author of this commentary observes that, in the face of current economic pressures, comprehensive, longitudinal national outcomes data from MSTP- and non-MSTP-funded MD-PhD programs will help verify the value provided by MD-PhD physician-scientists. She proposes that MD-PhD programs should better prepare the next generation of physician-scientists for future research environments, which will provide new technologies, venues, and modalities. These research environments will be more closely integrated within health care delivery systems, extend into diverse communities and regions, and employ complex technologies. MD-PhD physician-scientists also will train and gain expertise in broadening areas of research, such as health policy, health economics, clinical epidemiology, and medical informatics. Program leaders are ideally situated to foster innovative learning environments and methodologies. By sharing their innovations, they can help ensure production of a diverse MD-PhD physician-scientist workforce, prepared to engage in myriad research opportunities to meet patient and population needs in a new environment. PMID:24280863

  9. MD Study of Stokes Shifts in Ionic Liquids: Temperature Dependence.

    PubMed

    Wu, Eric C; Kim, Hyung J

    2016-05-26

    Effects of temperature on Stokes shifts, solvation structure, and dynamics in ionic liquids EMI(+)Tf2N(-), EMI(+)PF6(-), and BMI(+)PF6(-) (EMI(+) = 1-ethyl-3-methylimidazolium, BMI(+) = 1-butyl-3-methylimidazolium, Tf2N(-) = bis(trifluoromethylsulfonyl)imide, and PF6(-) = hexafluorophosphate) are investigated via molecular dynamics (MD) computer simulations in the temperature range 350 K ≤ T ≤ 500 K. Two different types of solutes are considered: a simple model diatomic solute and realistic coumarin 153, both of which are characterized by more polar S1 and less polar S0 states. In all three ionic liquids studied, the Stokes shift tends to decrease with increasing temperature. For coumarin 153, as T increases, the Franck-Condon energy for steady-state absorption decreases, whereas that for steady-state emission increases. Our findings indicate that the effective polarity of ionic liquids decreases as T increases. Their solvation dynamics are characterized by an ultrafast initial decay in the subpicosecond time scale, followed by slow dissipative relaxation, regardless of temperature. For both solutes, the solvent frequency that quantifies initial ultrafast dynamics shows little temperature dependence. By contrast, the long-time dissipative dynamics become significantly faster with rising T. Variations of solvation structure with temperature and their connection to Stokes shift and solvation dynamics are briefly examined. PMID:27133895

  10. MD studies on conformational behavior of a DNA photolyase enzyme

    NASA Astrophysics Data System (ADS)

    Dushanov, E.; Kholmurodov, Kh.; Yasuoka, K.; Krasavin, E.

    2013-11-01

    In this work, molecular dynamics (MD) simulations were performed on a DNA photolyase protein with two cofactors, FAD (flavin adenine dinucleotide) and MTHF (methenyltetrahydrofolate), inside the enzyme pocket. A DNA photolyase is a highly efficient light-driven enzyme that repairs the UV-induced cyclobutane-pyrimidine dimer in damaged DNA. We were aimed to compare the conformational changes of the FAD cofactor and other constituent fragments of the molecular system under consideration. The conformational behavior of the FAD molecule is very important for understanding the functional and structural properties of the DNA repair protein photolyase. The photoactive FAD is an essential cofactor both for specificial binding to damaged DNA and for catalysis. The second chromophore (MTHF or 8-HDF) is not necessary for catalysis and has no effect on specific enzyme—substrate binding. The obtained results were discussed to gain insight into the light-driven mechanism of DNA repair by a DNA photolyase enzyme—based on the enzyme structure, the FAD mobility, and conformation shape.

  11. 77 FR 73967 - Drawbridge Operation Regulation; Bear Creek, Dundalk, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-12

    ... Regulation; Bear Creek, Dundalk, MD'' in the Federal Register (77 FR 5201). The rulemaking concerned would... to http://www.regulations.gov , inserting USCG-2011-1062 in the ``Search'' box, and then...

  12. Find an Orthopaedic Foot and Ankle MD/DO

    MedlinePlus

    ... AOFAS / FootCareMD / Find a Surgeon Find an Orthopaedic Foot & Ankle Surgeon Page Content The Orthopaedic Distinction Who are Orthopaedic Foot & Ankle Surgeons? Orthopaedic foot and ankle surgeons are ...

  13. Ten-Microsecond Molecular Dynamics Simulation of a Fast-Folding WW Domain

    PubMed Central

    Freddolino, Peter L.; Liu, Feng; Gruebele, Martin; Schulten, Klaus

    2008-01-01

    All-atom molecular dynamics (MD) simulations of protein folding allow analysis of the folding process at an unprecedented level of detail. Unfortunately, such simulations have not yet reached their full potential both due to difficulties in sufficiently sampling the microsecond timescales needed for folding, and because the force field used may yield neither the correct dynamical sequence of events nor the folded structure. The ongoing study of protein folding through computational methods thus requires both improvements in the performance of molecular dynamics programs to make longer timescales accessible, and testing of force fields in the context of folding simulations. We report a ten-microsecond simulation of an incipient downhill-folding WW domain mutant along with measurement of a molecular time and activated folding time of 1.5 microseconds and 13.3 microseconds, respectively. The protein simulated in explicit solvent exhibits several metastable states with incorrect topology and does not assume the native state during the present simulations. PMID:18339748

  14. Understanding nucleic acid structural changes by comparing wide-angle x-ray scattering (WAXS) experiments to molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Pabit, Suzette A.; Katz, Andrea M.; Tolokh, Igor S.; Drozdetski, Aleksander; Baker, Nathan; Onufriev, Alexey V.; Pollack, Lois

    2016-05-01

    Wide-angle x-ray scattering (WAXS) is emerging as a powerful tool for increasing the resolution of solution structure measurements of biomolecules. Compared to its better known complement, small angle x-ray scattering (SAXS), WAXS targets higher scattering angles and can enhance structural studies of molecules by accessing finer details of solution structures. Although the extension from SAXS to WAXS is easy to implement experimentally, the computational tools required to fully harness the power of WAXS are still under development. Currently, WAXS is employed to study structural changes and ligand binding in proteins; however, the methods are not as fully developed for nucleic acids. Here, we show how WAXS can qualitatively characterize nucleic acid structures as well as the small but significant structural changes driven by the addition of multivalent ions. We show the potential of WAXS to test all-atom molecular dynamics (MD) simulations and to provide insight into understanding how the trivalent ion cobalt(III) hexammine (CoHex) affects the structure of RNA and DNA helices. We find that MD simulations capture the RNA structural change that occurs due to addition of CoHex.

  15. Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses

    PubMed Central

    Barata, Teresa S.; Teo, Ian; Brocchini, Steve; Zloh, Mire; Shaunak, Sunil

    2011-01-01

    The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2's hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4′phosphate on the di-glucosamine of LPS to Ser118 on MD-2; (ii) LPS to Lys91 on MD-2; (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamine's carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2's hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design

  16. Alkyl Chain Length and Temperature Effects on Structural Properties of Pyrrolidinium-Based Ionic Liquids: A Combined Atomistic Simulation and Small-Angle X-ray Scattering Study

    SciTech Connect

    Li, Song; Bañuelos, José Leobardo; Guo, Jianchang; Anovitz, Lawrence; Rother, Gernot; Shaw, Robert W.; Hillesheim, Patrick C.; Dai, Sheng; Baker, Gary A.; Cummings, Peter T.

    2011-12-21

    Molecular dynamics (MD) simulations of 1-alkyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide ([CnMPy][Tf₂N], n = 3, 4, 6, 8, 10) were conducted using an all-atom model. Radial distribution functions (RDF) were computed and structure functions were generated to compare with new X-ray scattering experimental results, reported herein. The scattering peaks in the structure functions generally shift to lower Q values with increased temperature for all the liquids in this series. However, the first sharp diffraction peak (FSDP) in the longer alkyl chain liquids displays a marked shift to higher Q values with increasing temperature. Alkyl chain-dependent ordering of the polar groups and increased tail aggregation with increasing alkyl chain length were observed in the partial pair correlation functions and the structure functions. The reasons for the observed alkyl chain-dependent phenomena and temperature effects were explored.

  17. Alkyl Chain Length and Temperature Effects on Structural Properties of Pyrrolidinium-Based Ionic Liquids: A Combined Atomistic Simulation and Small-Angle X-ray Scattering Study.

    SciTech Connect

    Li, Song; Banuelos, Jose Leo; Guo, Jianchang; Anovitz, Lawrence {Larry} M; Rother, Gernot; Shaw, Robert W; Hillesheim, Patrick C; Dai, Sheng; Baker, Gary A; Cummings, Peter T

    2011-01-01

    Molecular dynamics (MD) simulations of 1-alkyl-1-methylpyrrolidinium 12 bis(trifluoromethanesulfonyl)imide ([CnMPy][Tf2N], n = 3, 4, 6, 8, 10) were conducted 13 using an all-atom model. Radial distribution functions (RDF) were computed and structure 14 functions were generated to compare with new X-ray scattering experimental results, 15 reported herein. The scattering peaks in the structure functions generally shift to lower Q 16 values with increased temperature for all the liquids in this series. However, the first sharp 17 diffraction peak (FSDP) in the longer alkyl chain liquids displays a marked shift to higher Q 18 values with increasing temperature. Alkyl chain-dependent ordering of the polar groups and 19 increased tail aggregation with increasing alkyl chain length were observed in the partial pair 20 correlation functions and the structure functions. The reasons for the observed alkyl chain- 21 dependent phenomena and temperature effects were explored.

  18. 76 FR 53346 - Airworthiness Directives; The Boeing Company Model DC-9-81 (MD-81), DC-9-82 (MD-82), DC-9-83 (MD...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-26

    ... proposed AD affects Model MD-80 series airplanes. We issued AD 2011-01-11, Amendment 39-16565 (76 FR 430... under Executive Order 13132. This proposed AD would not have a substantial direct effect on the States... 12866, (2) Is not a ``significant rule'' under the DOT Regulatory Policies and Procedures (44 FR...

  19. MdSOS2L1 forms a complex with MdMYB1 to control vacuolar pH by transcriptionally regulating MdVHA-B1 in apples.

    PubMed

    Sun, Cui-Hui; Zhang, Quan-Yan; Sun, Mei-Hong; Hu, Da-Gang

    2016-03-01

    Vacuolar pH is important and involves in many different physiological processes in plants. A recent paper published in Plant Physiology reveals that MdMYB1 regulates vacuolar pH by directly transcriptionally regulating proton pump genes and malate transporters genes, such as V-ATPase subunit gene MdVHA-B1. Here, we found that MdSOS2L1 in vitro did not directly interact with MdMYB1, however, in vivo formed a complex with MdMYB1 in the nucleus to regulate MdVHA-B1-mediated vacuolar acidification. This finding shed light on the role of MdSOS2L1 in transcriptionally regulating MdVHA-B1 in addition to its post-modified function in apples. PMID:26910596

  20. Characteristics of energy exchange between inter- and intramolecular degrees of freedom in crystalline 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) with implications for coarse-grained simulations of shock waves in polyatomic molecular crystals

    NASA Astrophysics Data System (ADS)

    Kroonblawd, Matthew P.; Sewell, Thomas D.; Maillet, Jean-Bernard

    2016-02-01

    In this report, we characterize the kinetics and dynamics of energy exchange between intramolecular and intermolecular degrees of freedom (DoF) in crystalline 1,3,5-triamino-2,4,6-trinitrobenzene (TATB). All-atom molecular dynamics (MD) simulations are used to obtain predictions for relaxation from certain limiting initial distributions of energy between the intra- and intermolecular DoF. The results are used to parameterize a coarse-grained Dissipative Particle Dynamics at constant Energy (DPDE) model for TATB. Each TATB molecule in the DPDE model is represented as an all-atom, rigid-molecule mesoparticle, with explicit external (molecular translational and rotational) DoF and coarse-grained implicit internal (vibrational) DoF. In addition to conserving linear and angular momentum, the DPDE equations of motion conserve the total system energy provided that particles can exchange energy between their external and internal DoF. The internal temperature of a TATB molecule is calculated using an internal equation of state, which we develop here, and the temperatures of the external and internal DoF are coupled using a fluctuation-dissipation relation. The DPDE force expression requires specification of the input parameter σ that determines the rate at which energy is exchanged between external and internal DoF. We adjusted σ based on the predictions for relaxation processes obtained from MD simulations. The parameterized DPDE model was employed in large-scale simulations of shock compression of TATB. We show that the rate of energy exchange governed by σ can significantly influence the transient behavior of the system behind the shock.

  1. Characteristics of energy exchange between inter- and intramolecular degrees of freedom in crystalline 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) with implications for coarse-grained simulations of shock waves in polyatomic molecular crystals.

