Convergence and Sampling in Determining Free Energy Landscapes for Membrane Protein Association

PubMed Central

2016-01-01

Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein–lipid and protein–protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable to describe the binding and unbinding transitions, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein–lipid binding PMFs for ANT/cardiolipin and Kir2.2/PIP2, using umbrella sampling on a distance coordinate. These highlight the importance of replica exchange between windows for convergence. The use of two independent sets of simulations, initiated from bound and unbound states, provide strong evidence for simulation convergence. For a model protein–protein interaction within a membrane, center-of-mass distance is shown to be a poor collective variable for describing transmembrane helix–helix dimerization. Instead, we employ an alternative intermolecular distance matrix RMS (DRMS) coordinate to obtain converged PMFs for the association of the glycophorin transmembrane domain. While the coarse-grained force field gives a reasonable Kd for dimerization, the majority of the bound population is revealed to be in a near-native conformation. Thus, the combination of a refined reaction coordinate with improved sampling reveals previously unnoticed complexities of the dimerization free energy landscape. We propose the use of replica-exchange umbrella sampling starting from different initial conditions as a robust approach for calculation of the binding energies in membrane simulations. PMID:27807980

Convergence and Sampling in Determining Free Energy Landscapes for Membrane Protein Association.

PubMed

Domański, Jan; Hedger, George; Best, Robert B; Stansfeld, Phillip J; Sansom, Mark S P

2017-04-20

Potential of mean force (PMF) calculations are used to characterize the free energy landscape of protein-lipid and protein-protein association within membranes. Coarse-grained simulations allow binding free energies to be determined with reasonable statistical error. This accuracy relies on defining a good collective variable to describe the binding and unbinding transitions, and upon criteria for assessing the convergence of the simulation toward representative equilibrium sampling. As examples, we calculate protein-lipid binding PMFs for ANT/cardiolipin and Kir2.2/PIP 2 , using umbrella sampling on a distance coordinate. These highlight the importance of replica exchange between windows for convergence. The use of two independent sets of simulations, initiated from bound and unbound states, provide strong evidence for simulation convergence. For a model protein-protein interaction within a membrane, center-of-mass distance is shown to be a poor collective variable for describing transmembrane helix-helix dimerization. Instead, we employ an alternative intermolecular distance matrix RMS (D RMS ) coordinate to obtain converged PMFs for the association of the glycophorin transmembrane domain. While the coarse-grained force field gives a reasonable K d for dimerization, the majority of the bound population is revealed to be in a near-native conformation. Thus, the combination of a refined reaction coordinate with improved sampling reveals previously unnoticed complexities of the dimerization free energy landscape. We propose the use of replica-exchange umbrella sampling starting from different initial conditions as a robust approach for calculation of the binding energies in membrane simulations.

A Simple and Accurate Method To Calculate Free Energy Profiles and Reaction Rates from Restrained Molecular Simulations of Diffusive Processes.

PubMed

Ovchinnikov, Victor; Nam, Kwangho; Karplus, Martin

2016-08-25

A method is developed to obtain simultaneously free energy profiles and diffusion constants from restrained molecular simulations in diffusive systems. The method is based on low-order expansions of the free energy and diffusivity as functions of the reaction coordinate. These expansions lead to simple analytical relationships between simulation statistics and model parameters. The method is tested on 1D and 2D model systems; its accuracy is found to be comparable to or better than that of the existing alternatives, which are briefly discussed. An important aspect of the method is that the free energy is constructed by integrating its derivatives, which can be computed without need for overlapping sampling windows. The implementation of the method in any molecular simulation program that supports external umbrella potentials (e.g., CHARMM) requires modification of only a few lines of code. As a demonstration of its applicability to realistic biomolecular systems, the method is applied to model the α-helix ↔ β-sheet transition in a 16-residue peptide in implicit solvent, with the reaction coordinate provided by the string method. Possible modifications of the method are briefly discussed; they include generalization to multidimensional reaction coordinates [in the spirit of the model of Ermak and McCammon (Ermak, D. L.; McCammon, J. A. J. Chem. Phys. 1978, 69, 1352-1360)], a higher-order expansion of the free energy surface, applicability in nonequilibrium systems, and a simple test for Markovianity. In view of the small overhead of the method relative to standard umbrella sampling, we suggest its routine application in the cases where umbrella potential simulations are appropriate.

Puckering free energy of pyranoses: A NMR and metadynamics-umbrella sampling investigation

NASA Astrophysics Data System (ADS)

Autieri, E.; Sega, M.; Pederiva, F.; Guella, G.

2010-09-01

We present the results of a combined metadynamics-umbrella sampling investigation of the puckered conformers of pyranoses described using the GROMOS 45a4 force field. The free energy landscape of Cremer-Pople puckering coordinates has been calculated for the whole series of α and β aldohexoses, showing that the current force field parameters fail in reproducing proper puckering free energy differences between chair conformers. We suggest a modification to the GROMOS 45a4 parameter set which improves considerably the agreement of simulation results with theoretical and experimental estimates of puckering free energies. We also report on the experimental measurement of altrose conformer populations by means of NMR spectroscopy, which show good agreement with the predictions of current theoretical models.

Computational analysis for selectivity of histone deacetylase inhibitor by replica-exchange umbrella sampling molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Tsukamoto, Shuichiro; Sakae, Yoshitake; Itoh, Yukihiro; Suzuki, Takayoshi; Okamoto, Yuko

2018-03-01

We performed protein-ligand docking simulations with a ligand T247, which has been reported as a selective inhibitor of a histone deacetylase HDAC3, by the replica-exchange umbrella sampling method in order to estimate the free energy profiles along ligand docking pathways of HDAC3-T247 and HDAC2-T247 systems. The simulation results showed that the docked state of the HDAC3-T247 system is more stable than that of the HDAC2-T247 system although the amino-acid sequences and structures of HDAC3 and HDAC2 are very similar. By comparing structures obtained from the simulations of both systems, we found the difference between structures of hydrophobic residues at the entrance of the catalytic site. Moreover, we performed conventional molecular dynamics simulations of HDAC3 and HDAC2 systems without T247, and the results also showed the same difference of the hydrophobic structures. Therefore, we consider that this hydrophobic structure contributes to the stabilization of the docked state of the HDAC3-T247 system. Furthermore, we show that Tyr209, which is one of the hydrophobic residues in HDAC2, plays a key role in the instability from the simulation results of a mutated-HDAC2 system.

Enhanced and effective conformational sampling of protein molecular systems for their free energy landscapes.

PubMed

Higo, Junichi; Ikebe, Jinzen; Kamiya, Narutoshi; Nakamura, Haruki

2012-03-01

Protein folding and protein-ligand docking have long persisted as important subjects in biophysics. Using multicanonical molecular dynamics (McMD) simulations with realistic expressions, i.e., all-atom protein models and an explicit solvent, free-energy landscapes have been computed for several systems, such as the folding of peptides/proteins composed of a few amino acids up to nearly 60 amino-acid residues, protein-ligand interactions, and coupled folding and binding of intrinsically disordered proteins. Recent progress in conformational sampling and its applications to biophysical systems are reviewed in this report, including descriptions of several outstanding studies. In addition, an algorithm and detailed procedures used for multicanonical sampling are presented along with the methodology of adaptive umbrella sampling. Both methods control the simulation so that low-probability regions along a reaction coordinate are sampled frequently. The reaction coordinate is the potential energy for multicanonical sampling and is a structural identifier for adaptive umbrella sampling. One might imagine that this probability control invariably enhances conformational transitions among distinct stable states, but this study examines the enhanced conformational sampling of a simple system and shows that reasonably well-controlled sampling slows the transitions. This slowing is induced by a rapid change of entropy along the reaction coordinate. We then provide a recipe to speed up the sampling by loosening the rapid change of entropy. Finally, we report all-atom McMD simulation results of various biophysical systems in an explicit solvent.

Mechanistic insights into Pin1 peptidyl-prolyl cis-trans isomerization from umbrella sampling simulations.

PubMed

Di Martino, Giovanni Paolo; Masetti, Matteo; Cavalli, Andrea; Recanatini, Maurizio

2014-11-01

The peptidyl-proyl isomerase Pin1 plays a key role in the regulation of phospho(p)-Ser/Thr-Pro proteins, acting as a molecular timer of the cell cycle. After recognition of these motifs, Pin1 catalyzes the rapid cis-trans isomerization of proline amide bonds of substrates, contributing to maintain the equilibrium between the two conformations. Although a great interest has arisen on this enzyme, its catalytic mechanism has long been debated. Here, the cis-trans isomerization of a model peptide system was investigated by means of umbrella sampling simulations in the Pin1-bound and unbound states. We obtained free energy barriers consistent with experimental data, and identified several enzymatic features directly linked to the acceleration of the prolyl bond isomerization. In particular, an enhanced autocatalysis, the stabilization of perturbed ground state conformations, and the substrate binding in a procatalytic conformation were found as main contributions to explain the lowering of the isomerization free energy barrier. © 2014 Wiley Periodicals, Inc.

Quantifying Density Fluctuations in Volumes of All Shapes and Sizes Using Indirect Umbrella Sampling

NASA Astrophysics Data System (ADS)

Patel, Amish J.; Varilly, Patrick; Chandler, David; Garde, Shekhar

2011-10-01

Water density fluctuations are an important statistical mechanical observable and are related to many-body correlations, as well as hydrophobic hydration and interactions. Local water density fluctuations at a solid-water surface have also been proposed as a measure of its hydrophobicity. These fluctuations can be quantified by calculating the probability, P v ( N), of observing N waters in a probe volume of interest v. When v is large, calculating P v ( N) using molecular dynamics simulations is challenging, as the probability of observing very few waters is exponentially small, and the standard procedure for overcoming this problem (umbrella sampling in N) leads to undesirable impulsive forces. Patel et al. (J. Phys. Chem. B 114:1632, 2010) have recently developed an indirect umbrella sampling (INDUS) method, that samples a coarse-grained particle number to obtain P v ( N) in cuboidal volumes. Here, we present and demonstrate an extension of that approach to volumes of other basic shapes, like spheres and cylinders, as well as to collections of such volumes. We further describe the implementation of INDUS in the NPT ensemble and calculate P v ( N) distributions over a broad range of pressures. Our method may be of particular interest in characterizing the hydrophobicity of interfaces of proteins, nanotubes and related systems.

Numerical simulation of flow field in umbrella wind turbine

NASA Astrophysics Data System (ADS)

Daorina, Bao; Xiaoxue, Wang; Wei, Shang; Yadong, Liu; Daorina, Bao; Xiaoxue, Wang; Wei, Shang; Yadong, Liu

2018-05-01

Umbrella wind turbine can control the swept area by adjusting the shrinking angle of the rotor so as to ensure that output power is near the rated value. This is very helpful for the utilization of wind energy in sandstorms and typhoon-prone areas of our country. In this paper, Fluent software is used to simulate the velocity field and pressure field of 5kW Umbrella Wind Turbine at 0° 45°and 60°angle of contraction. The results provide a theoretical basis for further improving the power adjustment mechanism of Umbrella Wind Turbines, At the same time, it also provide a reference for our country to perfect the wind energy utilization system about the typhoon environment in the coastal areas.

Free Energies of Quantum Particles: The Coupled-Perturbed Quantum Umbrella Sampling Method.

PubMed

Glover, William J; Casey, Jennifer R; Schwartz, Benjamin J

2014-10-14

We introduce a new simulation method called Coupled-Perturbed Quantum Umbrella Sampling that extends the classical umbrella sampling approach to reaction coordinates involving quantum mechanical degrees of freedom. The central idea in our method is to solve coupled-perturbed equations to find the response of the quantum system's wave function along a reaction coordinate of interest. This allows for propagation of the system's dynamics under the influence of a quantum biasing umbrella potential and provides a method to rigorously undo the effects of the bias to compute equilibrium ensemble averages. In this way, one can drag electrons into regions of high free energy where they would otherwise not go, thus enabling chemistry by fiat. We demonstrate the applicability of our method for two condensed-phase systems of interest. First, we consider the interaction of a hydrated electron with an aqueous sodium cation, and we calculate a potential of mean force that shows that an e(-):Na(+) contact pair is the thermodynamically favored product starting from either a neutral sodium atom or the separate cation and electron species. Second, we present the first determination of a hydrated electron's free-energy profile relative to an air/water interface. For the particular model parameters used, we find that the hydrated electron is more thermodynamically stable in the bulk rather than at the interface. Our analysis suggests that the primary driving force keeping the electron away from the interface is the long-range electron-solvent polarization interaction rather than the short-range details of the chosen pseudopotential.