    PubMed

    Kroonblawd, Matthew P; Sewell, Thomas D; Maillet, Jean-Bernard

    2016-02-14

    In this report, we characterize the kinetics and dynamics of energy exchange between intramolecular and intermolecular degrees of freedom (DoF) in crystalline 1,3,5-triamino-2,4,6-trinitrobenzene (TATB). All-atom molecular dynamics (MD) simulations are used to obtain predictions for relaxation from certain limiting initial distributions of energy between the intra- and intermolecular DoF. The results are used to parameterize a coarse-grained Dissipative Particle Dynamics at constant Energy (DPDE) model for TATB. Each TATB molecule in the DPDE model is represented as an all-atom, rigid-molecule mesoparticle, with explicit external (molecular translational and rotational) DoF and coarse-grained implicit internal (vibrational) DoF. In addition to conserving linear and angular momentum, the DPDE equations of motion conserve the total system energy provided that particles can exchange energy between their external and internal DoF. The internal temperature of a TATB molecule is calculated using an internal equation of state, which we develop here, and the temperatures of the external and internal DoF are coupled using a fluctuation-dissipation relation. The DPDE force expression requires specification of the input parameter σ that determines the rate at which energy is exchanged between external and internal DoF. We adjusted σ based on the predictions for relaxation processes obtained from MD simulations. The parameterized DPDE model was employed in large-scale simulations of shock compression of TATB. We show that the rate of energy exchange governed by σ can significantly influence the transient behavior of the system behind the shock. PMID:26874491

  2. Cummins MD & HD Accessory Hybridization CRADA -Annual Report FY15

    SciTech Connect

    Deter, Dean D.

    2015-10-01

    There are many areas of MD and HD vehicles that can be improved by new technologies and optimized control strategies. Component optimization and idle reduction need to be addressed, this is best done by a two part approach that includes selecting the best component technology, and/or architecture, and optimized controls that are vehicle focused. While this is a common focus in the light duty industry it has been gaining momentum in the MD and HD market as the market gets more competitive and the regulations become more stringent. When looking into systems optimization and idle reduction technologies, affected vehicle systems must first be considered, and if possible included in the new architecture to get the most benefit out of these new capabilities. Typically, when looking into idle reduction or component optimization for MD/HD, the vehicle s accessories become a prime candidate for electrification or hybridization. While this has already been studied on light duty vehicles (especially on hybrids and electric vehicles) it has not made any head way or market penetration in most MD and HD applications. If hybrids and electric MD and HD vehicles begin to break into the market this would be a necessary step into the ability to make those vehicles successful by allowing for independent, optimized operation separate from the engine.

  3. Structural refinement from restrained-ensemble simulations based on EPR/DEER data: application to T4 lysozyme.

    PubMed

    Islam, Shahidul M; Stein, Richard A; McHaourab, Hassane S; Roux, Benoît

    2013-05-01

    DEER (double electron-electron resonance) is a powerful pulsed ESR (electron spin resonance) technique allowing the determination of distance histograms between pairs of nitroxide spin-labels linked to a protein in a native-like solution environment. However, exploiting the huge amount of information provided by ESR/DEER histograms to refine structural models is extremely challenging. In this study, a restrained ensemble (RE) molecular dynamics (MD) simulation methodology is developed to address this issue. In RE simulation, the spin-spin distance distribution histograms calculated from a multiple-copy MD simulation are enforced, via a global ensemble-based energy restraint, to match those obtained from ESR/DEER experiments. The RE simulation is applied to 51 ESR/DEER distance histogram data from spin-labels inserted at 37 different positions in T4 lysozyme (T4L). The rotamer population distribution along the five dihedral angles connecting the nitroxide ring to the protein backbone is determined and shown to be consistent with available information from X-ray crystallography. For the purpose of structural refinement, the concept of a simplified nitroxide dummy spin-label is designed and parametrized on the basis of these all-atom RE simulations with explicit solvent. It is demonstrated that RE simulations with the dummy nitroxide spin-labels imposing the ESR/DEER experimental distance distribution data are able to systematically correct and refine a series of distorted T4L structures, while simple harmonic distance restraints are unsuccessful. This computationally efficient approach allows experimental restraints from DEER experiments to be incorporated into RE simulations for efficient structural refinement. PMID:23510103

  4. Comparing Fast Pressure Jump and Temperature Jump Protein Folding Experiments and Simulations

    PubMed Central

    Prigozhin, Maxim B.; Schulten, Klaus; Gruebele, Martin

    2016-01-01

    The unimolecular folding reaction of small proteins is now amenable to a very direct mechanistic comparison between experiment and simulation. We present such a comparison of microsecond pressure and temperature jump refolding kinetics of the engineered WW domain FiP35, a model system for beta sheet folding. Both perturbations produce experimentally a faster and a slower kinetic phase, the “slow” microsecond phase being activated. The fast phase shows differences between perturbation methods and is closer to the downhill limit by temperature jump, but closer to the transiently populated intermediate limit by pressure jump. These observations make more demands on simulations of the folding process than just a rough comparison of time scales. To complement experiments, we calculated several pressure jump and temperature jump all-atom molecular dynamics trajectories in explicit solvent, where FiP35 folded in five of the six simulations. We analyzed our pressure jump simulations by kinetic modeling and found that the pressure jump experiments and MD simulations are most consistent with a 4-state kinetic mechanism. Together, our experimental and computational data highlight FiP35’s position at the boundary where activated intermediates and downhill folding meet, and we show that this model protein is an excellent candidate for further pressure jump molecular dynamics studies to compare experiment and modeling at the folding mechanism level. PMID:25988868

  5. 76 FR 60889 - Stephen L. Reitman, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-30

    ... substances properly if entrusted with a DEA registration.''' Id. (quoting Leonardo v. Lopez, M.D., 54 FR... has demonstrated his sobriety for only one year. See Lopez, 54 FR 36915; see also Robert L. Dougherty, M.D., 76 FR 16823 (2011); Robert A. Leslie, M.D., 64 FR 25908 (1999); Mary M. Miller, M.D., 63...

  6. 3MdB: the Mexican Million Models database

    NASA Astrophysics Data System (ADS)

    Morisset, C.; Delgado-Inglada, G.

    2014-10-01

    The 3MdB is an original effort to construct a large multipurpose database of photoionization models. This is a more modern version of a previous attempt based on Cloudy3D and IDL tools. It is accessed by MySQL requests. The models are obtained using the well known and widely used Cloudy photoionization code (Ferland et al, 2013). The database is aimed to host grids of models with different references to identify each project and to facilitate the extraction of the desired data. We present here a description of the way the database is managed and some of the projects that use 3MdB. Anybody can ask for a grid to be run and stored in 3MdB, to increase the visibility of the grid and the potential side applications of it.

  7. AstroMD: A Multi Dimensional Visualization and Analysis Toolkit for Astrophysics

    NASA Astrophysics Data System (ADS)

    Becciani, U.; Antonuccio-Delogu, V.; Gheller, C.; Calori, L.; Buonomo, F.; Imboden, S.

    2010-10-01

    Over the past few years, the role of visualization for scientific purpose has grown up enormously. Astronomy makes an extended use of visualization techniques to analyze data, and scientific visualization has became a fundamental part of modern researches in Astronomy. With the evolution of high performance computers, numerical simulations have assumed a great role in the scientific investigation, allowing the user to run simulation with higher and higher resolution. Data produced in these simulations are often multi-dimensional arrays with several physical quantities. These data are very hard to manage and to analyze efficiently. Consequently the data analysis and visualization tools must follow the new requirements of the research. AstroMD is a tool for data analysis and visualization of astrophysical data and can manage different physical quantities and multi-dimensional data sets. The tool uses virtual reality techniques by which the user has the impression of travelling through a computer-based multi-dimensional model.

  8. 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.

  9. 77 FR 64709 - Airworthiness Directives; MD Helicopters, Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-23

    ...), Model MD900 helicopters. The existing AD requires a visual inspection, and if necessary, an eddy current..., at 77 FR 18963, the Federal Register published our notice of proposed rulemaking (NPRM), which...-117, dated January 14, 2011 (SB). The SB specifies an initial 100-hour and recurring 300-hour...

  10. 77 FR 74908 - Maryland Disaster Number MD-00025

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-18

    ... ADMINISTRATION Maryland Disaster Number MD-00025 AGENCY: U.S. Small Business Administration. ACTION: Amendment 1... completed loan applications to: U.S. Small Business Administration, Processing and Disbursement Center... Disaster Assistance, U.S. Small Business Administration, 409 3rd Street SW., Suite 6050, Washington,...

  11. 78 FR 3496 - Maryland Disaster Number MD-00025

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-16

    ... ADMINISTRATION Maryland Disaster Number MD-00025 AGENCY: U.S. Small Business Administration. ACTION: Amendment 3... completed loan applications to: U.S. Small Business Administration, Processing and Disbursement Center... Disaster Assistance, U.S. Small Business Administration, 409 3rd Street SW., Suite 6050, Washington,...

  12. Physical Properties of Near-Earth Asteroid 2011 MD

    NASA Astrophysics Data System (ADS)

    Mommert, M.; Farnocchia, D.; Hora, J. L.; Chesley, S. R.; Trilling, D. E.; Chodas, P. W.; Mueller, M.; Harris, A. W.; Smith, H. A.; Fazio, G. G.

    2014-07-01

    We report on observations of near-Earth asteroid 2011 MD with the Spitzer Space Telescope. We have spent 19.9 hr of observing time with channel 2 (4.5 μm) of the Infrared Array Camera and detected the target within the 2σ positional uncertainty ellipse. Using an asteroid thermophysical model and a model of nongravitational forces acting upon the object, we constrain the physical properties of 2011 MD, based on the measured flux density and available astrometry data. We estimate 2011 MD to be (6+4-2) m in diameter with a geometric albedo of 0.3+0.4-0.2 (uncertainties are 1σ). We find the asteroid's most probable bulk density to be (1.1+0.7-0.5) g cm-3, which implies a total mass of (50-350) t and a macroporosity of >=65%, assuming a material bulk density typical of non-primitive meteorite materials. A high degree of macroporosity suggests that 2011 MD is a rubble-pile asteroid, the rotation of which is more likely to be retrograde than prograde.

  13. 75 FR 10172 - Drawbridge Operation Regulation; Chester River, Chestertown, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-05

    ... Operation Regulations; Chester River, Chestertown, MD'' in the Federal Register (74 FR 48889). We received... SECURITY Coast Guard 33 CFR Part 117 RIN 1625-AA09 Drawbridge Operation Regulation; Chester River... drawbridge operation regulations of the S213 Bridge, at mile 26.8, across Chester River at Chestertown,...

  14. 77 FR 5201 - Drawbridge Operation Regulation; Bear Creek, Dundalk, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-02

    ... Federal Register (73 FR 3316). Public Meeting We do not now plan to hold a public meeting. But you may... SECURITY Coast Guard 33 CFR Part 117 RIN 1625-AA09 Drawbridge Operation Regulation; Bear Creek, Dundalk, MD... change the regulation governing the operation of the Baltimore County highway bridge at Wise...

  15. 76 FR 9225 - Drawbridge Operation Regulation; Curtis Creek, Baltimore, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-17

    ... Regulations; Curtis Creek, Baltimore, MD'' in the Federal Register (74 FR 50707). The temporary deviation... complete structural repairs and replacement of the grid deck, floor beams and stringers. DATES: This... February 17, 2011 to November 30, 2011. During the replacement of the grid deck, floor beams and...

  16. 76 FR 36447 - Safety Zone; Patuxent River, Patuxent River, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-22

    ..., 2008, issue of the Federal Register (73 FR 3316). Public meeting We do not now plan to hold a public... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA00 Safety Zone; Patuxent River, Patuxent River, MD AGENCY... a temporary safety zone during the ``NAS Patuxent River Air Expo '11'', which consists of...

  17. 75 FR 1705 - Drawbridge Operation Regulations; Curtis Creek, Baltimore, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-13

    ...The Commander, Fifth Coast Guard District, has issued a temporary deviation from the regulations governing the operation of the I695 Bridge across Curtis Creek, mile 0.9, at Baltimore, MD. The deviation is necessary to facilitate mechanical repairs to the bridge. This temporary deviation allows the drawbridge to remain in the closed position during the deviation...

  18. 78 FR 11725 - Maryland Disaster Number MD-00024

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-19

    ... From the Federal Register Online via the Government Publishing Office SMALL BUSINESS ADMINISTRATION Maryland Disaster Number MD-00024 AGENCY: U.S. Small Business Administration. ACTION: Amendment 1... Federal Domestic Assistance Numbers 59002 and 59008) James E. Rivera, Associate Administrator for...

  19. 76 FR 70527 - Maryland Disaster Number MD-00018

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-14

    ... From the Federal Register Online via the Government Publishing Office SMALL BUSINESS ADMINISTRATION Maryland Disaster Number MD-00018 AGENCY: U.S. Small Business Administration. ACTION: Amendment 1... Assistance Numbers 59002 and 59008) James E. Rivera, Associate Administrator for Disaster Assistance....

  20. 76 FR 70528 - Maryland Disaster Number MD-00018

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-14

    ... From the Federal Register Online via the Government Publishing Office SMALL BUSINESS ADMINISTRATION Maryland Disaster Number MD-00018 AGENCY: U.S. Small Business Administration. ACTION: Amendment 2... Numbers 59002 and 59008) James E. Rivera, Associate Administrator for Disaster Assistance. BILLING...

  1. Spectroscopic studies beyond N = 152 neutron gap : decay of {sup 255 ovr sub 101}Md and {sup 256 ovr sub 101}Md.

    SciTech Connect

    Ahmad, I.; Chasman, R. R.; Fields, P. R.

    2000-01-01

    The isotopes {sup 255}Md and {sup 256}Md were produced by the irradiation of {sup 253}Es with 35-45 MeV {alpha} particles by ({alpha},n) and ({alpha},2n) reactions and were removed from the target by a helium jet system. {alpha}, {gamma}, and {alpha}-{gamma} coincidence spectra were measured with Si and Ge(Li) detectors. From the EC decays of {sup 255}Md and {sup 256}Md, levels in {sup 255}Fm and {sup 256}Fm were deduced. Favored {alpha} decay of {sup 255}Md was found to populate the 7/2{sup -}[514] single-particle state in {sup 251}Es, thus establishing the 7/2{sup -}[514] as the {sup 255}Md ground state. Several {gamma} rays were observed in the {sub 256}Md {alpha}-{gamma} coincidence spectrum. {sup 256}Fm is the heaviest nucleus in which excited intrinsic states have been identified.

  2. Spectroscopic studies beyond the N=152 neutron gap: Decay of {sub 101}{sup 255}Md and {sub 101}{sup 256}Md

    SciTech Connect

    Ahmad, I.; Chasman, R. R.; Fields, P. R.

    2000-04-01

    The isotopes {sup 255}Md and {sup 256}Md were produced by the irradiation of {sup 253}Es with 35-45 MeV {alpha} particles by ({alpha},n) and ({alpha},2n) reactions and were removed from the target by a helium jet system. {alpha}, {gamma}, and {alpha}-{gamma} coincidence spectra were measured with Si and Ge(Li) detectors. From the EC decays of {sup 255}Md and {sup 256}Md, levels in {sup 255}Fm and {sup 256}Fm were deduced. Favored {alpha} decay of {sup 255}Md was found to populate the 7/2{sup -}[514] single-particle state in {sup 251}Es, thus establishing the 7/2{sup -}[514] as the {sup 255}Md ground state. Several {gamma} rays were observed in the {sup 256}Md {alpha}-{gamma} coincidence spectrum. {sup 256}Fm is the heaviest nucleus in which excited intrinsic states have been identified. (c) 2000 The American Physical Society.

  3. Mechanistic model of sodium/proton antiport based on X-ray crystal structures and molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Beckstein, Oliver; Dotson, David L.; Lee, Chiara; Yashiro, Shoko; Uzdavinys, Povilas; von Ballmoos, Christoph; Drew, David; Cameron, Alexander D.

    2015-03-01

    Na+/H+ antiporters are membrane proteins that are vital for cell homeostasis but the mechanistic details of their transport mechanism remain unclear, in particular, how Na+ and protons bind to the transporter. We recently solved X-ray crystal structures for two such antiporters (NhaA and NapA) in two different conformations of the transport cycle. All-atom molecular dynamics (MD) simulations (for a total simulated time > 10 μ s), indicate that sodium binding is dependent on the charge states of two conserved aspartate residues. A conserved lysine forms a previously unidentified salt bridge with one of the asparates. Under simulated physiological pH the presence of a Na+ ion disrupts and breaks the salt bridge in NhaA. To quantify proton binding, we then performed heuristic pKa calculations on our ensemble of simulations. The calculations support our novel hypothesis that the conserved lysine in these antiporter binds protons in a sodium-dependent manner and thus acts as part of the transport machinery. In conjunction with simulations of the conformational transition we propose a new mechanistic model of ion binding for the CPA2 class of antiporters within the larger framework of the alternating access mechanism of transmembrane transport.

  4. Linearly scaling and almost Hamiltonian dielectric continuum molecular dynamics simulations through fast multipole expansions

    NASA Astrophysics Data System (ADS)

    Lorenzen, Konstantin; Mathias, Gerald; Tavan, Paul

    2015-11-01

    Hamiltonian Dielectric Solvent (HADES) is a recent method [S. Bauer et al., J. Chem. Phys. 140, 104103 (2014)] which enables atomistic Hamiltonian molecular dynamics (MD) simulations of peptides and proteins in dielectric solvent continua. Such simulations become rapidly impractical for large proteins, because the computational effort of HADES scales quadratically with the number N of atoms. If one tries to achieve linear scaling by applying a fast multipole method (FMM) to the computation of the HADES electrostatics, the Hamiltonian character (conservation of total energy, linear, and angular momenta) may get lost. Here, we show that the Hamiltonian character of HADES can be almost completely preserved, if the structure-adapted fast multipole method (SAMM) as recently redesigned by Lorenzen et al. [J. Chem. Theory Comput. 10, 3244-3259 (2014)] is suitably extended and is chosen as the FMM module. By this extension, the HADES/SAMM forces become exact gradients of the HADES/SAMM energy. Their translational and rotational invariance then guarantees (within the limits of numerical accuracy) the exact conservation of the linear and angular momenta. Also, the total energy is essentially conserved—up to residual algorithmic noise, which is caused by the periodically repeated SAMM interaction list updates. These updates entail very small temporal discontinuities of the force description, because the employed SAMM approximations represent deliberately balanced compromises between accuracy and efficiency. The energy-gradient corrected version of SAMM can also be applied, of course, to MD simulations of all-atom solvent-solute systems enclosed by periodic boundary conditions. However, as we demonstrate in passing, this choice does not offer any serious advantages.

  5. Linearly scaling and almost Hamiltonian dielectric continuum molecular dynamics simulations through fast multipole expansions

    SciTech Connect

    Lorenzen, Konstantin; Mathias, Gerald; Tavan, Paul

    2015-11-14

    Hamiltonian Dielectric Solvent (HADES) is a recent method [S. Bauer et al., J. Chem. Phys. 140, 104103 (2014)] which enables atomistic Hamiltonian molecular dynamics (MD) simulations of peptides and proteins in dielectric solvent continua. Such simulations become rapidly impractical for large proteins, because the computational effort of HADES scales quadratically with the number N of atoms. If one tries to achieve linear scaling by applying a fast multipole method (FMM) to the computation of the HADES electrostatics, the Hamiltonian character (conservation of total energy, linear, and angular momenta) may get lost. Here, we show that the Hamiltonian character of HADES can be almost completely preserved, if the structure-adapted fast multipole method (SAMM) as recently redesigned by Lorenzen et al. [J. Chem. Theory Comput. 10, 3244-3259 (2014)] is suitably extended and is chosen as the FMM module. By this extension, the HADES/SAMM forces become exact gradients of the HADES/SAMM energy. Their translational and rotational invariance then guarantees (within the limits of numerical accuracy) the exact conservation of the linear and angular momenta. Also, the total energy is essentially conserved—up to residual algorithmic noise, which is caused by the periodically repeated SAMM interaction list updates. These updates entail very small temporal discontinuities of the force description, because the employed SAMM approximations represent deliberately balanced compromises between accuracy and efficiency. The energy-gradient corrected version of SAMM can also be applied, of course, to MD simulations of all-atom solvent-solute systems enclosed by periodic boundary conditions. However, as we demonstrate in passing, this choice does not offer any serious advantages.

  6. Apple fruit copper amine oxidase isoforms: peroxisomal MdAO1 prefers diamines as substrates, whereas extracellular MdAO2 exclusively utilizes monoamines.

    PubMed

    Zarei, Adel; Trobacher, Christopher P; Cooke, Alison R; Meyers, Ashley J; Hall, J Christopher; Shelp, Barry J

    2015-01-01

    4-Aminobutyrate (GABA) accumulates in apple fruit during controlled atmosphere storage. A potential source of GABA is the polyamine putrescine, which can be oxidized via copper-containing amine oxidase (CuAO), resulting in the production 4-aminobutanal/Δ(1)-pyrroline, with the consumption of O2 and release of H2O2 and ammonia. Five putative CuAO genes (MdAO genes) were cloned from apple (Malus domestica Borkh. cv. Empire) fruit, and the deduced amino acid sequences found to contain the active sites typically conserved in CuAOs. Genes encoding two of these enzymes, MdAO1 and MdAO2, were highly expressed in apple fruit and selected for further analysis. Amino acid sequence analysis predicted the presence of a C-terminal peroxisomal targeting signal 1 tripeptide in MdAO1 and an N-terminal signal peptide and N-glycosylation site in MdAO2. Transient expression of green fluorescent fusion proteins in Arabidopsis protoplasts or onion epidermal cells revealed a peroxisomal localization for MdAO1 and an extracellular localization for MdAO2. The enzymatic activities of purified recombinant MdAO1 and MdAO2 were measured continuously as H2O2 production using a coupled reaction. MdAO1 did not use monoamines or polyamines and displayed high catalytic efficiency for 1,3-diaminopropane, putrescine and cadaverine, whereas MdAO2 exclusively utilized aliphatic and aromatic monoamines, including 2-phenylethylamine and tyramine. Together, these results indicate that MdAO1 may contribute to GABA production via putrescine oxidation in the peroxisome of apple fruit under controlled atmosphere conditions. MdAO2 seems to be involved in deamination of 2-phenylethylamine, which is a step in the biosynthesis of 2-phenylethanol, a contributor to fruit flavor and flower fragrance. PMID:25378687

  7. Molecular energetics in the capsomere of virus-like particle revealed by molecular dynamics simulations.

    PubMed

    Zhang, Lin; Tang, Ronghong; Bai, Shu; Connors, Natalie K; Lua, Linda H L; Chuan, Yap P; Middelberg, Anton P J; Sun, Yan

    2013-05-01

    Virus-like particles (VLPs) are highly organized nanoparticles that have great potential in vaccinology, gene therapy, drug delivery, and materials science. However, the application of VLPs is hindered by obstacles in their design and production due to low efficiency of self-assembly. In the present study, all-atom (AA) molecular dynamics (MD) simulations coupled with the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method are utilized to examine the molecular interactions in the capsomere of a murine polyomavirus (MPV) VLP. It is found that both low ionic strength and the intracapsomere disulfide bonds are favorable for maintaining a stable capsomere. Simulation results examining the effects of solution conditions on the stabilization of a capsomere were verified by calorimetry experiments. Simulation results of free energy decomposition indicate that hydrophobic interaction is favorable for the formation of a capsomere, whereas electrostatic interaction is unfavorable. With increasing ionic strength, the dominant interaction for the stabilization of a capsomere changes from hydrophobic to electrostatic. By comprehensive analyses, the key amino acid residues (hot spots) in VP1 protein aiding formation of a capsomere in different solution conditions have been identified. These results provide molecular insights into the stabilization of building blocks for VLP and are expected to have implications in their partitioning between the correct and off-pathway reactions in VLP assembly. PMID:23586433

  8. Molecular Dynamics Simulation Study of the Selectivity of a Silica Polymer for Ibuprofen.

    PubMed

    Concu, Riccardo; Cordeiro, M Natalia D S

    2016-01-01

    In the past few years, the sol-gel polycondensation technique has been increasingly employed with great success as an alternative approach to the preparation of molecularly imprinted materials (MIMs). The main aim of this study was to study, through a series of molecular dynamics (MD) simulations, the selectivity of an imprinted silica xerogel towards a new template-the (±)-2-(P-Isobutylphenyl) propionic acid (Ibuprofen, IBU). We have previously demonstrated the affinity of this silica xerogel toward a similar molecule. In the present study, we simulated the imprinting process occurring in a sol-gel mixture using the Optimized Potentials for Liquid Simulations-All Atom (OPLS-AA) force field, in order to evaluate the selectivity of this xerogel for a template molecule. In addition, for the first time, we have developed and verified a new parameterisation for the Ibuprofen(®) based on the OPLS-AA framework. To evaluate the selectivity of the polymer, we have employed both the radial distribution functions, interaction energies and cluster analyses. PMID:27399685

  9. Molecular Dynamics Simulation Study of the Selectivity of a Silica Polymer for Ibuprofen

    PubMed Central

    Concu, Riccardo; Cordeiro, M. Natalia D. S.

    2016-01-01

    In the past few years, the sol-gel polycondensation technique has been increasingly employed with great success as an alternative approach to the preparation of molecularly imprinted materials (MIMs). The main aim of this study was to study, through a series of molecular dynamics (MD) simulations, the selectivity of an imprinted silica xerogel towards a new template—the (±)-2-(P-Isobutylphenyl) propionic acid (Ibuprofen, IBU). We have previously demonstrated the affinity of this silica xerogel toward a similar molecule. In the present study, we simulated the imprinting process occurring in a sol-gel mixture using the Optimized Potentials for Liquid Simulations-All Atom (OPLS-AA) force field, in order to evaluate the selectivity of this xerogel for a template molecule. In addition, for the first time, we have developed and verified a new parameterisation for the Ibuprofen® based on the OPLS-AA framework. To evaluate the selectivity of the polymer, we have employed both the radial distribution functions, interaction energies and cluster analyses. PMID:27399685

  10. Can maitake MD-fraction aid cancer patients?

    PubMed

    Kodama, Noriko; Komuta, Kiyoshi; Nanba, Hiroaki

    2002-06-01

    Maitake mushroom (Grifola frondosa) MD-fraction containing beta-1,6 glucan with beta-1,3 branched chains has previously exhibited strong anticancer activity by increasing immune-competent cell activity.1,2 In this non-random case series, a combination of MD-fraction and whole maitake powder was investigated to determine its effectiveness for 22- to 57-year-old cancer patients in stages II-IV. Cancer regression or significant symptom improvement was observed in 58.3 percent of liver cancer patients, 68.8 percent of breast cancer patients, and 62.5 percent of lung cancer patients. The trial found a less than 10-20 percent improvement for leukemia, stomach cancer, and brain cancer patients. Furthermore, when maitake was taken in addition to chemotherapy, immune-competent cell activities were enhanced 1.2-1.4 times, compared with chemotherapy alone. Animal studies have supported the use of maitake MD-fraction for cancer. PMID:12126464

  11. 77 FR 67669 - Wayne D. Longmore, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-13

    .... Edwards, M.D., 75 FR 49,991 (DEA 2010); Joseph Baumstarck, M.D., 74 FR 17,525 (DEA 2009). In this case... Baumstarck, M.D., 74 FR at 17,527 (DEA 2009). Thus, because there is no dispute that the Respondent lacks... cancellation); William R. Lockridge, M.D., 71 FR 77,791, 77,797 (DEA 2006) (interpreting 21 CFR 1301.52(a)...