Mechanism and Energetics of Charybdotoxin Unbinding from a Potassium Channel from Molecular Dynamics Simulations

PubMed Central

Chen, Po-chia; Kuyucak, Serdar

2009-01-01

Ion channel-toxin complexes are ideal systems for computational studies of protein-ligand interactions, because, in most cases, the channel axis provides a natural reaction coordinate for unbinding of a ligand and a wealth of physiological data is available to check the computational results. We use a recently determined structure of a potassium channel-charybdotoxin complex in molecular dynamics simulations to investigate the mechanism and energetics of unbinding. Pairs of residues on the channel protein and charybdotoxin that are involved in the binding are identified, and their behavior is traced during umbrella-sampling simulations as charybdotoxin is moved away from the binding site. The potential of mean force for the unbinding of charybdotoxin is constructed from the umbrella sampling simulations using the weighted histogram analysis method, and barriers observed are correlated with specific breaking of interactions and influx of water molecules into the binding site. Charybdotoxin is found to undergo conformational changes as a result of the reaction coordinate choice—a nontrivial decision for larger ligands—which we explore in detail, and for which we propose solutions. Agreement between the calculated and the experimental binding energies is obtained once the energetic consequences of these conformational changes are included in the calculations. PMID:19348743

Convergence of Free Energy Profile of Coumarin in Lipid Bilayer

PubMed Central

2012-01-01

Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (∼7 μs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z-constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from “pulling” coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives. PMID:22545027

Convergence of Free Energy Profile of Coumarin in Lipid Bilayer.

PubMed

Paloncýová, Markéta; Berka, Karel; Otyepka, Michal

2012-04-10

Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (∼7 μs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z-constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from "pulling" coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives.

Finite Element Simulation of NiTi Umbrella-Shaped Implant Used on Femoral Head under Different Loadings.

PubMed

Mehrabi, Reza; Dorri, Milad; Elahinia, Mohammad

2017-03-12

In this study, an umbrella-shaped device that is used for osteonecrosis treatment is simulated. The femoral head is subjected to various complex loadings as a result of a person's daily movements. Implant devices used in the body are made of shape memory alloy materials because of their remarkable resistance to wear and corrosion, good biocompatibility, and variable mechanical properties. Since this NiTi umbrella-shaped implant is simultaneously under several loadings, a 3-D model of shape memory alloy is utilized to investigate the behavior of the implant under different conditions. Shape memory and pseudo-elasticity behavior of NiTi is analyzed using a numerical model. The simulation is performed within different temperatures and in an isothermal condition with varied and complex loadings. The objective of this study is to evaluate the performance of the device under thermal and multi-axial forces via numerically study. Under tensile loading, the most critical points are on the top part of the implant. It is also shown that changes in temperature have a minor effect on the Von Mises stress. Applied forces and torques have significant influence on the femoral head. Simulations results indicate that the top portion of the umbrella is under the most stress when embedded in the body. Consequently, the middle, curved portion of the umbrella is under the least amount of stress.

Finite Element Simulation of NiTi Umbrella-Shaped Implant Used on Femoral Head under Different Loadings

PubMed Central

Mehrabi, Reza; Dorri, Milad; Elahinia, Mohammad

2017-01-01

In this study, an umbrella-shaped device that is used for osteonecrosis treatment is simulated. The femoral head is subjected to various complex loadings as a result of a person’s daily movements. Implant devices used in the body are made of shape memory alloy materials because of their remarkable resistance to wear and corrosion, good biocompatibility, and variable mechanical properties. Since this NiTi umbrella-shaped implant is simultaneously under several loadings, a 3-D model of shape memory alloy is utilized to investigate the behavior of the implant under different conditions. Shape memory and pseudo-elasticity behavior of NiTi is analyzed using a numerical model. The simulation is performed within different temperatures and in an isothermal condition with varied and complex loadings. The objective of this study is to evaluate the performance of the device under thermal and multi-axial forces via numerically study. Under tensile loading, the most critical points are on the top part of the implant. It is also shown that changes in temperature have a minor effect on the Von Mises stress. Applied forces and torques have significant influence on the femoral head. Simulations results indicate that the top portion of the umbrella is under the most stress when embedded in the body. Consequently, the middle, curved portion of the umbrella is under the least amount of stress. PMID:28952502

Pickett angles and Cremer-Pople coordinates as collective variables for the enhanced sampling of six-membered ring conformations

NASA Astrophysics Data System (ADS)

Sega, M.; Autieri, E.; Pederiva, F.

2011-01-01

Although completely equivalent for the description of puckered ring conformers, the two popular coordinates sets of Strauss-Pickett dihedral angles and Cremer-Pople spherical coordinates are shown to have contrasting features when employed as collective variables in free-energy calculations with accelerated sampling techniques. Results from a 100 ns molecular dynamics simulation at conformational equilibrium and from combined metadynamics/umbrella sampling calculations of glucose are exploited to elucidate these differences.

Self-Learning Adaptive Umbrella Sampling Method for the Determination of Free Energy Landscapes in Multiple Dimensions

PubMed Central

Wojtas-Niziurski, Wojciech; Meng, Yilin; Roux, Benoit; Bernèche, Simon

2013-01-01

The potential of mean force describing conformational changes of biomolecules is a central quantity that determines the function of biomolecular systems. Calculating an energy landscape of a process that depends on three or more reaction coordinates might require a lot of computational power, making some of multidimensional calculations practically impossible. Here, we present an efficient automatized umbrella sampling strategy for calculating multidimensional potential of mean force. The method progressively learns by itself, through a feedback mechanism, which regions of a multidimensional space are worth exploring and automatically generates a set of umbrella sampling windows that is adapted to the system. The self-learning adaptive umbrella sampling method is first explained with illustrative examples based on simplified reduced model systems, and then applied to two non-trivial situations: the conformational equilibrium of the pentapeptide Met-enkephalin in solution and ion permeation in the KcsA potassium channel. With this method, it is demonstrated that a significant smaller number of umbrella windows needs to be employed to characterize the free energy landscape over the most relevant regions without any loss in accuracy. PMID:23814508

Enhanced sampling simulations of DNA step parameters.

PubMed

Karolak, Aleksandra; van der Vaart, Arjan

2014-12-15

A novel approach for the selection of step parameters as reaction coordinates in enhanced sampling simulations of DNA is presented. The method uses three atoms per base and does not require coordinate overlays or idealized base pairs. This allowed for a highly efficient implementation of the calculation of all step parameters and their Cartesian derivatives in molecular dynamics simulations. Good correlation between the calculated and actual twist, roll, tilt, shift, and slide parameters is obtained, while the correlation with rise is modest. The method is illustrated by its application to the methylated and unmethylated 5'-CATGTGACGTCACATG-3' double stranded DNA sequence. One-dimensional umbrella simulations indicate that the flexibility of the central CG step is only marginally affected by methylation. © 2014 Wiley Periodicals, Inc.

Efficient Construction of Free Energy Profiles of Breathing Metal–Organic Frameworks Using Advanced Molecular Dynamics Simulations

PubMed Central

2017-01-01

In order to reliably predict and understand the breathing behavior of highly flexible metal–organic frameworks from thermodynamic considerations, an accurate estimation of the free energy difference between their different metastable states is a prerequisite. Herein, a variety of free energy estimation methods are thoroughly tested for their ability to construct the free energy profile as a function of the unit cell volume of MIL-53(Al). The methods comprise free energy perturbation, thermodynamic integration, umbrella sampling, metadynamics, and variationally enhanced sampling. A series of molecular dynamics simulations have been performed in the frame of each of the five methods to describe structural transformations in flexible materials with the volume as the collective variable, which offers a unique opportunity to assess their computational efficiency. Subsequently, the most efficient method, umbrella sampling, is used to construct an accurate free energy profile at different temperatures for MIL-53(Al) from first principles at the PBE+D3(BJ) level of theory. This study yields insight into the importance of the different aspects such as entropy contributions and anharmonic contributions on the resulting free energy profile. As such, this thorough study provides unparalleled insight in the thermodynamics of the large structural deformations of flexible materials. PMID:29131647

Efficient Construction of Free Energy Profiles of Breathing Metal-Organic Frameworks Using Advanced Molecular Dynamics Simulations.

PubMed

Demuynck, Ruben; Rogge, Sven M J; Vanduyfhuys, Louis; Wieme, Jelle; Waroquier, Michel; Van Speybroeck, Veronique

2017-12-12

In order to reliably predict and understand the breathing behavior of highly flexible metal-organic frameworks from thermodynamic considerations, an accurate estimation of the free energy difference between their different metastable states is a prerequisite. Herein, a variety of free energy estimation methods are thoroughly tested for their ability to construct the free energy profile as a function of the unit cell volume of MIL-53(Al). The methods comprise free energy perturbation, thermodynamic integration, umbrella sampling, metadynamics, and variationally enhanced sampling. A series of molecular dynamics simulations have been performed in the frame of each of the five methods to describe structural transformations in flexible materials with the volume as the collective variable, which offers a unique opportunity to assess their computational efficiency. Subsequently, the most efficient method, umbrella sampling, is used to construct an accurate free energy profile at different temperatures for MIL-53(Al) from first principles at the PBE+D3(BJ) level of theory. This study yields insight into the importance of the different aspects such as entropy contributions and anharmonic contributions on the resulting free energy profile. As such, this thorough study provides unparalleled insight in the thermodynamics of the large structural deformations of flexible materials.

How maltose influences structural changes to bind to maltose-binding protein: results from umbrella sampling simulation.

PubMed

Mascarenhas, Nahren Manuel; Kästner, Johannes

2013-02-01

A well-studied periplasmic-binding protein involved in the abstraction of maltose is maltose-binding protein (MBP), which undergoes a ligand-induced conformational transition from an open (ligand-free) to a closed (ligand-bound) state. Umbrella sampling simulations have been us to estimate the free energy of binding of maltose to MBP and to trace the potential of mean force of the unbinding event using the center-of-mass distance between the protein and ligand as the reaction coordinate. The free energy thus obtained compares nicely with the experimentally measured value justifying our theoretical basis. Measurement of the domain angle (N-terminal-domain - hinge - C-terminal-domain) along the unbinding pathway established the existence of three different states. Starting from a closed state, the protein shifts to an open conformation during the initial unbinding event of the ligand then resides in a semi-open conformation and later resides predominantly in an open-state. These transitions along the ligand unbinding pathway have been captured in greater depth using principal component analysis. It is proposed that in mixed-model, both conformational selection and an induced-fit mechanism combine to the ligand recognition process in MBP. Copyright © 2012 Wiley Periodicals, Inc.

Of mice and men: Dissecting the interaction between Listeria monocytogenes Internalin A and E-cadherin

PubMed Central

Genheden, Samuel; Eriksson, Leif A

2013-01-01

We report a study of the interaction between internalin A (inlA) and human or murine E-cadherin (Ecad). inlA is used by Listeria monocytogenes to internalize itself into host cell, but the bacterium is unable to invade murine cells, which has been attributed to the difference in sequence between hEcad and mEcad. Using molecular dynamics simulations, MM/GBSA free energy calculations, hydrogen bond analysis, water characterization and umbrella sampling, we provide a complete atomistic picture of the binding between inlA and Ecad. We dissect key residues in the protein–protein interface and analyze the energetics using MM/GBSA. From this analysis it is clear that the binding of inlA–mEcad is weaker than inlA–hEcad, on par with the experimentally observed inability of inlA to bind to mEcad. However, extended MD simulations of 200 ns in length show no destabilization of the inlA–mEcad complex and the estimation of the potential of mean force (PMF) using umbrella sampling corroborates this conclusion. The binding strength computed from the PMFs show no significant difference between the two protein complexes. Hence, our study suggests that the inability of L. monocytogenes to invade murine cells cannot be explained by processes at the nanosecond to sub-microsecond time scale probed by the simulations performed here. PMID:24688730

Of mice and men: Dissecting the interaction between Listeria monocytogenes Internalin A and E-cadherin.

PubMed

Genheden, Samuel; Eriksson, Leif A

2013-01-01

We report a study of the interaction between internalin A (inlA) and human or murine E-cadherin (Ecad). inlA is used by Listeria monocytogenes to internalize itself into host cell, but the bacterium is unable to invade murine cells, which has been attributed to the difference in sequence between hEcad and mEcad. Using molecular dynamics simulations, MM/GBSA free energy calculations, hydrogen bond analysis, water characterization and umbrella sampling, we provide a complete atomistic picture of the binding between inlA and Ecad. We dissect key residues in the protein-protein interface and analyze the energetics using MM/GBSA. From this analysis it is clear that the binding of inlA-mEcad is weaker than inlA-hEcad, on par with the experimentally observed inability of inlA to bind to mEcad. However, extended MD simulations of 200 ns in length show no destabilization of the inlA-mEcad complex and the estimation of the potential of mean force (PMF) using umbrella sampling corroborates this conclusion. The binding strength computed from the PMFs show no significant difference between the two protein complexes. Hence, our study suggests that the inability of L. monocytogenes to invade murine cells cannot be explained by processes at the nanosecond to sub-microsecond time scale probed by the simulations performed here.