  12. 78 FR 7813 - Sanjay Trivedi, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-04

    ... authority''); Beverley P. Edwards, M.D., 75 FR 49,991 (DEA 2010); Joseph Baumstarck, M.D., 74 FR 17,525 (DEA... Florida. Consequently, his DEA registration must be revoked. See Joseph Baumstarck, M.D., 74 FR 17,525, 17... Coast Specialty Pharmacy, 76 FR 66,965 (DEA 2011); Roy Chi Lung, M.D., 74 FR 20,346 (DEA 2009);...

  13. 76 FR 71370 - Silviu Ziscovici, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-17

    ... the state in which he does business. See Scott Sandarg, D.M.D., 74 FR 17,528 (DEA 2009); David W. Wang, M.D., 72 FR 54,297 (DEA 2007); Sheran ] Arden Yeates, M.D., 71 FR 39,130 (DEA 2006); Dominick A. Ricci, M.D., 58 FR 51,104 (DEA 1993); Bobby Watts M.D., 53 Fed. Reg. 11,919 (DEA 1988)....

  14. 76 FR 71374 - Joseph Giacchino, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-17

    ...); Agostino Carlucci, M.D., 49 FR 33,184, 33,184-85 (1984). Rather, what matters--as DEA has repeatedly held... does business. See Scott Sandarg, DMD, 74 FR 17528 (DEA 2009); David W. Wang, M.D., 72 FR 54297 (DEA 2007); Sheran Arden Yeates, M.D., 71 FR 39130 (DEA 2006); Dominick A. Ricci, M.D., 58 FR 51104...

  15. 76 FR 71369 - Robert G. Crummie, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-17

    ... authority under the laws of the state in which he does business. See Scott Sandarg, D.M.D., 74 FR 17528 (DEA 2009); David W. Wang, M.D., 72 FR 54297 (DEA 2007); Sheran Arden Yeates, M.D., 71 FR 39130 (DEA 2006); Dominick A. Ricci, M.D., 58 FR 51104 (DEA 1993); Bobby Watts M.D., 53 FR 11919 (DEA 1988). In the...

  16. The Application Research of MD5 Encryption Algorithm in DCT Digital Watermarking

    NASA Astrophysics Data System (ADS)

    Xijin, Wang; Linxiu, Fan

    This article did the preliminary study of the application of algorithm for MD5 in the digital watermark. It proposed that copyright information will be encrypted using an algorithm MD5, and made rules for the second value image watermarks, through DCT algorithm that embeds an image by the carrier. The extraction algorithms can pick up the watermark and restore MD5 code.

  17. Validity of the Medical College Admission Test for Predicting MD-PhD Student Outcomes

    ERIC Educational Resources Information Center

    Bills, James L.; VanHouten, Jacob; Grundy, Michelle M.; Chalkley, Roger; Dermody, Terence S.

    2016-01-01

    The Medical College Admission Test (MCAT) is a quantitative metric used by MD and MD-PhD programs to evaluate applicants for admission. This study assessed the validity of the MCAT in predicting training performance measures and career outcomes for MD-PhD students at a single institution. The study population consisted of 153 graduates of the…

  18. Crystal structure of soluble MD-1 and its interaction with lipid IVa

    SciTech Connect

    Yoon, Sung-il; Hong, Minsun; Han, Gye Won; Wilson, Ian A.

    2010-07-22

    Lipopolysaccharide (LPS) of Gram-negative bacteria is a common pathogen-associated molecular pattern (PAMP) that induces potent innate immune responses. The host immune response against LPS is triggered by myeloid differentiation factor 2 (MD-2) in association with Toll-like receptor 4 (TLR4) on the cell surface. The MD-2/TLR4-mediated LPS response is regulated by the evolutionarily related complex of MD-1 and Toll-like receptor homolog RP105. Here, we report crystallographic and biophysical data that demonstrate a previously unidentified direct interaction of MD-1 with LPS. The crystal structure of chicken MD-1 (cMD-1) at 2.0 {angstrom} resolution exhibits a {beta}-cup-like fold, similar to MD-2, that encloses a hydrophobic cavity between the two {beta}-sheets. A lipid-like moiety was observed inside the cavity, suggesting the possibility of a direct MD-1/LPS interaction. LPS was subsequently identified as an MD-1 ligand by native gel electrophoresis and gel filtration analyses. The crystal structure of cMD-1 with lipid IVa, an LPS precursor, at 2.4 {angstrom} resolution revealed that the lipid inserts into the deep hydrophobic cavity of the {beta}-cup-like structure, but with some important differences compared with MD-2. These findings suggest that soluble MD-1 alone, in addition to its complex with RP105, can regulate host LPS sensitivity.

  19. 76 FR 5686 - Drawbridge Operation Regulation; Pocomoke River, Pocomoke City, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-02

    ... SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulation; Pocomoke River, Pocomoke City, MD... operation of the Route 675 Bridge across Pocomoke River, mile 15.6, at Pocomoke City, MD. The deviation... at Pocomoke City MD, has a vertical clearance in the closed position of three feet above mean...

  20. 76 FR 81826 - Drawbridge Operation Regulation; Pocomoke River, Pocomoke City, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulation; Pocomoke River, Pocomoke City, MD... operation of the Route 675 Bridge across Pocomoke River, mile 15.6, at Pocomoke City, MD. The deviation... across Pocomoke River, mile 15.6 at Pocomoke City, MD, has a vertical clearance in the closed position...

  1. 76 FR 23185 - Drawbridge Operation Regulation; Isle of Wight (Sinepuxent) Bay, Ocean City, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-26

    ... (Sinepuxent) Bay, Ocean City, MD in the Federal Register (75 FR 236). We received no comments on the proposed... (Sinepuxent) Bay, Ocean City, MD AGENCY: Coast Guard, DHS. ACTION: Final rule. SUMMARY: The Coast Guard is..., mile 0.5, at Ocean City, MD. This rule will require any mariner requesting an opening in the ]...

  2. 78 FR 39604 - Safety Zone; Northside Park Pier Fireworks Display, Assawoman Bay, Ocean City, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-02

    ..., Assawoman Bay, Ocean City, MD AGENCY: Coast Guard, DHS. ACTION: Temporary final rule. SUMMARY: The Coast Guard is establishing a temporary safety zone on the navigable waters of Assawoman Bay in Ocean City, MD... pier at Northside Park in Ocean City, MD. The fireworks debris fallout area will extend over...

  3. 78 FR 76322 - Thomas Neuschatz, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-17

    ...(f). ``These factors are . . . considered in the disjunctive.'' Robert A. Leslie, M.D., 68 FR 15227... Kevin Dennis, M.D., 78 FR 52787, 52794 (2013); MacKay v. DEA, 664 F.3d 808, 816 (10th Cir. 2010). The...-contested case. Gabriel Sanchez, M.D., 78 FR 59060, 59063 (2013). Having considered all of the factors,\\3\\...

  4. 75 FR 52461 - Drawbridge Operation Regulation; Pocomoke River, Snow Hill, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-26

    ... SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulation; Pocomoke River, Snow Hill, MD AGENCY... the S12 ] Bridge across the Pocomoke River, mile 29.9, at Snow Hill, MD. The deviation restricts the... hours advance notice is given. The S12 Bridge across Pocomoke River, mile 29.9 at Snow Hill MD, has...

  5. Full-Scale Crash Test of a MD-500 Helicopter with Deployable Energy Absorbers

    NASA Technical Reports Server (NTRS)

    Kellas, Sotiris; Jackson, Karen E.; Littell, Justin D.

    2010-01-01

    A new externally deployable energy absorbing system was demonstrated during a full-scale crash test of an MD-500 helicopter. The deployable system is a honeycomb structure and utilizes composite materials in its construction. A set of two Deployable Energy Absorbers (DEAs) were fitted on the MD-500 helicopter for the full-scale crash demonstration. Four anthropomorphic dummy occupants were also used to assess human survivability. A demonstration test was performed at NASA Langley's Landing and Impact Research Facility (LandIR). The test involved impacting the helicopter on a concrete surface with combined forward and vertical velocity components of 40-ft/s and 26-ft/s, respectively. The objectives of the test were to evaluate the performance of the DEA concept under realistic crash conditions and to generate test data for validation of dynamic finite element simulations. Descriptions of this test as well as other component and full-scale tests leading to the helicopter test are discussed. Acceleration data from the anthropomorphic dummies showed that dynamic loads were successfully attenuated to within non-injurious levels. Moreover, the airframe itself survived the relatively severe impact and was retested to provide baseline data for comparison for cases with and without DEAs.

  6. Exploring the RING-catalyzed ubiquitin transfer mechanism by MD and QM/MM calculations.

    PubMed

    Zhen, Yunmei; Qin, Guangrong; Luo, Cheng; Jiang, Hualiang; Yu, Kunqian; Chen, Guanghui

    2014-01-01

    Ubiquitylation is a universal mechanism for controlling cellular functions. A large family of ubiquitin E3 ligases (E3) mediates Ubiquitin (Ub) modification. To facilitate Ub transfer, RING E3 ligases bind both the substrate and ubiquitin E2 conjugating enzyme (E2) linked to Ub via a thioester bond to form a catalytic complex. The mechanism of Ub transfer catalyzed by RING E3 remains elusive. By employing a combined computational approach including molecular modeling, molecular dynamics (MD) simulations, and quantum mechanics/molecular mechanics (QM/MM) calculations, we characterized this catalytic mechanism in detail. The three-dimensional model of dimeric RING E3 ligase RNF4 RING, E2 ligase UbcH5A, Ub and the substrate SUMO2 shows close contact between the substrate and Ub transfer catalytic center. Deprotonation of the substrate lysine by D117 on UbcH5A occurs with almost no energy barrier as calculated by MD and QM/MM calculations. Then, the side chain of the activated lysine gets close to the thioester bond via a conformation change. The Ub transfer pathway begins with a nucleophilic addition that forms an oxyanion intermediate of a 4.23 kcal/mol energy barrier followed by nucleophilic elimination, resulting in a Ub modified substrate by a 5.65 kcal/mol energy barrier. These results provide insight into the mechanism of RING-catalyzed Ub transfer guiding the discovery of Ub system inhibitors. PMID:25003393

  7. A QM/MM-MD study on protein electronic properties: Circular dichroism spectra of oxytocin and insulin

    NASA Astrophysics Data System (ADS)

    Kitagawa, Yuya; Akinaga, Yoshinobu; Kawashima, Yukio; Jung, Jaewoon; Ten-no, Seiichiro

    2012-06-01

    A QM/MM (quantum-mechanical/molecular-mechanical) molecular-dynamics approach based on the generalized hybrid-orbital (GHO) method, in conjunction with the second-order perturbation (MP2) theory and the second-order approximate coupled-cluster (CC2) model, is employed to calculate electronic property accounting for a protein environment. Circular dichroism (CD) spectra originating from chiral disulfide bridges of oxytocin and insulin at room temperature are computed. It is shown that the sampling of thermal fluctuation of molecular geometries facilitated by the GHO-MD method plays an important role in the obtained spectra. It is demonstrated that, while the protein environments in an oxytocin molecule have significant electrostatic influence on its chiral center, it is compensated by solvent induced charges. This gives a reasonable explanation to experimental observations. GHO-MD simulations starting from different experimental structures of insulin indicate that existence of the disulfide bridges with negative dihedral angles is crucial.

  8. 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

  9. Repair materials and processes for the MD-11 Composite Tailcone

    NASA Astrophysics Data System (ADS)

    Yamamoto, Tetsuya; Bonnar, Gerard R.

    This paper describes field and depot level repair methods for the MD-11 Composite Tailcone. The repair materials, processing methods, and mechanical properties of the test specimens and subcomponents are discussed. According to recent tests, the dry carbon cloth and the liquid resin matrix that can be cured under 93 C have better processing and mechanical properties than the 121 C curing prepregs and film adhesives. The moisture in the parent CFRP is the main cause of creating voids in the adhesive layer during the 121 C/vacuum pressure cure cycle. The lower processing temperature (wet layup) showed better results than higher processing temperature (prepreg/adhesive layup) for composite repair.

  10. An Insight into the Environmental Effects of the Pocket of the Active Site of the Enzyme. Ab initio ONIOM-Molecular Dynamics (MD) Study on Cytosine Deaminase

    SciTech Connect

    Matsubara, Toshiaki; Dupuis, Michel; Aida, Misako

    2008-02-01

    We applied the ONIOM-molecular dynamics (MD) method to cytosine deaminase to examine the environmental effects of the amino acid residues in the pocket of the active site on the substrate taking account of their thermal motion. The ab initio ONIOM-MD simulations show that the substrate uracil is strongly perturbed by the amino acid residue Ile33, which sandwiches the uracil with His62, through the steric contact due to the thermal motion. As a result, the magnitude of the thermal oscillation of the potential energy and structure of the substrate uracil significantly increases. TM and MA were partly supported 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.

  11. pMD-Membrane: A Method for Ligand Binding Site Identification in Membrane-Bound Proteins

    PubMed Central

    Gorfe, Alemayehu A.

    2015-01-01

    Probe-based or mixed solvent molecular dynamics simulation is a useful approach for the identification and characterization of druggable sites in drug targets. However, thus far the method has been applied only to soluble proteins. A major reason for this is the potential effect of the probe molecules on membrane structure. We have developed a technique to overcome this limitation that entails modification of force field parameters to reduce a few pairwise non-bonded interactions between selected atoms of the probe molecules and bilayer lipids. We used the resulting technique, termed pMD-membrane, to identify allosteric ligand binding sites on the G12D and G13D oncogenic mutants of the K-Ras protein bound to a negatively charged lipid bilayer. In addition, we show that differences in probe occupancy can be used to quantify changes in the accessibility of druggable sites due to conformational changes induced by membrane binding or mutation. PMID:26506102

  12. Fluorescence of PRODAN in Water: a Computational QM/MM MD Study

    SciTech Connect

    Pederzoli, Marek; Sobek, Lukas; Brabec, Jiri; Kowalski, Karol; Cwiklik, Lukasz; Pittner, Jiri

    2014-03-28

    Fluorescent properties of PRODAN (6-propionyl-2-dimethylaminonaphthalene) in water were studied by means of excited state molecular dynamics simulations employing a combined quantum mechanical and molecular mechanical approach with the time-dependent density functional theory (TD-DFT QM/MM MD). The state of the art coupled cluster method was used to benchmark density functional theory calculations. The influence of the water environment on PRODAN emission was investigated by employing several computational schemes with varying description of the solvent. The issue of the molecular geometry of the excited state PRODAN molecule in water was addressed. The experimental emission spectrum was reproduced for the planar excited state conformer of PRODAN in the extended environment of 300 explicit water molecules. The planar conformer was shown to be predominantly responsible for fluorescence. The twisted isomer is strongly stabilized in water, but rapidly evolve towards a conical intersection, and hence the twisted conformer is fluorescently inactive.

  13. Atomistic Simulation of Solubilization of Polycyclic Aromatic Hydrocarbons in a Sodium Dodecyl Sulfate Micelle.

    PubMed

    Liang, Xujun; Marchi, Massimo; Guo, Chuling; Dang, Zhi; Abel, Stéphane

    2016-04-19

    Solubilization of two polycyclic aromatic hydrocarbons (PAHs), naphthalene (NAP, 2-benzene-ring PAH) and pyrene (PYR, 4-benzene-ring PAH), into a sodium dodecyl sulfate (SDS) micelle was studied through all-atom molecular dynamics (MD) simulations. We find that NAP as well as PYR could move between the micelle shell and core regions, contributing to their distribution in both regions of the micelle at any PAH concentration. Moreover, both NAP and PYR prefer to stay in the micelle shell region, which may arise from the greater volume of the micelle shell, the formation of hydrogen bonds between NAP and water, and the larger molecular volume of PYR. The PAHs are able to form occasional clusters (from dimer to octamer) inside the micelle during the simulation time depending on the PAH concentration in the solubilization systems. Furthermore, the micelle properties (i.e., size, shape, micelle internal structure, alkyl chain conformation and orientation, and micelle internal dynamics) are found to be nearly unaffected by the solubilized PAHs, which is irrespective of the properties and concentrations of PAHs. PMID:27049522

  14. Simulations of the folding/unfolding of biomolecules under solvent, and pressure perturbations

    NASA Astrophysics Data System (ADS)

    Garcia, Angel

    2012-02-01

    Proteins exhibit marginal stability, determined by the balance of many competing effects. This stability can be perturbed by changes in temperature, pH, pressure, and other solvent conditions. Osmolytes are small organic compounds that modulate the conformational equilibrium, folded (F) and unfolded (U), of proteins as cosolvents. Protecting osmolytes such as trimethylamine N-oxide (TMAO), glycerol, and sugars that push the equilibrium toward F play a crucial role in maintaining the function of intracellular proteins in extreme environmental conditions. Urea is a denaturing osmolyte that shifts the equilibrium toward U. We will describe calculations of the reversible folding/unfolding equilibrium, under various solution conditions that include urea, high pressure, and different charge states of the Trp-cage miniprotein. The folding/unfolding equilibrium is studied using all-atom Replica exchange MD simulations. For urea, the simulations capture the experimentally observed linear dependence of unfolding free energy on urea concentration. We find that the denaturation is driven by favorable direct interaction of urea with the protein through both electrostatic and van der Waals forces and quantify their contribution. Though the magnitude of direct electrostatic interaction of urea is larger than van der Waals, the difference between unfolded and folded ensembles is dominated by the van der Waals interaction. We also find that hydrogen bonding of urea to the peptide backbone does not play a dominant role in denaturation. The unfolded ensemble sampled depends on urea concentration, with greater urea concentration favoring conformations with greater solvent exposure.

  15. Md-ACS1 and Md-AC01 genotyping of apple breeding parents and suitability for marker-assisted selection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fruit ethylene production genotypes for Md-ACS1 and Md-ACO1 were determined for 60 apple cultivars/selections and 35 advanced breeding selections. Two alleles for each gene are commonly found in cultivated apple. Earlier studies showed that genotypes homozygous for the ACS1-2 allele produce less eth...

  16. LifeBridge new publication: Md.MD. Listing of 1,200 physicians a major part of consumer-type magazine.

    PubMed

    Botvin, Judith D

    2004-01-01

    LifeBridge Health, Baltimore, created a directory of its physicians, which developed into a 100-page consumer magazine titled Md.MD A Directory of the Region's Finest Physicians. Written and designed in-house, the premier edition paid for itself, thanks to publishing partner, Alter Communications. The premier edition was mailed to 50,000 Baltimore area homes last September. PMID:15022542

  17. Computer simulation studies of Aβ37-42 aggregation thermodynamics and kinetics in water and salt solution.

    PubMed

    Yang, Y Isaac; Gao, Yi Qin

    2015-01-22

    In vivo self-assembly of proteins into aggregates known as amyloids is related to many diseases. Although a large number of studies have been performed on the formation of amyloid, the molecular mechanism of polypeptide aggregation remains largely unclear. In this paper, we studied the aggregation of amyloid-forming peptide Aβ37-42 using all-atom molecular dynamics simulations. Using the integrated temperature sampling (ITS) simulation method, we observed the reversible formation of Aβ37-42 oligomers. The free-energy landscape for the polypeptide association was calculated, and aggregated states were then defined based on the landscape. To explore the kinetics and especially salt effects on the process of polypeptide aggregation, normal MD simulations were performed in pure water and NaCl solution, respectively. We then used the transition path theory (TPT) to analyze the transition network of polypeptide aggregation in solution. The dominant pathways of Aβ37-42 aggregation were found to differ significantly in pure water and the salt solution, indicating the change of molecular mechanism of polypeptide aggregation with the solution conditions. PMID:24861904

  18. Simulation of screw dislocation motion in iron by molecular dynamics simulations.

    PubMed

    Domain, Christophe; Monnet, Ghiath

    2005-11-18

    Molecular dynamics (MD) simulations are used to investigate the response of a/2<111> screw dislocation in iron submitted to pure shear strain. The dislocation glides and remains in a (110) plane; the motion occurs exclusively through the nucleation and propagation of double kinks. The critical stress is calculated as a function of the temperature. A new method is developed and used to determine the activation energy of the double kink mechanism from MD simulations. It is shown that the differences between experimental and simulation conditions lead to a significant difference in activation energy. These differences are explained, and the method developed provides the link between MD and mesoscopic simulations. PMID:16384158

  19. Full-Scale Crash Test of an MD-500 Helicopter

    NASA Technical Reports Server (NTRS)

    Littell, Justin

    2011-01-01

    A full-scale crash test was successfully conducted in March 2010 of an MD-500 helicopter at NASA Langley Research Center s Landing and Impact Research Facility. The reasons for conducting this test were threefold: 1 To generate data to be used with finite element computer modeling efforts, 2 To study the crashworthiness features typically associated with a small representative helicopter, and 3 To compare aircraft response to data collected from a previously conducted MD-500 crash test, which included an externally deployable energy absorbing (DEA) concept. Instrumentation on the airframe included accelerometers on various structural components of the airframe; and strain gages on keel beams, skid gear and portions of the skin. Three Anthropomorphic Test Devices and a specialized Human Surrogate Torso Model were also onboard to collect occupant loads for evaluation with common injury risk criteria. This paper presents background and results from this crash test conducted without the DEA concept. These results showed accelerations of approximately 30 to 50 g on the airframe at various locations, little energy attenuation through the airframe, and moderate to high probability of occupant injury for a variety of injury criteria.

  20. Error and efficiency of simulated tempering simulations

    PubMed Central

    Rosta, Edina; Hummer, Gerhard

    2010-01-01

    We derive simple analytical expressions for the error and computational efficiency of simulated tempering (ST) simulations. The theory applies to the important case of systems whose dynamics at long times is dominated by the slow interconversion between two metastable states. An extension to the multistate case is described. We show that the relative gain in efficiency of ST simulations over regular molecular dynamics (MD) or Monte Carlo (MC) simulations is given by the ratio of their reactive fluxes, i.e., the number of transitions between the two states summed over all ST temperatures divided by the number of transitions at the single temperature of the MD or MC simulation. This relation for the efficiency is derived for the limit in which changes in the ST temperature are fast compared to the two-state transitions. In this limit, ST is most efficient. Our expression for the maximum efficiency gain of ST simulations is essentially identical to the corresponding expression derived by us for replica exchange MD and MC simulations [E. Rosta and G. Hummer, J. Chem. Phys. 131, 165102 (2009)] on a different route. We find quantitative agreement between predicted and observed efficiency gains in a test against ST and replica exchange MC simulations of a two-dimensional Ising model. Based on the efficiency formula, we provide recommendations for the optimal choice of ST simulation parameters, in particular, the range and number of temperatures, and the frequency of attempted temperature changes. PMID:20095723

  1. Error and efficiency of simulated tempering simulations.

    PubMed

    Rosta, Edina; Hummer, Gerhard

    2010-01-21

    We derive simple analytical expressions for the error and computational efficiency of simulated tempering (ST) simulations. The theory applies to the important case of systems whose dynamics at long times is dominated by the slow interconversion between two metastable states. An extension to the multistate case is described. We show that the relative gain in efficiency of ST simulations over regular molecular dynamics (MD) or Monte Carlo (MC) simulations is given by the ratio of their reactive fluxes, i.e., the number of transitions between the two states summed over all ST temperatures divided by the number of transitions at the single temperature of the MD or MC simulation. This relation for the efficiency is derived for the limit in which changes in the ST temperature are fast compared to the two-state transitions. In this limit, ST is most efficient. Our expression for the maximum efficiency gain of ST simulations is essentially identical to the corresponding expression derived by us for replica exchange MD and MC simulations [E. Rosta and G. Hummer, J. Chem. Phys. 131, 165102 (2009)] on a different route. We find quantitative agreement between predicted and observed efficiency gains in a test against ST and replica exchange MC simulations of a two-dimensional Ising model. Based on the efficiency formula, we provide recommendations for the optimal choice of ST simulation parameters, in particular, the range and number of temperatures, and the frequency of attempted temperature changes. PMID:20095723

  2. [Professor Frantisek Por MD and Professor Robert Klopstock MD, students at Budapest and Prague Faculties of Medicine].

    PubMed

    Mydlík, M; Derzsiová, K

    2010-11-01

    Professor Frantisek Por MD and Professor Robert Klopstock MD were contemporaries, both born in 1899, one in Zvolen, the other in Dombovar, at the time of Austro-Hungarian Monarchy. Prof. Por attended the Faculty of Medicine in Budapest from 1918 to 1920, and Prof. Klopstock studied at the same place between 1917 and 1919. From 1920 until graduation on 6th February 1926, Prof. Por continued his studies at the German Faculty of Medicine, Charles University in Prague. Prof. Klopstock had to interrupt his studies in Budapest due to pulmonary tuberculosis; he received treatment at Tatranske Matliare where he befriended Franz Kafka. Later, upon Kafka's encouragement, he changed institutions and continued his studies at the German Faculty of Medicine, Charles University in Prague, where he graduated the first great go. It is very likely that, during their studies in Budapest and Prague, both professors met repeatedly, even though their life paths later separated. Following his graduation, Prof. Por practiced as an internist in Prague, later in Slovakia, and from 1945 in Kosice. In 1961, he was awarded the title of university professor of internal medicine at the Faculty of Medicine, Pavol Jozef Safarik University in Kosice, where he practiced until his death in 1980. Prof. Klopstock continued his studies in Kiel and Berlin. After his graduation in 1933, he practiced in Berlin as a surgeon and in 1938 left for USA. In 1962, he was awarded the title of university professor of pulmonary surgery in NewYork, where he died in 1972. PMID:21250499

  3. 78 FR 28229 - Prospective Grant of Exclusive License: Device and System for Expression Microdissection (xMD)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-14

    ... for Expression Microdissection (xMD) AGENCY: National Institutes of Health, HHS. ACTION: Notice... Activated Microtransfer;'' and all continuing applications and foreign counterparts to xMD Diagnostics, LLC... Field''). xMD Diagnostics, LLC (xMD) shall be the only entity granted rights in the Exclusive Field...