Chloride Ion Transport by the E. coli CLC Cl-/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study.

PubMed

Wang, Chun-Hung; Duster, Adam W; Aydintug, Baris O; Zarecki, MacKenzie G; Lin, Hai

2018-01-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl - ion migration through the transmembrane domain of a prototypical E. coli CLC Cl - /H + antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl - . Moving the anion into the external binding site (S ext ) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl - traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl - exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl - along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl - changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl - and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl - ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl - transport.

Chloride Ion Transport by the E. coli CLC Cl−/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study

PubMed Central

Wang, Chun-Hung; Duster, Adam W.; Aydintug, Baris O.; Zarecki, MacKenzie G.; Lin, Hai

2018-01-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl− ion migration through the transmembrane domain of a prototypical E. coli CLC Cl−/H+ antiporter by employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found to be critical for full access of the channel entrance by Cl−. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl− traveled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl− exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl− along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing π bonds (e.g., the Tyr445 side chain), while the charges of the H atoms coordinating Cl− changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers (~10 kcal/mol) than the MM PMF (~2 kcal/mol). Binding energy calculations indicated that the interactions between Cl− and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing π bonds, missing the stabilizations of the Cl− ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl− transport. PMID:29594103

Chloride Ion Transport by the E. coli CLC Cl–/H+ Antiporter: A Combined Quantum-Mechanical and Molecular-Mechanical Study

NASA Astrophysics Data System (ADS)

Wang, Chun-Hung; Duster, Adam W.; Aydintug, Baris O.; Zarecki, MacKenzie G.; Lin, Hai

2018-03-01

We performed steered molecular dynamics (SMD) and umbrella sampling simulations of Cl– ion migration through the transmembrane domain of a prototypical E. coli CLC Cl–/H+ antiporter employing combined quantum-mechanical (QM) and molecular-mechanical (MM) calculations. The SMD simulations revealed interesting conformational changes of the protein. While no large-amplitude motions of the protein were observed during pore opening, the side chain rotation of the protonated external gating residue Glu148 was found critical to full access of the channel entrance by Cl–. Moving the anion into the external binding site (Sext) induced small-amplitude shifting of the protein backbone at the N-terminal end of helix F. As Cl– travelled through the pore, rigid-body swinging motions of helix R separated it from helix D. Helix R returned to its original position once Cl– exited the channel. Population analysis based on polarized wavefunction from QM/MM calculations discovered significant (up to 20%) charge loss for Cl– along the ion translocation pathway inside the pore. The delocalized charge was redistributed onto the pore residues, especially the functional groups containing pi bonds (e.g. the Tyr445 side chain), while the charges of the H atoms coordinating Cl– changed almost negligibly. Potentials of mean force computed from umbrella sampling at the QM/MM and MM levels both displayed barriers at the same locations near the pore entrance and exit. However, the QM/MM PMF showed higher barriers ( 10 kcal/mol) than the MM PMF ( 2 kcal/mol). Binding energy calculations indicated that the interactions between Cl– and certain pore residues were overestimated by the semi-empirical PM3 Hamiltonian and underestimated by the CHARMM36 force fields, both of which were employed in the umbrella sampling simulations. In particular, CHARMM36 underestimated binding interactions for the functional groups containing pi bonds, missing the stabilizations of the Cl– ion due to electron delocalization. The results suggested that it is important to explore these quantum effects for accurate descriptions of the Cl– transport.

GENESIS 1.1: A hybrid-parallel molecular dynamics simulator with enhanced sampling algorithms on multiple computational platforms.

PubMed

Kobayashi, Chigusa; Jung, Jaewoon; Matsunaga, Yasuhiro; Mori, Takaharu; Ando, Tadashi; Tamura, Koichi; Kamiya, Motoshi; Sugita, Yuji

2017-09-30

GENeralized-Ensemble SImulation System (GENESIS) is a software package for molecular dynamics (MD) simulation of biological systems. It is designed to extend limitations in system size and accessible time scale by adopting highly parallelized schemes and enhanced conformational sampling algorithms. In this new version, GENESIS 1.1, new functions and advanced algorithms have been added. The all-atom and coarse-grained potential energy functions used in AMBER and GROMACS packages now become available in addition to CHARMM energy functions. The performance of MD simulations has been greatly improved by further optimization, multiple time-step integration, and hybrid (CPU + GPU) computing. The string method and replica-exchange umbrella sampling with flexible collective variable choice are used for finding the minimum free-energy pathway and obtaining free-energy profiles for conformational changes of a macromolecule. These new features increase the usefulness and power of GENESIS for modeling and simulation in biological research. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Use of simulation-based learning in undergraduate nurse education: An umbrella systematic review.

PubMed

Cant, Robyn P; Cooper, Simon J

2017-02-01

To conduct a systematic review to appraise and review evidence on the impact of simulation-based education for undergraduate/pre-licensure nursing students, using existing reviews of literature. An umbrella review (review of reviews). Cumulative Index of Nursing and Allied Health Literature (CINAHLPlus), PubMed, and Google Scholar. Reviews of literature conducted between 2010 and 2015 regarding simulation-based education for pre-licensure nursing students. The Joanna Briggs Institute methodology for conduct of an umbrella review was used to inform the review process. Twenty-five systematic reviews of literature were included, of which 14 were recent (2013-2015). Most described the level of evidence of component studies as a mix of experimental and quasi-experimental designs. The reviews measured around 14 different main outcome variables, thus limiting the number of primary studies that each individual review could pool to appraise. Many reviews agreed on the key learning outcome of knowledge acquisition, although no overall quantitative effect was derived. Three of four high-quality reviews found that simulation supported psychomotor development; a fourth found too few high quality studies to make a statistical comparison. Simulation statistically improved self-efficacy in pretest-posttest studies, and in experimental designs self-efficacy was superior to that of other teaching methods; lower level research designs limiting further comparison. The reviews commonly reported strong student satisfaction with simulation education and some reported improved confidence and/or critical thinking. This umbrella review took a global view of 25 reviews of simulation research in nursing education, comprising over 700 primary studies. To discern overall outcomes across reviews, statistical comparison of quantitative results (effect size) must be the key comparator. Simulation-based education contributes to students' learning in a number of ways when integrated into pre-licensure nursing curricula. Overall, use of a constellation of instruments and a lack of high quality study designs mean that there are still some gaps in evidence of effects that need to be addressed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Calculation of Free Energy Landscape in Multi-Dimensions with Hamiltonian-Exchange Umbrella Sampling on Petascale Supercomputer.

PubMed

Jiang, Wei; Luo, Yun; Maragliano, Luca; Roux, Benoît

2012-11-13

An extremely scalable computational strategy is described for calculations of the potential of mean force (PMF) in multidimensions on massively distributed supercomputers. The approach involves coupling thousands of umbrella sampling (US) simulation windows distributed to cover the space of order parameters with a Hamiltonian molecular dynamics replica-exchange (H-REMD) algorithm to enhance the sampling of each simulation. In the present application, US/H-REMD is carried out in a two-dimensional (2D) space and exchanges are attempted alternatively along the two axes corresponding to the two order parameters. The US/H-REMD strategy is implemented on the basis of parallel/parallel multiple copy protocol at the MPI level, and therefore can fully exploit computing power of large-scale supercomputers. Here the novel technique is illustrated using the leadership supercomputer IBM Blue Gene/P with an application to a typical biomolecular calculation of general interest, namely the binding of calcium ions to the small protein Calbindin D9k. The free energy landscape associated with two order parameters, the distance between the ion and its binding pocket and the root-mean-square deviation (rmsd) of the binding pocket relative the crystal structure, was calculated using the US/H-REMD method. The results are then used to estimate the absolute binding free energy of calcium ion to Calbindin D9k. The tests demonstrate that the 2D US/H-REMD scheme greatly accelerates the configurational sampling of the binding pocket, thereby improving the convergence of the potential of mean force calculation.

Exploring high dimensional free energy landscapes: Temperature accelerated sliced sampling

NASA Astrophysics Data System (ADS)

Awasthi, Shalini; Nair, Nisanth N.

2017-03-01

Biased sampling of collective variables is widely used to accelerate rare events in molecular simulations and to explore free energy surfaces. However, computational efficiency of these methods decreases with increasing number of collective variables, which severely limits the predictive power of the enhanced sampling approaches. Here we propose a method called Temperature Accelerated Sliced Sampling (TASS) that combines temperature accelerated molecular dynamics with umbrella sampling and metadynamics to sample the collective variable space in an efficient manner. The presented method can sample a large number of collective variables and is advantageous for controlled exploration of broad and unbound free energy basins. TASS is also shown to achieve quick free energy convergence and is practically usable with ab initio molecular dynamics techniques.

Selectivity trend of gas separation through nanoporous graphene

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

Liu, Hongjun; Chen, Zhongfang; Dai, Sheng

2014-01-29

We demonstrate that porous graphene can efficiently separate gases according to their molecular sizes using molecular dynamic (MD) simulations,. The flux sequence from the classical MD simulation is H 2>CO 2>>N 2>Ar>CH 4, which generally follows the trend in the kinetic diameters. Moreover, this trend is also confirmed from the fluxes based on the computed free energy barriers for gas permeation using the umbrella sampling method and kinetic theory of gases. Both brute-force MD simulations and free-energy calcualtions lead to the flux trend consistent with experiments. Case studies of two compositions of CO 2/N 2 mixtures further demonstrate the separationmore » capability of nanoporous graphene.« less

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

NASA Astrophysics Data System (ADS)

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

2012-11-01

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.

Umbrella Sampling and X-ray Crystallographic Analysis Unveil an Arg-Asp Gate Facilitating Inhibitor Binding Inside Phosphopantetheine Adenylyltransferase Allosteric Cleft.

PubMed

Mondal, A; Chatterjee, R; Datta, S

2018-02-08

Phosphopantetheine adenylyltransferase (PPAT) is a rate-limiting enzyme essential for biosynthesis of coenzyme A (CoA), which in turn is responsible to regulate the secretion of exotoxins via type III secretion system in Pseudomonas aeruginosa, causing severe health concerns ranging from nosocomial infections to respiratory failure. Acetyl coenzyme A (AcCoA) is a newly reported inhibitor of PPAT, believed to regulate the cellular levels of CoA and thereby the pathogenesis. Very little is known so far regarding the mechanistic details of AcCoA binding inside PPAT-binding cleft. Herein, we have used extensive umbrella sampling simulations to decipher mechanistic insight into the inhibitor accommodation inside the binding cavity. We found that R90 and D94 residues act like a gate near the binding cavity to accommodate and stabilize the incoming ligand. Mutational models concerning these residues also show considerable difference in AcCoA-binding thermodynamics. To substantiate our findings, we have solved the first crystal structure of apo-PPAT from P. aeruginosa, which also found to agree with the simulation results. Collectively, these results describe the mechanistic details of accommodation of inhibitor molecule inside PPAT-binding cavity and also offer valuable insight into regulating cellular levels of CoA/AcCoA and thus controlling the pathogenicity.

Improvement of fluorescence intensity of nitrogen vacancy centers in self-formed diamond microstructures

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

Furuyama, S.; Yaita, J.; Kondo, M.

2015-10-19

We present umbrella-shaped diamond microstructures with metal mirrors at the bottom in order to improve the amount of collected photons from nitrogen vacancy centers. The metal mirrors at the bottom are self-aligned to the umbrella-shaped diamond microstructures which are selectively grown through holes created on a metal mask. By the finite-difference time-domain simulations, we found that the umbrella-shaped microstructures, which have an effect similar to solid immersion lens, could collect photons more efficiently than bulk or pillar-shaped microstructures. Improvement of the fluorescence intensity by factors of from 3 to 5 is shown experimentally.

On the Use of Enveloping Distribution Sampling (EDS) to Compute Free Enthalpy Differences between Different Conformational States of Molecules: Application to 310-, α-, and π-Helices.

PubMed

Lin, Zhixiong; Liu, Haiyan; Riniker, Sereina; van Gunsteren, Wilfred F

2011-12-13

Enveloping distribution sampling (EDS) is a powerful method to compute relative free energies from simulation. So far, the EDS method has only been applied to alchemical free energy differences, i.e., between different Hamiltonians defining different systems, and not yet to obtain free energy differences between different conformations or conformational states of a system. In this article, we extend the EDS formalism such that it can be applied to compute free energy differences of different conformations and apply it to compute the relative free enthalpy ΔG of 310-, α-, and π-helices of an alanine deca-peptide in explicit water solvent. The resulting ΔG values are compared to those obtained by standard thermodynamic integration (TI) and from so-called end-state simulations. A TI simulation requires the definition of a λ-dependent pathway which in the present case is based on hydrogen bonds of the different helical conformations. The values of ⟨(∂VTI)/(∂λ)⟩λ show a sharp change for a particular range of λ values, which is indicative of an energy barrier along the pathway, which lowers the accuracy of the resulting ΔG value. In contrast, in a two-state EDS simulation, an unphysical reference-state Hamiltonian which connects the parts of conformational space that are relevant to the different end states is constructed automatically; that is, no pathway needs to be defined. In the simulation using this reference state, both helices were sampled, and many transitions between them occurred, thus ensuring the accuracy of the resulting free enthalpy difference. According to the EDS simulations, the free enthalpy differences of the π-helix and the 310-helix versus the α-helix are 5 kJ mol(-1) and 47 kJ mol(-1), respectively, for an alanine deca-peptide in explicit SPC water solvent using the GROMOS 53A6 force field. The EDS method, which is a particular form of umbrella sampling, is thus applicable to compute free energy differences between conformational states as well as between systems and has definite advantages over the traditional TI and umbrella sampling methods to compute relative free energies.

Quantum mechanical free energy profiles with post-quantization restraints: Binding free energy of the water dimer over a broad range of temperatures

NASA Astrophysics Data System (ADS)

Bishop, Kevin P.; Roy, Pierre-Nicholas

2018-03-01

Free energy calculations are a crucial part of understanding chemical systems but are often computationally expensive for all but the simplest of systems. Various enhanced sampling techniques have been developed to improve the efficiency of these calculations in numerical simulations. However, the majority of these approaches have been applied using classical molecular dynamics. There are many situations where nuclear quantum effects impact the system of interest and a classical description fails to capture these details. In this work, path integral molecular dynamics has been used in conjunction with umbrella sampling, and it has been observed that correct results are only obtained when the umbrella sampling potential is applied to a single path integral bead post quantization. This method has been validated against a Lennard-Jones benchmark system before being applied to the more complicated water dimer system over a broad range of temperatures. Free energy profiles are obtained, and these are utilized in the calculation of the second virial coefficient as well as the change in free energy from the separated water monomers to the dimer. Comparisons to experimental and ground state calculation values from the literature are made for the second virial coefficient at higher temperature and the dissociation energy of the dimer in the ground state.

Quantum mechanical free energy profiles with post-quantization restraints: Binding free energy of the water dimer over a broad range of temperatures.

PubMed

Bishop, Kevin P; Roy, Pierre-Nicholas

2018-03-14

Free energy calculations are a crucial part of understanding chemical systems but are often computationally expensive for all but the simplest of systems. Various enhanced sampling techniques have been developed to improve the efficiency of these calculations in numerical simulations. However, the majority of these approaches have been applied using classical molecular dynamics. There are many situations where nuclear quantum effects impact the system of interest and a classical description fails to capture these details. In this work, path integral molecular dynamics has been used in conjunction with umbrella sampling, and it has been observed that correct results are only obtained when the umbrella sampling potential is applied to a single path integral bead post quantization. This method has been validated against a Lennard-Jones benchmark system before being applied to the more complicated water dimer system over a broad range of temperatures. Free energy profiles are obtained, and these are utilized in the calculation of the second virial coefficient as well as the change in free energy from the separated water monomers to the dimer. Comparisons to experimental and ground state calculation values from the literature are made for the second virial coefficient at higher temperature and the dissociation energy of the dimer in the ground state.

Nonequilibrium umbrella sampling in spaces of many order parameters

NASA Astrophysics Data System (ADS)

Dickson, Alex; Warmflash, Aryeh; Dinner, Aaron R.

2009-02-01

We recently introduced an umbrella sampling method for obtaining nonequilibrium steady-state probability distributions projected onto an arbitrary number of coordinates that characterize a system (order parameters) [A. Warmflash, P. Bhimalapuram, and A. R. Dinner, J. Chem. Phys. 127, 154112 (2007)]. Here, we show how our algorithm can be combined with the image update procedure from the finite-temperature string method for reversible processes [E. Vanden-Eijnden and M. Venturoli, "Revisiting the finite temperature string method for calculation of reaction tubes and free energies," J. Chem. Phys. (in press)] to enable restricted sampling of a nonequilibrium steady state in the vicinity of a path in a many-dimensional space of order parameters. For the study of transitions between stable states, the adapted algorithm results in improved scaling with the number of order parameters and the ability to progressively refine the regions of enforced sampling. We demonstrate the algorithm by applying it to a two-dimensional model of driven Brownian motion and a coarse-grained (Ising) model for nucleation under shear. It is found that the choice of order parameters can significantly affect the convergence of the simulation; local magnetization variables other than those used previously for sampling transition paths in Ising systems are needed to ensure that the reactive flux is primarily contained within a tube in the space of order parameters. The relation of this method to other algorithms that sample the statistics of path ensembles is discussed.

Method Evaluations for Adsorption Free Energy Calculations at the Solid/Water Interface through Metadynamics, Umbrella Sampling, and Jarzynski's Equality.

PubMed

Wei, Qichao; Zhao, Weilong; Yang, Yang; Cui, Beiliang; Xu, Zhijun; Yang, Xiaoning

2018-03-19

Considerable interest in characterizing protein/peptide-surface interactions has prompted extensive computational studies on calculations of adsorption free energy. However, in many cases, each individual study has focused on the application of free energy calculations to a specific system; therefore, it is difficult to combine the results into a general picture for choosing an appropriate strategy for the system of interest. Herein, three well-established computational algorithms are systemically compared and evaluated to compute the adsorption free energy of small molecules on two representative surfaces. The results clearly demonstrate that the characteristics of studied interfacial systems have crucial effects on the accuracy and efficiency of the adsorption free energy calculations. For the hydrophobic surface, steered molecular dynamics exhibits the highest efficiency, which appears to be a favorable method of choice for enhanced sampling simulations. However, for the charged surface, only the umbrella sampling method has the ability to accurately explore the adsorption free energy surface. The affinity of the water layer to the surface significantly affects the performance of free energy calculation methods, especially at the region close to the surface. Therefore, a general principle of how to discriminate between methodological and sampling issues based on the interfacial characteristics of the system under investigation is proposed. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed

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

2018-07-15

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

Replica exchange and expanded ensemble simulations as Gibbs sampling: simple improvements for enhanced mixing.

PubMed

Chodera, John D; Shirts, Michael R

2011-11-21

The widespread popularity of replica exchange and expanded ensemble algorithms for simulating complex molecular systems in chemistry and biophysics has generated much interest in discovering new ways to enhance the phase space mixing of these protocols in order to improve sampling of uncorrelated configurations. Here, we demonstrate how both of these classes of algorithms can be considered as special cases of Gibbs sampling within a Markov chain Monte Carlo framework. Gibbs sampling is a well-studied scheme in the field of statistical inference in which different random variables are alternately updated from conditional distributions. While the update of the conformational degrees of freedom by Metropolis Monte Carlo or molecular dynamics unavoidably generates correlated samples, we show how judicious updating of the thermodynamic state indices--corresponding to thermodynamic parameters such as temperature or alchemical coupling variables--can substantially increase mixing while still sampling from the desired distributions. We show how state update methods in common use can lead to suboptimal mixing, and present some simple, inexpensive alternatives that can increase mixing of the overall Markov chain, reducing simulation times necessary to obtain estimates of the desired precision. These improved schemes are demonstrated for several common applications, including an alchemical expanded ensemble simulation, parallel tempering, and multidimensional replica exchange umbrella sampling.

Making structural sense of dimerization interfaces of delta opioid receptor homodimers.

PubMed

Johnston, Jennifer M; Aburi, Mahalaxmi; Provasi, Davide; Bortolato, Andrea; Urizar, Eneko; Lambert, Nevin A; Javitch, Jonathan A; Filizola, Marta

2011-03-15

Opioid receptors, like other members of the G protein-coupled receptor (GPCR) family, have been shown to associate to form dimers and/or oligomers at the plasma membrane. Whether this association is stable or transient is not known. Recent compelling evidence suggests that at least some GPCRs rapidly associate and dissociate. We have recently calculated binding affinities from free energy estimates to predict transient association between mouse delta opioid receptor (DOR) protomers at a symmetric interface involving the fourth transmembrane (TM4) helix (herein termed "4" dimer). Here we present disulfide cross-linking experiments with DOR constructs with cysteines substituted at the extracellular ends of TM4 or TM5 that confirm the formation of DOR complexes involving these helices. Our results are consistent with the involvement of TM4 and/or TM5 at the DOR homodimer interface, but possibly with differing association propensities. Coarse-grained (CG) well-tempered metadynamics simulations of two different dimeric arrangements of DOR involving TM4 alone or with TM5 (herein termed "4/5" dimer) in an explicit lipid-water environment confirmed the presence of two structurally and energetically similar configurations of the 4 dimer, as previously assessed by umbrella sampling calculations, and revealed a single energetic minimum of the 4/5 dimer. Additional CG umbrella sampling simulations of the 4/5 dimer indicated that the strength of association between DOR protomers varies depending on the protein region at the interface, with the 4 dimer being more stable than the 4/5 dimer.

Removing systematic errors in interionic potentials of mean force computed in molecular simulations using reaction-field-based electrostatics

PubMed Central

Baumketner, Andrij

2009-01-01

The performance of reaction-field methods to treat electrostatic interactions is tested in simulations of ions solvated in water. The potential of mean force between sodium chloride pair of ions and between side chains of lysine and aspartate are computed using umbrella sampling and molecular dynamics simulations. It is found that in comparison with lattice sum calculations, the charge-group-based approaches to reaction-field treatments produce a large error in the association energy of the ions that exhibits strong systematic dependence on the size of the simulation box. The atom-based implementation of the reaction field is seen to (i) improve the overall quality of the potential of mean force and (ii) remove the dependence on the size of the simulation box. It is suggested that the atom-based truncation be used in reaction-field simulations of mixed media. PMID:19292522

Determinants of reactivity and selectivity in soluble epoxide hydrolase from quantum mechanics/molecular mechanics modeling.

PubMed

Lonsdale, Richard; Hoyle, Simon; Grey, Daniel T; Ridder, Lars; Mulholland, Adrian J

2012-02-28

Soluble epoxide hydrolase (sEH) is an enzyme involved in drug metabolism that catalyzes the hydrolysis of epoxides to form their corresponding diols. sEH has a broad substrate range and shows high regio- and enantioselectivity for nucleophilic ring opening by Asp333. Epoxide hydrolases therefore have potential synthetic applications. We have used combined quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations (at the AM1/CHARMM22 level) and high-level ab initio (SCS-MP2) QM/MM calculations to analyze the reactions, and determinants of selectivity, for two substrates: trans-stilbene oxide (t-SO) and trans-diphenylpropene oxide (t-DPPO). The calculated free energy barriers from the QM/MM (AM1/CHARMM22) umbrella sampling MD simulations show a lower barrier for phenyl attack in t-DPPO, compared with that for benzylic attack, in agreement with experiment. Activation barriers in agreement with experimental rate constants are obtained only with the highest level of QM theory (SCS-MP2) used. Our results show that the selectivity of the ring-opening reaction is influenced by several factors, including proximity to the nucleophile, electronic stabilization of the transition state, and hydrogen bonding to two active site tyrosine residues. The protonation state of His523 during nucleophilic attack has also been investigated, and our results show that the protonated form is most consistent with experimental findings. The work presented here illustrates how determinants of selectivity can be identified from QM/MM simulations. These insights may also provide useful information for the design of novel catalysts for use in the synthesis of enantiopure compounds.

Communication: Estimating the initial biasing potential for λ-local-elevation umbrella-sampling (λ-LEUS) simulations via slow growth

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

Bieler, Noah S.; Hünenberger, Philippe H., E-mail: phil@igc.phys.chem.ethz.ch

2014-11-28

In a recent article [Bieler et al., J. Chem. Theory Comput. 10, 3006–3022 (2014)], we introduced a combination of the λ-dynamics (λD) approach for calculating alchemical free-energy differences and of the local-elevation umbrella-sampling (LEUS) memory-based biasing method to enhance the sampling along the alchemical coordinate. The combined scheme, referred to as λ-LEUS, was applied to the perturbation of hydroquinone to benzene in water as a test system, and found to represent an improvement over thermodynamic integration (TI) in terms of sampling efficiency at equivalent accuracy. However, the preoptimization of the biasing potential required in the λ-LEUS method requires “filling up”more » all the basins in the potential of mean force. This introduces a non-productive pre-sampling time that is system-dependent, and generally exceeds the corresponding equilibration time in a TI calculation. In this letter, a remedy is proposed to this problem, termed the slow growth memory guessing (SGMG) approach. Instead of initializing the biasing potential to zero at the start of the preoptimization, an approximate potential of mean force is estimated from a short slow growth calculation, and its negative used to construct the initial memory. Considering the same test system as in the preceding article, it is shown that of the application of SGMG in λ-LEUS permits to reduce the preoptimization time by about a factor of four.« less

Communication: Estimating the initial biasing potential for λ-local-elevation umbrella-sampling (λ-LEUS) simulations via slow growth

NASA Astrophysics Data System (ADS)

Bieler, Noah S.; Hünenberger, Philippe H.