  4. The role of cultivar-specific expression patterns of MdACS3 gene on apple fruit ripening and quality

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethylene plays an important role in diverse physiological and developmental processes of plants. In apple, two ethylene biosynthesis genes, MdACS1 and MdACS3, are expressed in fruit tissues. While MdACS1 expresses at late ripening stages, expression of MdACS3 can be detected as early as 6 weeks befo...

  5. The cultivar-specific expression patterns of MdACS3 gene and apple fruit ripening and quality

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethylene plays an important role in diverse physiological and developmental processes of plants. In apple, two ethylene biosynthesis genes, MdACS1 and MdACS3, are expressed in fruit tissues. While MdACS1 expresses at late ripening stages, expression of MdACS3 can be detected as early as 6 weeks bef...

  6. Fred Loe, MD, and the history of trachoma.

    PubMed

    Feibel, Robert M

    2011-04-01

    Trachoma has been one of the most blinding diseases in the history of ophthalmology. From its initial description in antiquity until the late 1930s, no specific treatment or effective cure had been known, and the only expedient had been to destroy the diseased tissue containing the infectious agent, rendering the disease inactive. Virtually all medical, mechanical, and surgical treatments were unsatisfactory, with cure rates of approximately 20%. Therapy for trachoma had barely advanced from the measures used by the ancient Egyptian, Greek, and Roman physicians. All prior therapies became obsolete in 1938 when Fred Loe, MD, working on an American Indian reservation, introduced sulfanilamide as a treatment of trachoma, achieving a 90% cure rate. One of the most unusual aspects of Loe's career was that he had no formal training in ophthalmology and was completely self-taught as an ophthalmologist. PMID:21482877

  7. Thermal Sensitivity of MD Hematite: Implication for Magnetic Anomalies

    NASA Technical Reports Server (NTRS)

    Kletetschka, Gunther; Wasilewski, Peter J.; Taylor, Patrick T.

    1999-01-01

    Magnetic remanence of crustal rocks can reside in three common rock-forming magnetic minerals: magnetite, pyrrhotite, and hematite. Thermoremanent magnetization (TRM) of magnetite and pyrrhotite is carried mostly by single domain (SD) grains. The TRM of hematite grains, however, is carried mostly by multidomain (NM) grains. This characteristic is illustrated by TRM acquisition curves for hematite of variable grainsizes. The transition between truly NM behavior and tendency towards SD behavior his been established between hematite grainsizes of 0. 1 and 0.05 mm. Coarse grainsize of lower crustal rocks and the large sensitivity of MD hematite grains to acquire TRM indicates that hematite could be a significant contributor to long-wavelength magnetic anomalies.

  8. RADIATION PRESSURE DETECTION AND DENSITY ESTIMATE FOR 2011 MD

    SciTech Connect

    Micheli, Marco; Tholen, David J.; Elliott, Garrett T. E-mail: tholen@ifa.hawaii.edu

    2014-06-10

    We present our astrometric observations of the small near-Earth object 2011 MD (H ∼ 28.0), obtained after its very close fly-by to Earth in 2011 June. Our set of observations extends the observational arc to 73 days, and, together with the published astrometry obtained around the Earth fly-by, allows a direct detection of the effect of radiation pressure on the object, with a confidence of 5σ. The detection can be used to put constraints on the density of the object, pointing to either an unexpectedly low value of ρ=(640±330)kg m{sup −3} (68% confidence interval) if we assume a typical probability distribution for the unknown albedo, or to an unusually high reflectivity of its surface. This result may have important implications both in terms of impact hazard from small objects and in light of a possible retrieval of this target.

  9. Release of Native-like Gaseous Proteins from Electrospray Droplets via the Charged Residue Mechanism: Insights from Molecular Dynamics Simulations.

    PubMed

    McAllister, Robert G; Metwally, Haidy; Sun, Yu; Konermann, Lars

    2015-10-01

    The mechanism whereby gaseous protein ions are released from charged solvent droplets during electrospray ionization (ESI) remains a matter of debate. Also, it is unclear to what extent electrosprayed proteins retain their solution structure. Molecular dynamics (MD) simulations offer insights into the temporal evolution of protein systems. Surprisingly, there have been no all-atom simulations of the protein ESI process to date. The current work closes this gap by investigating the behavior of protein-containing aqueous nanodroplets that carry excess positive charge. We focus on "native ESI", where proteins initially adopt their biologically active solution structures. ESI proceeds while the protein remains entrapped within the droplet. Protein release into the gas phase occurs upon solvent evaporation to dryness. Droplet shrinkage is accompanied by ejection of charge carriers (Na(+) for the conditions chosen here), keeping the droplet at ∼85% of the Rayleigh limit throughout its life cycle. Any remaining charge carriers bind to the protein as the final solvent molecules evaporate. The outcome of these events is largely independent of the initial protein charge and the mode of charge carrier binding. ESI charge states and collision cross sections of the MD structures agree with experimental data. Our results confirm the Rayleigh/charged residue model (CRM). Field emission of excess Na(+) plays an ancillary role by governing the net charge of the shrinking droplet. Models that envision protein ejection from the droplet are not supported. Most nascent CRM ions retain native-like conformations. For unfolded proteins ESI likely proceeds along routes that are different from the native state mechanism explored here. PMID:26325619

  10. Self-assembly of endohedral metallofullerenes: a decisive role of cooling gas and metal–carbon bonding† †Electronic supplementary information (ESI) available: Additional information on metal–carbon bonding and MD simulations. See DOI: 10.1039/c5nr08645k Click here for additional data file.

    PubMed Central

    Deng, Qingming; Heine, Thomas

    2016-01-01

    The endohedral metallofullerene (EMF) self-assembly process in Sc/carbon vapor in the presence and absence of an inert cooling gas (helium) is systematically investigated using quantum chemical molecular dynamics simulations. It is revealed that the presence of He atoms accelerates the formation of pentagons and hexagons and reduces the size of the self-assembled carbon cages in comparison with analogous He-free simulations. As a result, the Sc/C/He system simulations produce a larger number of successful trajectories (i.e. leading to Sc-EMFs) with more realistic cage-size distribution than simulations of the Sc/C system. The main Sc encapsulation mechanism involves nucleation of several hexagons and pentagons with Sc atoms already at the early stages of carbon vapor condensation. In such proto-cages, both Sc–C σ-bonds and coordination bonds between Sc atoms and the π-system of the carbon network are present. Sc atoms are thus rather labile and can move along the carbon network, but the overall bonding is sufficiently strong to prevent dissociation even at temperatures around 2000 kelvin. Further growth of the fullerene cage results in the encapsulation of one or two Sc atoms within the fullerene. In agreement with experimental studies, an extension of the simulations to Fe and Ti as the metal component showed that Fe-EMFs are not formed at all, whereas Ti is prone to form Ti-EMFs with small cage sizes, including Ti@C28-T d and Ti@C30-C 2v(3). PMID:26815243

  11. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    SciTech Connect

    Okumura, Hisashi

    2015-12-31

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  12. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    NASA Astrophysics Data System (ADS)

    Okumura, Hisashi

    2015-12-01

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  13. Characterization of an Autophagy-Related Gene MdATG8i from Apple

    PubMed Central

    Wang, Ping; Sun, Xun; Jia, Xin; Wang, Na; Gong, Xiaoqing; Ma, Fengwang

    2016-01-01

    Nutrient deficiencies restrict apple (Malus sp.) tree growth and productivity in Northwest China. The process of autophagy, a conserved degradation pathway in eukaryotic cells, has important roles in nutrient-recycling and helps improve plant performance during periods of nutrient-starvation. Little is known about the functioning of autophagy-related genes (ATGs) in apple. In this study, one of the ATG8 gene family members MdATG8i was isolated from Malus domestica. MdATG8i has conserved putative tubulin binding sites and ATG7 interaction domains. A 1865-bp promoter region cloned from apple genome DNA was predicated to have cis-regulatory elements responsive to light, environmental stresses, and hormones. MdATG8i transcriptions were induced in response to leaf senescence, nitrogen depletion, and oxidative stress. At cellular level, MdATG8i protein was expressed in the nucleus and cytoplasm of onion epidermal cells. Yeast two-hybrid tests showed that MdATG8i could interact with MdATG7a and MdATG7b. In Arabidopsis, its heterologous expression was associated with enhanced vegetative growth, leaf senescence, and tolerance to nitrogen- and carbon-starvation. MdATG8i-overexpressing “Orin” apple callus lines also displayed improved tolerance to nutrient-limited conditions. Our results demonstrate that MdATG8i protein could function in autophagy in a conserved way, as a positive regulator in the response to nutrient-starvation. PMID:27252732

  14. Characterization of an Autophagy-Related Gene MdATG8i from Apple.

    PubMed

    Wang, Ping; Sun, Xun; Jia, Xin; Wang, Na; Gong, Xiaoqing; Ma, Fengwang

    2016-01-01

    Nutrient deficiencies restrict apple (Malus sp.) tree growth and productivity in Northwest China. The process of autophagy, a conserved degradation pathway in eukaryotic cells, has important roles in nutrient-recycling and helps improve plant performance during periods of nutrient-starvation. Little is known about the functioning of autophagy-related genes (ATGs) in apple. In this study, one of the ATG8 gene family members MdATG8i was isolated from Malus domestica. MdATG8i has conserved putative tubulin binding sites and ATG7 interaction domains. A 1865-bp promoter region cloned from apple genome DNA was predicated to have cis-regulatory elements responsive to light, environmental stresses, and hormones. MdATG8i transcriptions were induced in response to leaf senescence, nitrogen depletion, and oxidative stress. At cellular level, MdATG8i protein was expressed in the nucleus and cytoplasm of onion epidermal cells. Yeast two-hybrid tests showed that MdATG8i could interact with MdATG7a and MdATG7b. In Arabidopsis, its heterologous expression was associated with enhanced vegetative growth, leaf senescence, and tolerance to nitrogen- and carbon-starvation. MdATG8i-overexpressing "Orin" apple callus lines also displayed improved tolerance to nutrient-limited conditions. Our results demonstrate that MdATG8i protein could function in autophagy in a conserved way, as a positive regulator in the response to nutrient-starvation. PMID:27252732

  15. 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

    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

  16. Molecular Simulations of Solved Co-crystallized X-Ray Structures Identify Action Mechanisms of PDEδ Inhibitors.

    PubMed

    Salmas, Ramin Ekhteiari; Mestanoglu, Mert; Yurtsever, Mine; Noskov, Sergei Y; Durdagi, Serdar

    2015-09-15

    PDEδ is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDEδ targets to investigate mechanisms of action of six independent all-atom MD simulations. An analysis of atomic simulations combined with the molecular mechanic-Poisson-Boltzmann solvent accessible surface area/generalized Born solvent accessible surface area calculations led to the identification of action mechanisms for a panel of novel PDEδ inhibitors. To the best of our knowledge, this study is one of the first in silico investigations on co-crystallized PDEδ protein. A detailed atomic-scale understanding of the molecular mechanism of PDEδ inhibition may assist in the design of novel PDEδ inhibitors. One of the most common side effects for diverse small molecules/kinase inhibitors is their off-target interactions with cardiac ion channels and human-ether-a-go-go channel specifically. Thus, all of the studied PDEδ inhibitors are also screened in silico at the central cavities of hERG1 potassium channels. PMID:26340817

  17. pH dependence of ligand-induced human epidermal growth factor receptor activation investigated by molecular dynamics simulations.

    PubMed

    Dong, Jun; Zhang, Yonghui; Zhang, Zhiyong

    2016-06-01

    The activation of human epidermal growth factor receptor (hEGFR) involves a large conformational change in its soluble extracellular domains (sECD, residues 1-620), from a tethered to an extended conformation upon binding of ligands, such as EGF. It has been reported that this dynamic process is pH-dependent, that is, hEGFR can be activated by EGF at high pH to form an extended dimer but remains as an inactive monomer at low pH. In this paper, we perform all-atom molecular dynamics (MD) simulations starting from the tethered conformation of sECD:EGF complex, at pH 5.0 and 8.5, respectively. Simulation results indicate that sECD:EGF shows different dynamic properties between the two pHs, and the complex may have a higher tendency of activation at pH 8.5. Twenty residues, including 13 histidines, in sECD:EGF have different protonation states between the two pHs (calculated by the H++ server). The charge distribution at pH 8.5 is more favorable for forming an extended conformation toward the active state of sECD than that at pH 5.0. Our study may shed light on the mechanism of pH dependence of hEGFR activation. Graphical abstract pH dependence of ligand-induced human epidermal growth factor receptor activation. PMID:27179806

  18. Coupling molecular dynamics simulations with experiments for the rational design of indolicidin-analogous antimicrobial peptides.

    PubMed

    Tsai, Ching-Wei; Hsu, Ning-Yi; Wang, Chang-Hsu; Lu, Chia-Yu; Chang, Yung; Tsai, Hui-Hsu Gavin; Ruaan, Rouh-Chyu

    2009-09-25

    Antimicrobial peptides (AMPs) have attracted much interest in recent years because of their potential use as new-generation antibiotics. Indolicidin (IL) is a 13-residue cationic AMP that is effective against a broad spectrum of bacteria, fungi, and even viruses. Unfortunately, its high hemolytic activity retards its clinical applications. In this study, we adopted molecular dynamics (MD) simulations as an aid toward the rational design of IL analogues exhibiting high antimicrobial activity but low hemolysis. We employed long-timescale, multi-trajectory all-atom MD simulations to investigate the interactions of the peptide IL with model membranes. The lipid bilayer formed by the zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) was chosen as the model erythrocyte membrane; lipid bilayers formed from a mixture of POPC and the negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol were chosen to model bacterial membranes. MD simulations with a total simulation time of up to 4 micros revealed the mechanisms of the processes of IL adsorption onto and insertion into the membranes. The packing order of these lipid bilayers presumably correlated to the membrane stability upon IL adsorption and insertion. We used the degree of local membrane thinning and the reduction in the order parameter of the acyl chains of the lipids to characterize the membrane stability. The order of the mixed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol/POPC lipid bilayer reduced significantly upon the adsorption of IL. On the other hand, although the order of the pure-POPC lipid bilayer was perturbed slightly during the adsorption stage, the value was reduced more dramatically upon the insertion of IL into the membrane's hydrophobic region. The results imply that enhancing IL adsorption on the microbial membrane may amplify its antimicrobial activity, while the degree of hemolysis may be reduced through inhibition of IL insertion into the hydrophobic region

  19. 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

    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

  20. Sulforaphane inhibits the engagement of LPS with TLR4/MD2 complex by preferential binding to Cys133 in MD2.

    PubMed

    Koo, Jung Eun; Park, Zee-Yong; Kim, Nam Doo; Lee, Joo Young

    2013-05-10

    Toll-like receptors (TLRs) are key pattern-recognition receptors that recognize invading pathogens and non-microbial endogenous molecules to induce innate and adaptive immune responses. Since activation of TLRs is deeply implicated in the pathological progress of autoimmune diseases, sepsis, metabolic diseases, and cancer, modulation of TLR activity is considered one of the most important therapeutic approaches. Lipopolysaccharide (LPS), an endotoxin of gram-negative bacteria, is a well-known agonist for TLR4 triggering inflammation and septic shock. LPS interacts with TLR4 through binding to a hydrophobic pocket in myeloid differentiation 2 (MD2), a co-receptor of TLR4. In this study, we showed that sulforaphane (SFN) interfered with the binding of LPS to MD2 as determined by in vitro binding assay and co-immunoprecipitation of MD2 and LPS in a cell system. The inhibitory effect of SFN on the interaction of LPS and MD2 was reversed by thiol supplementation with N-acetyl-L-cysteine or dithiothreitol showing that the inhibitory effect of SFN is dependent on its thiol-modifying activity. Indeed, micro LC-MS/MS analysis showed that SFN preferentially formed adducts with Cys133 in the hydrophobic pocket of MD2, but not with Cys95 and Cys105. Molecular modeling showed that SFN bound to Cys133 blocks the engagement of LPS and lipid IVa to hydrophobic pocket of MD2. Our results demonstrate that SFN interrupts LPS engagement to TLR4/MD2 complex by direct binding to Cys133 in MD2. Our data suggest a novel mechanism for the anti-inflammatory activity of SFN, and provide a novel target for the regulation of TLR4-mediated inflammatory and immune responses by phytochemicals. PMID:23583403

  1. Membrane Mediated Antimicrobial and Antitumor Activity of Cathelicidin 6: Structural Insights from Molecular Dynamics Simulation on Multi-Microsecond Scale

    PubMed Central

    Sahoo, Bikash Ranjan; Fujiwara, Toshimichi

    2016-01-01

    The cathelicidin derived bovine antimicrobial peptide BMAP27 exhibits an effective microbicidal activity and moderate cytotoxicity towards erythrocytes. Irrespective of its therapeutic and multidimensional potentiality, the structural studies are still elusive. Moreover, the mechanism of BMAP27 mediated pore formation in heterogeneous lipid membrane systems is poorly explored. Here, we studied the effect of BMAP27 in model cell-membrane systems such as zwitterionic, anionic, thymocytes-like (TLM) and leukemia-like membranes (LLM) by performing molecular dynamics (MD) simulation longer than 100 μs. All-atom MD studies revealed a stable helical conformation in the presence of anionic lipids, however, significant loss of helicity was identified in TLM and zwitterionic systems. A peptide tilt (~45˚) and central kink (at residue F10) was found in anionic and LLM models, respectively, with an average membrane penetration of < 0.5 nm. Coarse-grained (CG) MD analysis on a multi-μs scale shed light on the membrane-dependent peptide and lipid organization. Stable micelle and end-to-end like oligomers were formed in zwitterionic and TLM models, respectively. In contrast, unstable oligomer formation and monomeric BMAP27 penetration were observed in anionic and LLM systems with selective anionic lipid aggregation (in LLM). Peptide penetration up to ~1.5 nm was observed in CG-MD systems with the BMAP27 C-terminal oriented towards the bilayer core. Structural inspection suggested membrane penetration by micelle/end-to-end like peptide oligomers (carpet-model like) in the zwitterionic/TLM systems, and transmembrane-mode (toroidal-pore like) in the anionic/LLM systems, respectively. Structural insights and energetic interpretation in BMAP27 mutant highlighted the role of F10 and hydrophobic residues in mediating a membrane-specific peptide interaction. Free energy profiling showed a favorable (-4.58 kcal mol-1 for LLM) and unfavorable (+0.17 kcal mol-1 for TLM) peptide insertion

  2. Suzuki-Trotter Formula for Real Time Dependent LDA II: Non-adiabatic MD

    NASA Astrophysics Data System (ADS)

    Miyamoto, Yoshiyuki; Sugino, Osamu

    1998-03-01

    In order to investigate ultrafast chemical reactions strongly coupled with electron dynamics, we must go beyond Born-Oppenheimer scheme. An ab-initio approach on this regime is quite challenging and applicable for many phenomena stimulated by electronic excitations. We have developed computational methods for a non-adiabatic molecular dynamics (MD) within the framework of the local density approximation (LDA) and pseudopotentials. The higher order Suziki-Trotter formula(M. Suzuki, J. Phys. Soc. Jpn. 61), L3015 (1992). for the time-evolution operator (e^fracihbarHΔ t) is found to be applicable even with use of separable non-local pseudopotentials(L. Kleinman, and D. M. Bylander, Phys. Rev. Lett. 48), 1425 (1982).. This formula enables us to perform numerically stable simulation for a long-time scale, during which orthonormality of wavefunctions is automatically conserved. At every time step, the Hellmann-Feynman force(J. Ihm, A. Zunger, and M. L. Cohen, J. Phys. C 12), 4409 (1979). on each atom is calculated to treat atomic motion within the classical Newton's equation. In this talk, a motion of an electronically excited K3 cluster is demonstrated as an example. During the simulation, sudden decrease of an expectation values of an excited electron is observed which can be attributed to non-radiative decay.

  3. 78 FR 52802 - Tin T. Win, M.D., Dismissal of Proceeding

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Drug Enforcement Administration Tin T. Win, M.D., Dismissal of Proceeding On February 27, 2013, I, the Administrator of the Drug Enforcement Administration, issued an Order to Show Cause and Immediate Suspension of Registration to Tin T. Win, M.D....

  4. 33 CFR 165.507 - Security Zone; Chesapeake Bay, between Sandy Point and Kent Island, MD.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., between Sandy Point and Kent Island, MD. 165.507 Section 165.507 Navigation and Navigable Waters COAST... Guard District § 165.507 Security Zone; Chesapeake Bay, between Sandy Point and Kent Island, MD. (a... to the eastern shore at Kent Island, Maryland. (c) Regulations. (1) All persons are required...

  5. 33 CFR 165.507 - Security Zone; Chesapeake Bay, between Sandy Point and Kent Island, MD.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., between Sandy Point and Kent Island, MD. 165.507 Section 165.507 Navigation and Navigable Waters COAST... Guard District § 165.507 Security Zone; Chesapeake Bay, between Sandy Point and Kent Island, MD. (a... to the eastern shore at Kent Island, Maryland. (c) Regulations. (1) All persons are required...

  6. 33 CFR 165.507 - Security Zone; Chesapeake Bay, between Sandy Point and Kent Island, MD.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., between Sandy Point and Kent Island, MD. 165.507 Section 165.507 Navigation and Navigable Waters COAST... Guard District § 165.507 Security Zone; Chesapeake Bay, between Sandy Point and Kent Island, MD. (a... to the eastern shore at Kent Island, Maryland. (c) Regulations. (1) All persons are required...

  7. Regulation of TLR4-associated MD-2 in intestinal epithelial cells: a comprehensive analysis

    PubMed Central

    Vamadevan, Arunan S.; Fukata, Masayuki; Arnold, Elizabeth T.; Thomas, Lisa S.; Hsu, David; Abreu, Maria T.

    2009-01-01

    The intestinal epithelium maintains a state of controlled inflammation despite continuous contact with Gram-negative commensal bacteria and lipopolysaccharide (LPS) on its luminal surface. Recognition of LPS by the TLR4/MD-2 complex results in proinflammatory gene expression and cytokine secretion in intestinal epithelial cells (IEC). We have shown that IEC express low levels of MD-2 and TLR4 and are poorly responsive to LPS. In this study, we did a comprehensive analysis to understand the immune-mediated and epigenetic mechanisms by which IEC down-regulate MD-2 expression. Expression of MD-2 and TLR4 mRNA was examined in human inflammatory bowel disease and intestinal epithelial cell lines (T84, HT-29, Caco-2). Nuclear factor-κB transcriptional activation was used as a measure of LPS responsiveness. Intestinal epithelial cellsin patients with IBD exhibited increased expression of MD-2 and TLR4 mRNA. Lipopolysaccharide responsiveness in IEC was polarized to the basolateral membrane. Bisulfite sequencing of the MD-2 promoter demonstrated methylation of CpG dinucleotides. Inhibition of methylation by 5-azacytidine and histone deactylation by trichostatin A, two forms of epigenetic silencing, resulted in increased mRNA expression of MD-2 in IEC. These results demonstrate various molecular mechanisms by which IEC down-regulate MD-2 and thereby protect against dysregulated inflammation to commensal bacteria in the intestinal lumen. PMID:19710105

  8. DNA methylation fluctuation induced by virus infection differs between MD-resistant and -susceptible chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marek’s disease (MD) is a lymphoproliferative disease induced by Marek’s disease virus (MDV). To augment vaccination, the host genetic resistance is of importance in MD control. While researchers have been largely focused on exploring the genetic differences between resistant and susceptible chicken...

  9. 78 FR 71660 - Zizhuang Li, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-29

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Drug Enforcement Administration Zizhuang Li, M.D.; Decision and Order On June 10, 2013, the Deputy Assistant Administrator, Office of Diversion Control, Drug Enforcement Administration, issued an Order to Show Cause to Zizhuang Li, M.D. (Applicant),...

  10. 78 FR 38363 - David A. Ruben, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Drug Enforcement Administration David A. Ruben, M.D.; Decision and Order On February 7, 2011, the Deputy Assistant Administrator, Office of Diversion Control, Drug Enforcement Administration, issued an Order to Show Cause to David A. Ruben, M.D....

  11. 33 CFR 110.71 - Jacobs Nose Cove, Elk River, Md.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Jacobs Nose Cove, Elk River, Md... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.71 Jacobs Nose Cove, Elk River, Md. The water area of Jacobs Nose Cove, on the west side of the mouth of Elk River, Maryland, comprising the...

  12. 76 FR 50950 - Drawbridge Operation Regulation; Isle of Wight (Sinepuxent) Bay, Ocean City, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-17

    ... Federal Register (73 FR 3316). Public Meeting We do not now plan to hold a public meeting. But you may... (Sinepuxent) Bay, Ocean City, MD AGENCY: Coast Guard, DHS. ACTION: Notice of proposed rulemaking. SUMMARY: The... of Wight (Sinepuxent) Bay, mile 0.5, at Ocean City, MD. The proposed change will alter the dates...

  13. 76 FR 70346 - Drawbridge Operation Regulation; Isle of Wight (Sinepuxent) Bay, Ocean City, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-14

    ... FR 50950). We have not received any comments on the proposed rule. No public meeting was requested... (Sinepuxent) Bay, Ocean City, MD AGENCY: Coast Guard, DHS. ACTION: Final rule. SUMMARY: The Coast Guard is..., mile 0.5, at Ocean City, MD. This rule will add dates that the bridge is allowed to remain in...