2014-11-01

In a recent article [Bieler et al., J. Chem. Theory Comput. 10, 3006-3022 (2014)], we introduced a combination of the λ-dynamics (λD) approach for calculating alchemical free-energy differences and of the local-elevation umbrella-sampling (LEUS) memory-based biasing method to enhance the sampling along the alchemical coordinate. The combined scheme, referred to as λ-LEUS, was applied to the perturbation of hydroquinone to benzene in water as a test system, and found to represent an improvement over thermodynamic integration (TI) in terms of sampling efficiency at equivalent accuracy. However, the preoptimization of the biasing potential required in the λ-LEUS method requires "filling up" all the basins in the potential of mean force. This introduces a non-productive pre-sampling time that is system-dependent, and generally exceeds the corresponding equilibration time in a TI calculation. In this letter, a remedy is proposed to this problem, termed the slow growth memory guessing (SGMG) approach. Instead of initializing the biasing potential to zero at the start of the preoptimization, an approximate potential of mean force is estimated from a short slow growth calculation, and its negative used to construct the initial memory. Considering the same test system as in the preceding article, it is shown that of the application of SGMG in λ-LEUS permits to reduce the preoptimization time by about a factor of four.

Crystal nucleation of colloidal hard dumbbells

NASA Astrophysics Data System (ADS)

Ni, Ran; Dijkstra, Marjolein

2011-01-01

Using computer simulations, we investigate the homogeneous crystal nucleation in suspensions of colloidal hard dumbbells. The free energy barriers are determined by Monte Carlo simulations using the umbrella sampling technique. We calculate the nucleation rates for the plastic crystal and the aperiodic crystal phase using the kinetic prefactor as determined from event driven molecular dynamics simulations. We find good agreement with the nucleation rates determined from spontaneous nucleation events observed in event driven molecular dynamics simulations within error bars of one order of magnitude. We study the effect of aspect ratio of the dumbbells on the nucleation of plastic and aperiodic crystal phases, and we also determine the structure of the critical nuclei. Moreover, we find that the nucleation of the aligned close-packed crystal structure is strongly suppressed by a high free energy barrier at low supersaturations and slow dynamics at high supersaturations.

Exhaustively sampling peptide adsorption with metadynamics.

PubMed

Deighan, Michael; Pfaendtner, Jim

2013-06-25

Simulating the adsorption of a peptide or protein and obtaining quantitative estimates of thermodynamic observables remains challenging for many reasons. One reason is the dearth of molecular scale experimental data available for validating such computational models. We also lack simulation methodologies that effectively address the dual challenges of simulating protein adsorption: overcoming strong surface binding and sampling conformational changes. Unbiased classical simulations do not address either of these challenges. Previous attempts that apply enhanced sampling generally focus on only one of the two issues, leaving the other to chance or brute force computing. To improve our ability to accurately resolve adsorbed protein orientation and conformational states, we have applied the Parallel Tempering Metadynamics in the Well-Tempered Ensemble (PTMetaD-WTE) method to several explicitly solvated protein/surface systems. We simulated the adsorption behavior of two peptides, LKα14 and LKβ15, onto two self-assembled monolayer (SAM) surfaces with carboxyl and methyl terminal functionalities. PTMetaD-WTE proved effective at achieving rapid convergence of the simulations, whose results elucidated different aspects of peptide adsorption including: binding free energies, side chain orientations, and preferred conformations. We investigated how specific molecular features of the surface/protein interface change the shape of the multidimensional peptide binding free energy landscape. Additionally, we compared our enhanced sampling technique with umbrella sampling and also evaluated three commonly used molecular dynamics force fields.

Statistically optimal analysis of state-discretized trajectory data from multiple thermodynamic states

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

Wu, Hao; Mey, Antonia S. J. S.; Noé, Frank

2014-12-07

We propose a discrete transition-based reweighting analysis method (dTRAM) for analyzing configuration-space-discretized simulation trajectories produced at different thermodynamic states (temperatures, Hamiltonians, etc.) dTRAM provides maximum-likelihood estimates of stationary quantities (probabilities, free energies, expectation values) at any thermodynamic state. In contrast to the weighted histogram analysis method (WHAM), dTRAM does not require data to be sampled from global equilibrium, and can thus produce superior estimates for enhanced sampling data such as parallel/simulated tempering, replica exchange, umbrella sampling, or metadynamics. In addition, dTRAM provides optimal estimates of Markov state models (MSMs) from the discretized state-space trajectories at all thermodynamic states. Under suitablemore » conditions, these MSMs can be used to calculate kinetic quantities (e.g., rates, timescales). In the limit of a single thermodynamic state, dTRAM estimates a maximum likelihood reversible MSM, while in the limit of uncorrelated sampling data, dTRAM is identical to WHAM. dTRAM is thus a generalization to both estimators.« less

Multistate λ-local-elevation umbrella-sampling (MS-λ-LEUS): method and application to the complexation of cations by crown ethers.

PubMed

Bieler, Noah S; Tschopp, Jan P; Hünenberger, Philippe H

2015-06-09

An extension of the λ-local-elevation umbrella-sampling (λ-LEUS) scheme [ Bieler et al. J. Chem. Theory Comput. 2014 , 10 , 3006 ] is proposed to handle the multistate (MS) situation, i.e. the calculation of the relative free energies of multiple physical states based on a single simulation. The key element of the MS-λ-LEUS approach is to use a single coupling variable Λ controlling successive pairwise mutations between the states of interest in a cyclic fashion. The Λ variable is propagated dynamically as an extended-system variable, using a coordinate transformation with plateaus and a memory-based biasing potential as in λ-LEUS. Compared to other available MS schemes (one-step perturbation, enveloping distribution sampling and conventional λ-dynamics) the proposed method presents a number of important advantages, namely: (i) the physical states are visited explicitly and over finite time periods; (ii) the extent of unphysical space required to ensure transitions is kept minimal and, in particular, one-dimensional; (iii) the setup protocol solely requires the topologies of the physical states; and (iv) the method only requires limited modifications in a simulation code capable of handling two-state mutations. As an initial application, the absolute binding free energies of five alkali cations to three crown ethers in three different solvents are calculated. The results are found to reproduce qualitatively the main experimental trends and, in particular, the experimental selectivity of 18C6 for K(+) in water and methanol, which is interpreted in terms of opposing trends along the cation series between the solvation free energy of the cation and the direct electrostatic interactions within the complex.

Modeling ash fall distribution from a Yellowstone supereruption

USGS Publications Warehouse

Mastin, Larry G.; Van Eaton, Alexa R.; Lowenstern, Jacob B.

2014-01-01

We used the volcanic ash transport and dispersion model Ash3d to estimate the distribution of ashfall that would result from a modern-day Plinian supereruption at Yellowstone volcano. The simulations required modifying Ash3d to consider growth of a continent-scale umbrella cloud and its interaction with ambient wind fields. We simulated eruptions lasting 3 days, 1 week, and 1 month, each producing 330 km3 of volcanic ash, dense-rock equivalent (DRE). Results demonstrate that radial expansion of the umbrella cloud is capable of driving ash upwind (westward) and crosswind (N-S) in excess of 1500 km, producing more-or-less radially symmetric isopachs that are only secondarily modified by ambient wind. Deposit thicknesses are decimeters to meters in the northern Rocky Mountains, centimeters to decimeters in the northern Midwest, and millimeters to centimeters on the East, West, and Gulf Coasts. Umbrella cloud growth may explain the extremely widespread dispersal of the ∼640 ka and 2.1 Ma Yellowstone tephra deposits in the eastern Pacific, northeastern California, southern California, and South Texas.

Essential energy space random walk via energy space metadynamics method to accelerate molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Li, Hongzhi; Min, Donghong; Liu, Yusong; Yang, Wei

2007-09-01

To overcome the possible pseudoergodicity problem, molecular dynamic simulation can be accelerated via the realization of an energy space random walk. To achieve this, a biased free energy function (BFEF) needs to be priori obtained. Although the quality of BFEF is essential for sampling efficiency, its generation is usually tedious and nontrivial. In this work, we present an energy space metadynamics algorithm to efficiently and robustly obtain BFEFs. Moreover, in order to deal with the associated diffusion sampling problem caused by the random walk in the total energy space, the idea in the original umbrella sampling method is generalized to be the random walk in the essential energy space, which only includes the energy terms determining the conformation of a region of interest. This essential energy space generalization allows the realization of efficient localized enhanced sampling and also offers the possibility of further sampling efficiency improvement when high frequency energy terms irrelevant to the target events are free of activation. The energy space metadynamics method and its generalization in the essential energy space for the molecular dynamics acceleration are demonstrated in the simulation of a pentanelike system, the blocked alanine dipeptide model, and the leucine model.

Enzymatic Kinetic Isotope Effects from Path-Integral Free Energy Perturbation Theory.

PubMed

Gao, J

2016-01-01

Path-integral free energy perturbation (PI-FEP) theory is presented to directly determine the ratio of quantum mechanical partition functions of different isotopologs in a single simulation. Furthermore, a double averaging strategy is used to carry out the practical simulation, separating the quantum mechanical path integral exactly into two separate calculations, one corresponding to a classical molecular dynamics simulation of the centroid coordinates, and another involving free-particle path-integral sampling over the classical, centroid positions. An integrated centroid path-integral free energy perturbation and umbrella sampling (PI-FEP/UM, or simply, PI-FEP) method along with bisection sampling was summarized, which provides an accurate and fast convergent method for computing kinetic isotope effects for chemical reactions in solution and in enzymes. The PI-FEP method is illustrated by a number of applications, to highlight the computational precision and accuracy, the rule of geometrical mean in kinetic isotope effects, enhanced nuclear quantum effects in enzyme catalysis, and protein dynamics on temperature dependence of kinetic isotope effects. © 2016 Elsevier Inc. All rights reserved.

Kinetics and thermodynamics of gas diffusion in a NiFe hydrogenase.

PubMed

Topin, Jérémie; Rousset, Marc; Antonczak, Serge; Golebiowski, Jérôme

2012-03-01

We have investigated O₂ and H₂ transport across a NiFe hydrogenase at the atomic scale by means of computational methods. The Wild Type protein has been compared with the V74Q mutant. Two distinct methodologies have been applied to study the gas access to the active site. Temperature locally enhanced sampling simulations have emphasized the importance of protein dynamics on gas diffusion. The O₂ diffusion free energy profiles, obtained by umbrella sampling, are in agreement with the known kinetic data and show that in the V74Q mutant, the inhibition process is lowered from both a kinetic and a thermodynamic point of view. Copyright © 2011 Wiley Periodicals, Inc.

The liquid-liquid transition in supercooled ST2 water: a comparison between umbrella sampling and well-tempered metadynamics.

PubMed

Palmer, Jeremy C; Car, Roberto; Debenedetti, Pablo G

2013-01-01

We investigate the metastable phase behaviour of the ST2 water model under deeply supercooled conditions. The phase behaviour is examined using umbrella sampling (US) and well-tempered metadynamics (WT-MetaD) simulations to compute the reversible free energy surface parameterized by density and bond-orientation order. We find that free energy surfaces computed with both techniques clearly show two liquid phases in coexistence, in agreement with our earlier US and grand canonical Monte Carlo calculations [Y. Liu, J. C. Palmer, A. Z. Panagiotopoulos and P. G. Debenedetti, J Chem Phys, 2012, 137, 214505; Y. Liu, A. Z. Panagiotopoulos and P. G. Debenedetti, J Chem Phys, 2009, 131, 104508]. While we demonstrate that US and WT-MetaD produce consistent results, the latter technique is estimated to be more computationally efficient by an order of magnitude. As a result, we show that WT-MetaD can be used to study the finite-size scaling behaviour of the free energy barrier separating the two liquids for systems containing 192, 300 and 400 ST2 molecules. Although our results are consistent with the expected N(2/3) scaling law, we conclude that larger systems must be examined to provide conclusive evidence of a first-order phase transition and associated second critical point.

Making Structural Sense of Dimerization Interfaces of Delta Opioid Receptor Homodimers†

PubMed Central

2011-01-01

Opioid receptors, like other members of the G protein-coupled receptor (GPCR) family, have been shown to associate to form dimers and/or oligomers at the plasma membrane. Whether this association is stable or transient is not known. Recent compelling evidence suggests that at least some GPCRs rapidly associate and dissociate. We have recently calculated binding affinities from free energy estimates to predict transient association between mouse delta opioid receptor (DOR) protomers at a symmetric interface involving the fourth transmembrane (TM4) helix (herein termed “4” dimer). Here we present disulfide cross-linking experiments with DOR constructs with cysteines substituted at the extracellular ends of TM4 or TM5 that confirm the formation of DOR complexes involving these helices. Our results are consistent with the involvement of TM4 and/or TM5 at the DOR homodimer interface, but possibly with differing association propensities. Coarse-grained (CG) well-tempered metadynamics simulations of two different dimeric arrangements of DOR involving TM4 alone or with TM5 (herein termed “4/5” dimer) in an explicit lipid−water environment confirmed the presence of two structurally and energetically similar configurations of the 4 dimer, as previously assessed by umbrella sampling calculations, and revealed a single energetic minimum of the 4/5 dimer. Additional CG umbrella sampling simulations of the 4/5 dimer indicated that the strength of association between DOR protomers varies depending on the protein region at the interface, with the 4 dimer being more stable than the 4/5 dimer. PMID:21261298

Some Surprising Implications of NMR-directed Simulations of Substrate Recognition and Binding by Cytochrome P450cam (CYP101A1).

PubMed

Asciutto, Eliana K; Pochapsky, Thomas C

2018-04-27

Cytochrome P450 cam (CYP101A1) catalyzes the stereospecific 5-exo hydroxylation of d-camphor by molecular oxygen. Previously, residual dipolar couplings measured for backbone amide 1 H- 15 N correlations in both substrate-free and bound forms of CYP101A1 were used as restraints in soft annealing molecular dynamic simulations in order to identify average conformations of the enzyme with and without substrate bound. Multiple substrate-dependent conformational changes remote from the enzyme active site were identified, and site-directed mutagenesis and activity assays confirmed the importance of these changes in substrate recognition. The current work makes use of perturbation response scanning (PRS) and umbrella sampling molecular dynamic of the residual dipolar coupling-derived CYP101A1 structures to probe the roles of remote structural features in enforcing the regio- and stereospecific nature of the hydroxylation reaction catalyzed by CYP101A1. An improper dihedral angle Ψ was defined and used to maintain substrate orientation in the CYP101A1 active site, and it was observed that different values of Ψ result in different PRS response maps. Umbrella sampling methods show that the free energy of the system is sensitive to Ψ, and bound substrate forms an important mechanical link in the transmission of mechanical coupling through the enzyme structure. Finally, a qualitative approach to interpreting PRS maps in terms of the roles of secondary structural features is proposed. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

PubMed

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

2018-03-08

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

Geometric and energetic considerations of surface fluctuations during ion transfer across the water-immiscible organic liquid interface

NASA Astrophysics Data System (ADS)

Karnes, John J.; Benjamin, Ilan

2016-07-01

Molecular dynamics simulations and umbrella sampling free energy calculations are used to examine the thermodynamics, energetics, and structural fluctuations that accompany the transfer of a small hydrophilic ion (Cl-) across the water/nitrobenzene interface. By examining several constrained interface structures, we isolate the energetic costs of interfacial deformation and co-transfer of hydration waters during the ion transfer. The process is monitored using both energy-based solvation coordinates and a geometric coordinate recently introduced by Morita and co-workers to describe surface fluctuations. Our simulations show that these coordinates provide a complimentary description of the water surface fluctuations during the transfer and are necessary for elucidating the mechanism of the ion transfer.

Molecular dynamics simulation of the structure and dynamics of 5-HT3 serotonin receptor

NASA Astrophysics Data System (ADS)

Antonov, M. Yu.; Popinako, A. V.; Prokopiev, G. A.

2016-10-01

In this work, we investigated structure, dynamics and ion transportation in transmembrane domain of the 5-HT3 serotonin receptor. High-resolution (0.35 nm) structure of the 5-HT3 receptor in complex with stabilizing nanobodies was determined by protein crystallography in 2014 (Protein data bank (PDB) code 4PIR). Transmembrane domain of the structure was prepared in complex with explicit membrane environment (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC)) and solvent (TIP3P water model). Molecular dynamics protocols for simulation and stabilization of the transmembrane domain of the 5-HT3 receptor model were developed and 60 ns simulation of the structure was conducted in order to explore structural parameters of the system. We estimated the mean force profile for Na+ ions using umbrella sampling method.

Geochemical Reaction Mechanism Discovery from Molecular Simulation

DOE PAGES

Stack, Andrew G.; Kent, Paul R. C.

2014-11-10

Methods to explore reactions using computer simulation are becoming increasingly quantitative, versatile, and robust. In this review, a rationale for how molecular simulation can help build better geochemical kinetics models is first given. We summarize some common methods that geochemists use to simulate reaction mechanisms, specifically classical molecular dynamics and quantum chemical methods and discuss their strengths and weaknesses. Useful tools such as umbrella sampling and metadynamics that enable one to explore reactions are discussed. Several case studies wherein geochemists have used these tools to understand reaction mechanisms are presented, including water exchange and sorption on aqueous species and mineralmore » surfaces, surface charging, crystal growth and dissolution, and electron transfer. The impact that molecular simulation has had on our understanding of geochemical reactivity are highlighted in each case. In the future, it is anticipated that molecular simulation of geochemical reaction mechanisms will become more commonplace as a tool to validate and interpret experimental data, and provide a check on the plausibility of geochemical kinetic models.« less

Efficient parallel implementations of QM/MM-REMD (quantum mechanical/molecular mechanics-replica-exchange MD) and umbrella sampling: isomerization of H2O2 in aqueous solution.

PubMed

Fedorov, Dmitri G; Sugita, Yuji; Choi, Cheol Ho

2013-07-03

An efficient parallel implementation of QM/MM-based replica-exchange molecular dynamics (REMD) as well as umbrella samplings techniques was proposed by adopting the generalized distributed data interface (GDDI). Parallelization speed-up of 40.5 on 48 cores was achieved, making our QM/MM-MD engine a robust tool for studying complex chemical dynamics in solution. They were comparatively used to study the torsional isomerization of hydrogen peroxide in aqueous solution. All results by QM/MM-REMD and QM/MM umbrella sampling techniques yielded nearly identical potentials of mean force (PMFs) regardless of the particular QM theories for solute, showing that the overall dynamics are mainly determined by solvation. Although the entropic penalty of solvent rearrangements exists in cisoid conformers, it was found that both strong intermolecular hydrogen bonding and dipole-dipole interactions preferentially stabilize them in solution, reducing the torsional free-energy barrier at 0° by about 3 kcal/mol as compared to that in gas phase.

Maintaining animal assemblages through single-species management: the case of threatened caribou in boreal forest.

PubMed

Bichet, Orphé; Dupuch, Angélique; Hébert, Christian; Le Borgne, Hélène Le; Fortin, Daniel

2016-03-01

With the intensification of human activities, preserving animal populations is a contemporary challenge of critical importance. In this context, the umbrella species concept is appealing because preserving a single species should result in the protection of multiple co-occurring species. Practitioners, though, face the task of having to find suitable umbrellas to develop single-species management guidelines. In North America, boreal forests must be managed to facilitate the recovery of the threatened boreal caribou (Rangifer tarandus). Yet, the effect of caribou conservation on co-occurring animal species remains poorly documented. We tested if boreal caribou can constitute an effective umbrella for boreal fauna. Birds, small mammals, and insects were sampled along gradients of post-harvest and post-fire forest succession. Predictive models of occupancy were developed from the responses of 95 species to characteristics of forest stands and their surroundings. We then assessed the similarity of species occupancy expected between simulated harvested landscapes and a 90 000-km2 uncut landscape. Managed landscapes were simulated based on three levels of disturbance, two timber-harvest rotation cycles, and dispersed or aggregated cut-blocks. We found that management guidelines that were more likely to maintain caribou populations should also better preserve animal assemblages. Relative to fragmentation or harvest cycle, we detected a stronger effect of habitat loss on species assemblages. Disturbing 22%, 35%, and 45% of the landscape should result, respectively, in 80%, 60%, and 40% probability for caribou populations to be sustainable; in turn, this should result in regional species assemblages with Jaccard similarity indices of 0.86, 0.79, and 0.74, respectively, relative to the uncut landscape. Our study thus demonstrates the value of single-species management for animal conservation. Our quantitative approach allows for the evaluation of management guidelines prior to implementation, thereby providing a tool for establishing suitable compromises between economic and environmental sustainability of human activities.

A generic implementation of replica exchange with solute tempering (REST2) algorithm in NAMD for complex biophysical simulations

NASA Astrophysics Data System (ADS)

Jo, Sunhwan; Jiang, Wei

2015-12-01

Replica Exchange with Solute Tempering (REST2) is a powerful sampling enhancement algorithm of molecular dynamics (MD) in that it needs significantly smaller number of replicas but achieves higher sampling efficiency relative to standard temperature exchange algorithm. In this paper, we extend the applicability of REST2 for quantitative biophysical simulations through a robust and generic implementation in greatly scalable MD software NAMD. The rescaling procedure of force field parameters controlling REST2 "hot region" is implemented into NAMD at the source code level. A user can conveniently select hot region through VMD and write the selection information into a PDB file. The rescaling keyword/parameter is written in NAMD Tcl script interface that enables an on-the-fly simulation parameter change. Our implementation of REST2 is within communication-enabled Tcl script built on top of Charm++, thus communication overhead of an exchange attempt is vanishingly small. Such a generic implementation facilitates seamless cooperation between REST2 and other modules of NAMD to provide enhanced sampling for complex biomolecular simulations. Three challenging applications including native REST2 simulation for peptide folding-unfolding transition, free energy perturbation/REST2 for absolute binding affinity of protein-ligand complex and umbrella sampling/REST2 Hamiltonian exchange for free energy landscape calculation were carried out on IBM Blue Gene/Q supercomputer to demonstrate efficacy of REST2 based on the present implementation.

To simulate or not to simulate: what are the questions?

PubMed

Dudai, Yadin; Evers, Kathinka

2014-10-22

Simulation is a powerful method in science and engineering. However, simulation is an umbrella term, and its meaning and goals differ among disciplines. Rapid advances in neuroscience and computing draw increasing attention to large-scale brain simulations. What is the meaning of simulation, and what should the method expect to achieve? We discuss the concept of simulation from an integrated scientific and philosophical vantage point and pinpoint selected issues that are specific to brain simulation.

QM/MM free energy simulations: recent progress and challenges

PubMed Central

Lu, Xiya; Fang, Dong; Ito, Shingo; Okamoto, Yuko; Ovchinnikov, Victor

2016-01-01

Due to the higher computational cost relative to pure molecular mechanical (MM) simulations, hybrid quantum mechanical/molecular mechanical (QM/MM) free energy simulations particularly require a careful consideration of balancing computational cost and accuracy. Here we review several recent developments in free energy methods most relevant to QM/MM simulations and discuss several topics motivated by these developments using simple but informative examples that involve processes in water. For chemical reactions, we highlight the value of invoking enhanced sampling technique (e.g., replica-exchange) in umbrella sampling calculations and the value of including collective environmental variables (e.g., hydration level) in metadynamics simulations; we also illustrate the sensitivity of string calculations, especially free energy along the path, to various parameters in the computation. Alchemical free energy simulations with a specific thermodynamic cycle are used to probe the effect of including the first solvation shell into the QM region when computing solvation free energies. For cases where high-level QM/MM potential functions are needed, we analyze two different approaches: the QM/MM-MFEP method of Yang and co-workers and perturbative correction to low-level QM/MM free energy results. For the examples analyzed here, both approaches seem productive although care needs to be exercised when analyzing the perturbative corrections. PMID:27563170

Dynamic information for cardiotoxin protein desorption from a methyl-terminated self-assembled monolayer using steered molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Hung, Shih-Wei; Hsiao, Pai-Yi; Chieng, Ching-Chang

2011-05-01

Dynamic information, such as force, structural change, interaction energy, and potential of mean force (PMF), about the desorption of a single cardiotoxin (CTX) protein from a methyl-terminated self-assembled monolayer (SAM) surface was investigated by means of steered molecular dynamics (SMD) simulations. The simulation results indicated that Loop I is the first loop to depart from the SAM surface, which is in good agreement with the results of the nuclear magnetic resonance spectroscopy experiment. The free energy landscape and the thermodynamic force of the CTX desorption process was represented by the PMF and by the derivative of PMF with respect to distance, respectively. By applying Jarzynski's equality, the PMF can be reconstructed from the SMD simulation. The PMFs, calculated by different estimators based upon Jarzynski's equality, were compared with the conventional umbrella sampling method. The best estimation was obtained by using the fluctuation-dissipation estimator with a pulling velocity of v = 0.25 nm/ns for the present study.