  14. Genome-wide histone modification profile induced by MDV in MD-resistant and -susceptible chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marek’s disease (MD) is a lymphoproliferative disease in chicken caused by oncogenic Marek’s disease virus (MDV). MD is characterized by infiltration of proliferating lymphoid cells in organs, such as peripheral nerve, skin, muscle, liver, spleen, heart, kidney, gonads and proventriculus. Epigenetic...

  15. 77 FR 29692 - Segun M. Rasaki, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-18

    ...'s action at which he may ultimately prevail.'' Kamal Tiwari, M.D., 76 FR 71604, 71606 (2011); see also Bourne Pharmacy, Inc., 72 FR 18273, 18274 (2007); Anne Lazar Thorn, 62 FR 12847 (1997...., 67 FR 35,582 (DEA 2002); Michael G. Dolin, M.D., 65 Fed. Reg. 5661 (DEA 2000); see also Philip...

  16. 75 FR 21528 - Airworthiness Directives; McDonnell Douglas Corporation Model MD-90-30 Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... Policies and Procedures (44 FR 11034, February 26, 1979), and 3. Will not have a significant economic... Douglas Corporation Model MD- 90-30 Airplanes AGENCY: Federal Aviation Administration (FAA), DOT. ACTION... certain Model MD-90-30 airplanes. This proposed AD would require inspecting for corrosion of the...

  17. 78 FR 67086 - Safety Zone, Submarine Cable Replacement Operations, Kent Island Narrows; Queen Anne's County, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-08

    ...The Coast Guard proposes to establish a temporary safety zone encompassing certain waters of Kent Island Narrows in Queen Anne's County, MD. This action is necessary to provide for the safety of mariners and their vessels on navigable waters during submarine cable replacement operations at the Kent Island Narrows (MD-18B) Bridge. This action is intended to restrict vessel traffic movement to......

  18. Registration of mutant population of MD 15 M4 Gossypium hirsutum L. with enhanced fiber quality

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutant population of MD 15 M4 (Reg. No. ,PI ) is a unique germplasm population of upland cotton (Gossypium hirsutum L.). This germplasm was developed by USDA-ARS, Stoneville, MS in 2008 and released in June, 2012. About 5000 seeds of a Mississippi Delta line, MD 15 were chemically mutagenized with 3...

  19. 33 CFR 110.71 - Jacobs Nose Cove, Elk River, Md.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Jacobs Nose Cove, Elk River, Md... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.71 Jacobs Nose Cove, Elk River, Md. The water area of Jacobs Nose Cove, on the west side of the mouth of Elk River, Maryland, comprising the...

  20. 33 CFR 110.71 - Jacobs Nose Cove, Elk River, Md.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Jacobs Nose Cove, Elk River, Md... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.71 Jacobs Nose Cove, Elk River, Md. The water area of Jacobs Nose Cove, on the west side of the mouth of Elk River, Maryland, comprising the...

  1. 33 CFR 110.71 - Jacobs Nose Cove, Elk River, Md.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Jacobs Nose Cove, Elk River, Md... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.71 Jacobs Nose Cove, Elk River, Md. The water area of Jacobs Nose Cove, on the west side of the mouth of Elk River, Maryland, comprising the...

  2. 33 CFR 110.71 - Jacobs Nose Cove, Elk River, Md.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Jacobs Nose Cove, Elk River, Md... ANCHORAGES ANCHORAGE REGULATIONS Special Anchorage Areas § 110.71 Jacobs Nose Cove, Elk River, Md. The water area of Jacobs Nose Cove, on the west side of the mouth of Elk River, Maryland, comprising the...

  3. 77 FR 57126 - Henri Wetselaar, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Drug Enforcement Administration Henri Wetselaar, M.D.; Decision and Order On September 27, 2011, I, the Administrator of the Drug Enforcement Administration, issued an Order to Show Cause and Immediate Suspension of Registration to Henri Wetselaar, M.D....

  4. 76 FR 29640 - Special Local Regulations for Marine Events; Chester River, Chestertown, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-23

    ... Regulations for Marine Events; Chester River, Chestertown, MD'' in the Federal Register (76 FR 54). We... SECURITY Coast Guard 33 CFR Part 100 RIN 1625-AA08 Special Local Regulations for Marine Events; Chester... Party Festival,'' a marine event to be held on the waters of the Chester River, Chestertown, MD on...

  5. 75 FR 21167 - Special Local Regulations for Marine Events; Chester River, Chestertown, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-23

    ... Regulations for Marine Events; Chester River, Chestertown, MD'' in the Federal Register (75 FR 043). We... SECURITY Coast Guard 33 CFR Part 165 RIN 1625-AA08 Special Local Regulations for Marine Events; Chester... Party Festival'', a marine event to be held on the waters of the Chester River, Chestertown, MD on...

  6. 75 FR 57388 - Special Local Regulations for Marine Events; Patuxent River, Solomons, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-21

    ... Marine Events; Patuxent River, Solomons, MD'' in the Federal Register (75 FR 32866). Additionally, on... Local Regulations for Marine Events; Patuxent River, Solomons, MD'' in the Federal Register (75 FR 41789... SECURITY Coast Guard 33 CFR Part 100 RIN 1625-AA08 Special Local Regulations for Marine Events;...

  7. 77 FR 73677 - Stephanie A. Tarapchak, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-11

    ... (quoting Calvin Ramsey, M.D., 76 FR 20034, 20036 (2011)). See also Kamal Tiwari, M.D., 76 FR 71604, 71606... . . . dispensing of controlled substances.'' See, e.g., Richard H. Ng, 77 FR 29694 (2012); Segun M. Rasaki, 77 FR 29692 (2012); David W. Wang, 72 FR 54297 (2007). Rather, DEA's rule derives primarily from two...

  8. 76 FR 17673 - Bienvenido Tan, M.D.; Denial of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-30

    ... Enforcement Administration Bienvenido Tan, M.D.; Denial of Application On October 31, 2008, the Deputy... Show Cause to Bienvenido Tan, M.D. (Respondent), of Newhall, California. The Show Cause Order proposed..., contains manufacturers' recommendations as to the dosing of drug products. RX D, at 3. On January 28,...

  9. 76 FR 51424 - Satinder Dang, M.D.; Revocation of Registration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-18

    ... Respondent's registration.'' Id. (citing Harrell E. Robinson, M.D., 74 FR 61370, 61376-77 (2010)). The ALJ... Jeri Hassman, M.D., 75 FR 8194, 8227 (2010); Gonzales v. Oregon, 546 U.S. 243, 274 (2006)). Noting that... continuation of a registration is consistent with the public interest.'' Id. (citing Patrick W. Stodola, 74...

  10. 75 FR 66138 - George Mathew, M.D.; Denial of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-27

    ... Purchasing Controlled Substances over the Internet, 66 FR 21181. Therein, the Agency explained that ``Federal... Enforcement Administration George Mathew, M.D.; Denial of Application On September 19, 2005, I, the Deputy... Registration to George Mathew, M.D. (Respondent), of Seattle, Washington. The Order proposed the revocation...

  11. 78 FR 52787 - Kevin Dennis, M.D., Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF JUSTICE Drug Enforcement Administration Kevin Dennis, M.D., Decision and Order On April 12, 2011, the Deputy Assistant Administrator, Office of Diversion Control, issued an Order to Show Cause to Kevin Dennis, M.D....

  12. 77 FR 67673 - Fernando Valle, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-13

    ...); Sheran Arden Yeates, 71 FR 39130, 39131 (2006); Dominick A. Ricci, M.D., 58 FR 51104 (1993); Bobby Watts, M.D., 53 FR 11919 (1988). Notwithstanding the foregoing, the Respondent contends that the Emergency..., 20347 (2009); see also Scott Sandarg, D.M.D., 74 FR 17528, 174529 (2009); John B. Freitas, D.O., 74...

  13. 76 FR 75448 - Establishment of Class D and E Airspace; Frederick, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-02

    ... Class D and E airspace at Frederick, MD, to accommodate new Area Navigation (RNAV) Global Positioning... and E airspace for the new Frederick Municipal Airport, Frederick, MD (76 FR 50156) Docket No. FAA... Executive Order 12866; (2) is not a ``significant rule'' under DOT Regulatory Policies and Procedures (44...

  14. 76 FR 53942 - Richard A. Herbert, M.D.; Decision and Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-30

    ... deliberate ignorance as to the likelihood the drugs were being diverted. See Jeri Hassman, M.D., 75 FR 8194... [a registration] would be in the public interest.'' Mortimer B. Levin, D.O., 55 FR 8209, 8210 (1990..., M.D., 75 FR 66138, 66146 (2010) (under Federal law, where a physician issues a prescription...

  15. 78 FR 38001 - Special Local Regulations; Marine Events, Breton Bay; St. Mary's County, Leonardtown, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-25

    ...; St. Mary's County, Leonardtown, MD'' in the Federal Register (78 FR 21864). The rulemaking concerned... Breton Bay, in St. Mary's County, MD, effective from 8 a.m. on July 13, 2013 to 5 p.m. on July 14, 2013... SECURITY Coast Guard 33 CFR Part 100 RIN 1625-AA08 Special Local Regulations; Marine Events, Breton Bay;...

  16. 75 FR 27430 - Special Local Regulations for Marine Events; Patapsco River, Northwest Harbor, Baltimore, MD

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-17

    ...; Patapsco River, Northwest Harbor, Baltimore, MD'' in the Federal Register (75 FR 16374). We received no... River, Northwest Harbor, Baltimore, MD AGENCY: Coast Guard, DHS. ACTION: Temporary final rule. SUMMARY: The Coast Guard is establishing special local regulations during the ``Baltimore Dragon Boat...

  17. 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. PMID:27001155

  18. Breast reconstruction at the MD Anderson Cancer Center.

    PubMed

    Yu, Peirong

    2016-08-01

    The introduction of the transverse rectus abdominis myocutaneous flap in the 1970s marks the beginning of modern breast reconstruction although implants were available even earlier mainly for breast augmentation. Mastectomy techniques have evolved from the early Halsted radical mastectomy to the modern skin sparing mastectomy. The latter made possible using implants for breast reconstruction. Although prosthetic reconstruction provides a simpler procedure with quick recovery, autologous reconstruction offers more natural and long-lasting results especially in the setting of radiotherapy. Both forms have been extensively used at the MD Anderson Cancer Center (MDACC) while microsurgical breast reconstruction has been the hallmark of the MDACC experience. One of the most challenging areas of breast reconstruction is how to achieve good results without compromising adjuvant therapy when post-mastectomy radiotherapy is required. Managing upper extremity lymphedema following breast cancer treatment is another difficult issue which has gained great attention in recent years. This article highlights the important work in various aspects of breast reconstruction that has been done at the MDACC. PMID:27563563

  19. The value circle. A profile of J. Richard Gaintner, MD.

    PubMed

    Howard, R

    1999-01-01

    This article describes how the arrival of CEO J. Richard Gaintner, MD, at Shands HealthCare signaled a time for refocusing the organization's direction and helping physicians to cope with the changes buffeting the industry. He saw angst and disenfranchisement, sentiments that characterized not only Shands and the University of Florida Health Science Center, but also the entire establishment of American scientific medicine. Gaintner believes--and continually preaches--that practicing medicine in a cost-effective manner will improve, not harm, the quality of care. His willingness to face reality objectively is perhaps his greatest asset in helping physicians deal with managed care. He conveys heartfelt empathy with the day-to-day conflicts they face. But he does not allow himself the temporary luxury of cynicism, and he refuses to accept negativity and pessimism in others. Rather, he asks that physicians and managers understand the system and develop the capacity to work within it and take responsibility for improving it. Beyond exhorting physicians to be accountable for the success of the enterprise, Gaintner creates mechanisms for meaningful physician participation in enterprise management. PMID:10351728

  20. John Call Dalton, Jr., MD: America's first neurophysiologist.

    PubMed

    Fine, E J; Manteghi, T; Sobel, S H; Lohr, L A

    2000-09-26

    Before the discoveries of John Call Dalton, Jr., MD (1824-1889), innervation of laryngeal muscles, long-term effects of cerebellar lesions, and consequences of raised intracranial pressure were poorly understood. Dalton discovered that the posterior cricoarytenoid muscles adducted the vocal cords during inspiration. He confirmed Flourens' observations that acute ablation of the cerebellum of pigeons caused loss of coordination. Dalton observed that properly cared for pigeons gradually recovered "coordinating power." Dalton observed that prolonged raised intracranial pressure caused tachycardia and then fatal bradycardia in dogs. Before Dalton published his photographic atlas of the human brain, neuroanatomy atlases were sketched by Europeans and imported into the United States. Dalton's atlas of the human brain contained precise photographs of vertical and horizontal sections that equal modern works. Before Dalton introduced live demonstrations of animals, physiology was taught by recitation of texts only. Dalton was the first American-born professor to teach physiology employing demonstrations of live animals operated on under ether anesthesia. He wrote an essay advocating experimentation on animals as the proper method of acquiring knowledge of function and that humane animal experimentation would ultimately improve the health of man and animals. His eloquent advocacy for humane experimental physiology quelled attacks by contemporaneous antivivisectionists. Dalton was America's first experimental neurophysiologist. PMID:10994009