Surface force measurements and simulations of mussel-derived peptide adhesives on wet organic surfaces.

PubMed

Levine, Zachary A; Rapp, Michael V; Wei, Wei; Mullen, Ryan Gotchy; Wu, Chun; Zerze, Gül H; Mittal, Jeetain; Waite, J Herbert; Israelachvili, Jacob N; Shea, Joan-Emma

2016-04-19

Translating sticky biological molecules-such as mussel foot proteins (MFPs)-into synthetic, cost-effective underwater adhesives with adjustable nano- and macroscale characteristics requires an intimate understanding of the glue's molecular interactions. To help facilitate the next generation of aqueous adhesives, we performed a combination of surface forces apparatus (SFA) measurements and replica-exchange molecular dynamics (REMD) simulations on a synthetic, easy to prepare, Dopa-containing peptide (MFP-3s peptide), which adheres to organic surfaces just as effectively as its wild-type protein analog. Experiments and simulations both show significant differences in peptide adsorption on CH3-terminated (hydrophobic) and OH-terminated (hydrophilic) self-assembled monolayers (SAMs), where adsorption is strongest on hydrophobic SAMs because of orientationally specific interactions with Dopa. Additional umbrella-sampling simulations yield free-energy profiles that quantitatively agree with SFA measurements and are used to extract the adhesive properties of individual amino acids within the context of MFP-3s peptide adhesion, revealing a delicate balance between van der Waals, hydrophobic, and electrostatic forces.

Solvation structures of water in trihexyltetradecylphosphonium-orthoborate ionic liquids

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

Wang, Yong-Lei, E-mail: wangyonl@gmail.com; System and Component Design, Department of Machine Design, KTH Royal Institute of Technology, SE-100 44 Stockholm; Sarman, Sten

2016-08-14

Atomistic molecular dynamics simulations have been performed to investigate effective interactions of isolated water molecules dispersed in trihexyltetradecylphosphonium-orthoborate ionic liquids (ILs). The intrinsic free energy changes in solvating one water molecule from gas phase into bulk IL matrices were estimated as a function of temperature, and thereafter, the calculations of potential of mean force between two dispersed water molecules within different IL matrices were performed using umbrella sampling simulations. The systematic analyses of local ionic microstructures, orientational preferences, probability and spatial distributions of dispersed water molecules around neighboring ionic species indicate their preferential coordinations to central polar segments in orthoboratemore » anions. The effective interactions between two dispersed water molecules are partially or totally screened as their separation distance increases due to interference of ionic species in between. These computational results connect microscopic anionic structures with macroscopically and experimentally observed difficulty in completely removing water from synthesized IL samples and suggest that the introduction of hydrophobic groups to central polar segments and the formation of conjugated ionic structures in orthoborate anions can effectively reduce residual water content in the corresponding IL samples.« less

Accelerating Convergence in Molecular Dynamics Simulations of Solutes in Lipid Membranes by Conducting a Random Walk along the Bilayer Normal.

PubMed

Neale, Chris; Madill, Chris; Rauscher, Sarah; Pomès, Régis

2013-08-13

All molecular dynamics simulations are susceptible to sampling errors, which degrade the accuracy and precision of observed values. The statistical convergence of simulations containing atomistic lipid bilayers is limited by the slow relaxation of the lipid phase, which can exceed hundreds of nanoseconds. These long conformational autocorrelation times are exacerbated in the presence of charged solutes, which can induce significant distortions of the bilayer structure. Such long relaxation times represent hidden barriers that induce systematic sampling errors in simulations of solute insertion. To identify optimal methods for enhancing sampling efficiency, we quantitatively evaluate convergence rates using generalized ensemble sampling algorithms in calculations of the potential of mean force for the insertion of the ionic side chain analog of arginine in a lipid bilayer. Umbrella sampling (US) is used to restrain solute insertion depth along the bilayer normal, the order parameter commonly used in simulations of molecular solutes in lipid bilayers. When US simulations are modified to conduct random walks along the bilayer normal using a Hamiltonian exchange algorithm, systematic sampling errors are eliminated more rapidly and the rate of statistical convergence of the standard free energy of binding of the solute to the lipid bilayer is increased 3-fold. We compute the ratio of the replica flux transmitted across a defined region of the order parameter to the replica flux that entered that region in Hamiltonian exchange simulations. We show that this quantity, the transmission factor, identifies sampling barriers in degrees of freedom orthogonal to the order parameter. The transmission factor is used to estimate the depth-dependent conformational autocorrelation times of the simulation system, some of which exceed the simulation time, and thereby identify solute insertion depths that are prone to systematic sampling errors and estimate the lower bound of the amount of sampling that is required to resolve these sampling errors. Finally, we extend our simulations and verify that the conformational autocorrelation times estimated by the transmission factor accurately predict correlation times that exceed the simulation time scale-something that, to our knowledge, has never before been achieved.

Bennett's acceptance ratio and histogram analysis methods enhanced by umbrella sampling along a reaction coordinate in configurational space.

PubMed

Kim, Ilsoo; Allen, Toby W

2012-04-28

Free energy perturbation, a method for computing the free energy difference between two states, is often combined with non-Boltzmann biased sampling techniques in order to accelerate the convergence of free energy calculations. Here we present a new extension of the Bennett acceptance ratio (BAR) method by combining it with umbrella sampling (US) along a reaction coordinate in configurational space. In this approach, which we call Bennett acceptance ratio with umbrella sampling (BAR-US), the conditional histogram of energy difference (a mapping of the 3N-dimensional configurational space via a reaction coordinate onto 1D energy difference space) is weighted for marginalization with the associated population density along a reaction coordinate computed by US. This procedure produces marginal histograms of energy difference, from forward and backward simulations, with higher overlap in energy difference space, rendering free energy difference estimations using BAR statistically more reliable. In addition to BAR-US, two histogram analysis methods, termed Bennett overlapping histograms with US (BOH-US) and Bennett-Hummer (linear) least square with US (BHLS-US), are employed as consistency and convergence checks for free energy difference estimation by BAR-US. The proposed methods (BAR-US, BOH-US, and BHLS-US) are applied to a 1-dimensional asymmetric model potential, as has been used previously to test free energy calculations from non-equilibrium processes. We then consider the more stringent test of a 1-dimensional strongly (but linearly) shifted harmonic oscillator, which exhibits no overlap between two states when sampled using unbiased Brownian dynamics. We find that the efficiency of the proposed methods is enhanced over the original Bennett's methods (BAR, BOH, and BHLS) through fast uniform sampling of energy difference space via US in configurational space. We apply the proposed methods to the calculation of the electrostatic contribution to the absolute solvation free energy (excess chemical potential) of water. We then address the controversial issue of ion selectivity in the K(+) ion channel, KcsA. We have calculated the relative binding affinity of K(+) over Na(+) within a binding site of the KcsA channel for which different, though adjacent, K(+) and Na(+) configurations exist, ideally suited to these US-enhanced methods. Our studies demonstrate that the significant improvements in free energy calculations obtained using the proposed methods can have serious consequences for elucidating biological mechanisms and for the interpretation of experimental data.

Rare behavior of growth processes via umbrella sampling of trajectories

NASA Astrophysics Data System (ADS)

Klymko, Katherine; Geissler, Phillip L.; Garrahan, Juan P.; Whitelam, Stephen

2018-03-01

We compute probability distributions of trajectory observables for reversible and irreversible growth processes. These results reveal a correspondence between reversible and irreversible processes, at particular points in parameter space, in terms of their typical and atypical trajectories. Thus key features of growth processes can be insensitive to the precise form of the rate constants used to generate them, recalling the insensitivity to microscopic details of certain equilibrium behavior. We obtained these results using a sampling method, inspired by the "s -ensemble" large-deviation formalism, that amounts to umbrella sampling in trajectory space. The method is a simple variant of existing approaches, and applies to ensembles of trajectories controlled by the total number of events. It can be used to determine large-deviation rate functions for trajectory observables in or out of equilibrium.

Virtual-system-coupled adaptive umbrella sampling to compute free-energy landscape for flexible molecular docking.

PubMed

Higo, Junichi; Dasgupta, Bhaskar; Mashimo, Tadaaki; Kasahara, Kota; Fukunishi, Yoshifumi; Nakamura, Haruki

2015-07-30

A novel enhanced conformational sampling method, virtual-system-coupled adaptive umbrella sampling (V-AUS), was proposed to compute 300-K free-energy landscape for flexible molecular docking, where a virtual degrees of freedom was introduced to control the sampling. This degree of freedom interacts with the biomolecular system. V-AUS was applied to complex formation of two disordered amyloid-β (Aβ30-35 ) peptides in a periodic box filled by an explicit solvent. An interpeptide distance was defined as the reaction coordinate, along which sampling was enhanced. A uniform conformational distribution was obtained covering a wide interpeptide distance ranging from the bound to unbound states. The 300-K free-energy landscape was characterized by thermodynamically stable basins of antiparallel and parallel β-sheet complexes and some other complex forms. Helices were frequently observed, when the two peptides contacted loosely or fluctuated freely without interpeptide contacts. We observed that V-AUS converged to uniform distribution more effectively than conventional AUS sampling did. © 2015 Wiley Periodicals, Inc.

Molecular principle of the cyclin-dependent kinase selectivity of 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile derivatives revealed by molecular modeling studies.

PubMed

Kong, Xiaotian; Sun, Huiyong; Pan, Peichen; Tian, Sheng; Li, Dan; Li, Youyong; Hou, Tingjun

2016-01-21

Due to the high sequence identity of the binding pockets of cyclin-dependent kinases (CDKs), designing highly selective inhibitors towards a specific CDK member remains a big challenge. 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine derivatives are effective inhibitors of CDKs, among which the most promising inhibitor 12u demonstrates high binding affinity to CDK9 and attenuated binding affinity to other homologous kinases, such as CDK2. In this study, in order to rationalize the principle of the binding preference towards CDK9 over CDK2 and to explore crucial information that may aid the design of selective CDK9 inhibitors, MM/GBSA calculations based on conventional molecular dynamics (MD) simulations and enhanced sampling simulations (umbrella sampling and steered MD simulations) were carried out on two representative derivatives (12u and 4). The calculation results show that the binding specificity of 12u to CDK9 is primarily controlled by conformational change of the G-loop and variation of the van der Waals interactions. Furthermore, the enhanced sampling simulations revealed the different reaction coordinates and transient interactions of inhibitors 12u and 4 as they dissociate from the binding pockets of CDK9 and CDK2. The physical principles obtained from this study may facilitate the discovery and rational design of novel and specific inhibitors of CDK9.

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

Yang, Lu; Hanson, David E

Here we present the results on the study of surface properties of {beta}-HMX crystal utilizing molecular simulations. The surface polarity of three principal crystal surfaces are investigated by measuring the water contact angles. The calculated contact angles agree excellently with the values measured by experiment and show that the surface polarity of three crystal surfaces are different. The free energies and forces of detaching an Estane chain with and without nitroplasticizer from the three principal crystal surfaces were calculated using umbrella sampling technique. We find that the detaching free energy/force increases with the increasing HMX surface polarity. In addition, ourmore » results also show that nitroplasticizer plays an important role in the adhesion forces between Estane and HMX surfaces.« less

Greater sage-grouse as an umbrella species for shrubland passerine birds: a multiscale assessment

USGS Publications Warehouse

Hanser, Steven E.; Knick, Steven T.; Knick, Steven T.; Connelly, John W.

2011-01-01

Working groups and government agen-cies are planning and conducting land actions in sagebrush (Artemisia spp.) habitats to benefit Greater Sage-Grouse (Centrocercus urophasianus) populations. Managers have adopted an umbrella concept, creating habitat characteristics specific to sage-grouse requirements, in the belief that other wildlife species dependent on sagebrush will benefit. We tested the efficacy of this approach by first identifying the primary environmental gradients underlying sagebrush steppe bird com-munities (including Greater Sage-Grouse). We integrated field sampling for birds and vegetation with geographic information system (GIS) data to characterize 305 sites sampled throughout the current range of Greater Sage-Grouse in the Intermountain West, United States. The primary environmental axis defining the bird community represented a gradient from local-scale Wyoming/basin big sagebrush (A. t. ssp. wyomingensis/A. t. ssp. tridentata), and bare ground cover to local and regional grassland cover; the second axis repre-sented a transition from low-elevation Wyoming/basin big sagebrush and bare ground to mountain big sagebrush (A. t. ssp. vaseyana) and habitat edge. We identified the relative overlap of sage-grouse with 13 species of passerine birds along the multiscale gradients and estimated the width of the umbrella when applying management guidelines specific to sage-grouse. Passerine birds associated with sagebrush steppe habitats had high levels of overlap with Greater Sage-Grouse along the multiscale environmental gradients. However, the overlap of the umbrella was prima-rily a function of the broad range of sagebrush habitats used by sage-grouse. Management that focuses on creating a narrow set of plot-scale con-ditions will likely be less effective than restoration efforts that recognize landscape scale heterogene-ity and multiscale organization of habitats. These multiscale efforts may improve some sage-grouse habitats and strengthen the management umb-rella for shrub steppe passerine birds.

The dominant interaction between peptide and urea is electrostatic in nature: a molecular dynamics simulation study.

PubMed

Tobi, Dror; Elber, Ron; Thirumalai, Devarajan

2003-03-01

The conformational equilibrium of a blocked valine peptide in water and aqueous urea solution is studied using molecular dynamics simulations. Pair correlation functions indicate enhanced concentration of urea near the peptide. Stronger hydrogen bonding of urea-peptide compared to water-peptide is observed with preference for helical conformation. The potential of mean force, computed using umbrella sampling, shows only small differences between urea and water solvation that are difficult to quantify. The changes in solvent structure around the peptide are explained by favorable electrostatic interactions (hydrogen bonds) of urea with the peptide backbone. There is no evidence for significant changes in hydrophobic interactions in the two conformations of the peptide in urea solution. Our simulations suggest that urea denatures proteins by preferentially forming hydrogen bonds to the peptide backbone, reducing the barrier for exposing protein residues to the solvent, and reaching the unfolded state. Copyright 2003 Wiley Periodicals, Inc. Biopolymers: 359-369, 2003

Born-Oppenheimer ab initio QM/MM Molecular Dynamics Simulations of Enzyme Reactions

PubMed Central

Zhou, Yanzi; Wang, Shenglong; Li, Yongle; Zhang, Yingkai

2016-01-01

There are two key requirements for reliably simulating enzyme reactions: one is a reasonably accurate potential energy surface to describe the bond forming/breaking process as well as to adequately model the heterogeneous enzyme environment; the other is to perform extensive sampling since an enzyme system consists of at least thousands of atoms and its energy landscape is very complex. One attractive approach to meet both daunting tasks is Born-Oppenheimer ab initio QM/MM molecular dynamics simulation (aiQM/MM-MD) with umbrella sampling. In this chapter, we describe our recently developed pseudobond Q-Chem–Amber interface, which employs a combined electrostatic-mechanical embedding scheme with periodic boundary condition and the particle mesh Ewald method for long-range electrostatics interactions. In our implementation, Q-Chem and the sander module of Amber are combined at the source code level without using system calls, and all necessary data communications between QM and MM calculations are achieved via computer memory. We demonstrate the applicability of this pseudobond Q-Chem–Amber interface by presenting two examples, one reaction in aqueous solution and one enzyme reaction. Finally, we describe our established aiQM/MM-MD enzyme simulation protocol, which has been successfully applied to study more than a dozen enzymes. PMID:27498636

Early-Aggregation Studies of Polyglutamine in Solution

NASA Astrophysics Data System (ADS)

Fluitt, Aaron; de Pablo, Juan

2012-02-01

Several neurodegenerative diseases, notably Huntington's disease, are associated with certain proteins containing extended polyglutamine tracts. In all polyglutamine diseases, the age of onset is inversely correlated with the length of the polyglutamine domain beyond some pathological threshold. Diseased cells are characterized by intranuclear inclusions rich in aggregated polyglutamine. Experimental evidence suggests that oligomeric aggregate species, not mature amyloid fibrils, are the species most toxic to the cell. Little is known about the structures and aggregation dynamics of polyglutamine oligomers due to their short lifetimes. A better understanding of the pathway through which polyglutamine peptides form oligomeric aggregates will aid the design of therapies to inhibit their toxic activity. In this work, we report structural characterization of polyglutamine monomers and dimers from atomistic molecular dynamics simulations in explicit water. Umbrella sampling simulations reveal that the stability of the dimer species with respect to the disassociated monomers is an increasing function of the chain length.

Unconstrained Enhanced Sampling for Free Energy Calculations of Biomolecules: A Review

PubMed Central

Miao, Yinglong; McCammon, J. Andrew

2016-01-01

Free energy calculations are central to understanding the structure, dynamics and function of biomolecules. Yet insufficient sampling of biomolecular configurations is often regarded as one of the main sources of error. Many enhanced sampling techniques have been developed to address this issue. Notably, enhanced sampling methods based on biasing collective variables (CVs), including the widely used umbrella sampling, adaptive biasing force and metadynamics, have been discussed in a recent excellent review (Abrams and Bussi, Entropy, 2014). Here, we aim to review enhanced sampling methods that do not require predefined system-dependent CVs for biomolecular simulations and as such do not suffer from the hidden energy barrier problem as encountered in the CV-biasing methods. These methods include, but are not limited to, replica exchange/parallel tempering, self-guided molecular/Langevin dynamics, essential energy space random walk and accelerated molecular dynamics. While it is overwhelming to describe all details of each method, we provide a summary of the methods along with the applications and offer our perspectives. We conclude with challenges and prospects of the unconstrained enhanced sampling methods for accurate biomolecular free energy calculations. PMID:27453631

Unconstrained Enhanced Sampling for Free Energy Calculations of Biomolecules: A Review.

PubMed

Miao, Yinglong; McCammon, J Andrew

Free energy calculations are central to understanding the structure, dynamics and function of biomolecules. Yet insufficient sampling of biomolecular configurations is often regarded as one of the main sources of error. Many enhanced sampling techniques have been developed to address this issue. Notably, enhanced sampling methods based on biasing collective variables (CVs), including the widely used umbrella sampling, adaptive biasing force and metadynamics, have been discussed in a recent excellent review (Abrams and Bussi, Entropy, 2014). Here, we aim to review enhanced sampling methods that do not require predefined system-dependent CVs for biomolecular simulations and as such do not suffer from the hidden energy barrier problem as encountered in the CV-biasing methods. These methods include, but are not limited to, replica exchange/parallel tempering, self-guided molecular/Langevin dynamics, essential energy space random walk and accelerated molecular dynamics. While it is overwhelming to describe all details of each method, we provide a summary of the methods along with the applications and offer our perspectives. We conclude with challenges and prospects of the unconstrained enhanced sampling methods for accurate biomolecular free energy calculations.

Looking beyond rare species as umbrella species: Northern Bobwhites (Colinus virginianus) and conservation of grassland and shrubland birds

USGS Publications Warehouse

Crosby, Andrew D.; Elmore, R.D.; Leslie,, David M.; Will, Rodney E.

2015-01-01

Changes in land use and land cover throughout the eastern half of North America have caused substantial declines in populations of birds that rely on grassland and shrubland vegetation types, including socially and economically important game birds such as the Northern Bobwhite (Colinus virginianus; hereafter bobwhites). As much attention is focused on habitat management and restoration for bobwhites, they may act as an umbrella species for other bird species with similar habitat requirements. We quantified the relationship of bobwhites to the overall bird community and evaluated the potential for bobwhites to act as an umbrella species for grassland and shrubland birds. We monitored bobwhite presence and bird community composition within 31 sample units on selected private lands in the south-central United States from 2009 to 2011. Bobwhites were strongly associated with other grassland and shrubland birds and were a significant positive predictor for 9 species. Seven of these, including Bell's Vireo (Vireo bell), Dicksissel (Spiza americana), and Grasshopper Sparrow (Ammodramus savannarum), are listed as species of conservation concern. Species richness and occupancy probability of grassland and shrubland birds were higher relative to the overall bird community in sample units occupied by bobwhites. Our results show that bobwhites can act as an umbrella species for grassland and shrubland birds, although the specific species in any given situation will depend on region and management objectives. These results suggest that efficiency in conservation funding can be increased by using public interest in popular game species to leverage resources to meet multiple conservation objectives.

Revealing the favorable dissociation pathway of type II kinase inhibitors via enhanced sampling simulations and two-end-state calculations.

PubMed

Sun, Huiyong; Tian, Sheng; Zhou, Shunye; Li, Youyong; Li, Dan; Xu, Lei; Shen, Mingyun; Pan, Peichen; Hou, Tingjun

2015-02-13

How does a type II inhibitor bind to/unbind from a kinase target is still a confusing question because the small molecule occupies both the ATP pocket and the allosteric pocket of the kinase binding site. Here, by using enhanced sampling simulations (umbrella sampling, US) and two-end-state free energy calculations (MM/GSBA), we systemically studied the dissociation processes of two distinct small molecules escaping from the binding pocket of p38 MAP kinase through the allosteric channel and the ATP channel. The results show that the unbinding pathways along the allosteric channel have much lower PMF depths than those along the ATP channel, suggesting that the allosteric channel is more favorable for the dissociations of the two inhibitors and thereby supporting the general understanding that the largest channel of a target is usually the entry/exit pathway for the binding/dissociation of small molecules. Interestingly, the MM/GBSA approach yielded similar PMF profiles compared with those based on US, a much time consuming approach, indicating that for a general study, such as detecting the important transition state of a ligand binding/unbinding process, MM/GBSA may be a feasible choice.

Surface force measurements and simulations of mussel-derived peptide adhesives on wet organic surfaces

PubMed Central

Levine, Zachary A.; Rapp, Michael V.; Wei, Wei; Mullen, Ryan Gotchy; Wu, Chun; Zerze, Gül H.; Mittal, Jeetain; Waite, J. Herbert; Israelachvili, Jacob N.; Shea, Joan-Emma

2016-01-01

Translating sticky biological molecules—such as mussel foot proteins (MFPs)—into synthetic, cost-effective underwater adhesives with adjustable nano- and macroscale characteristics requires an intimate understanding of the glue’s molecular interactions. To help facilitate the next generation of aqueous adhesives, we performed a combination of surface forces apparatus (SFA) measurements and replica-exchange molecular dynamics (REMD) simulations on a synthetic, easy to prepare, Dopa-containing peptide (MFP-3s peptide), which adheres to organic surfaces just as effectively as its wild-type protein analog. Experiments and simulations both show significant differences in peptide adsorption on CH3-terminated (hydrophobic) and OH-terminated (hydrophilic) self-assembled monolayers (SAMs), where adsorption is strongest on hydrophobic SAMs because of orientationally specific interactions with Dopa. Additional umbrella-sampling simulations yield free-energy profiles that quantitatively agree with SFA measurements and are used to extract the adhesive properties of individual amino acids within the context of MFP-3s peptide adhesion, revealing a delicate balance between van der Waals, hydrophobic, and electrostatic forces. PMID:27036002

Essential energy space random walks to accelerate molecular dynamics simulations: Convergence improvements via an adaptive-length self-healing strategy

NASA Astrophysics Data System (ADS)

Zheng, Lianqing; Yang, Wei

2008-07-01

Recently, accelerated molecular dynamics (AMD) technique was generalized to realize essential energy space random walks so that further sampling enhancement and effective localized enhanced sampling could be achieved. This method is especially meaningful when essential coordinates of the target events are not priori known; moreover, the energy space metadynamics method was also introduced so that biasing free energy functions can be robustly generated. Despite the promising features of this method, due to the nonequilibrium nature of the metadynamics recursion, it is challenging to rigorously use the data obtained at the recursion stage to perform equilibrium analysis, such as free energy surface mapping; therefore, a large amount of data ought to be wasted. To resolve such problem so as to further improve simulation convergence, as promised in our original paper, we are reporting an alternate approach: the adaptive-length self-healing (ALSH) strategy for AMD simulations; this development is based on a recent self-healing umbrella sampling method. Here, the unit simulation length for each self-healing recursion is increasingly updated based on the Wang-Landau flattening judgment. When the unit simulation length for each update is long enough, all the following unit simulations naturally run into the equilibrium regime. Thereafter, these unit simulations can serve for the dual purposes of recursion and equilibrium analysis. As demonstrated in our model studies, by applying ALSH, both fast recursion and short nonequilibrium data waste can be compromised. As a result, combining all the data obtained from all the unit simulations that are in the equilibrium regime via the weighted histogram analysis method, efficient convergence can be robustly ensured, especially for the purpose of free energy surface mapping.

Multiensemble Markov models of molecular thermodynamics and kinetics.

PubMed

Wu, Hao; Paul, Fabian; Wehmeyer, Christoph; Noé, Frank

2016-06-07

We introduce the general transition-based reweighting analysis method (TRAM), a statistically optimal approach to integrate both unbiased and biased molecular dynamics simulations, such as umbrella sampling or replica exchange. TRAM estimates a multiensemble Markov model (MEMM) with full thermodynamic and kinetic information at all ensembles. The approach combines the benefits of Markov state models-clustering of high-dimensional spaces and modeling of complex many-state systems-with those of the multistate Bennett acceptance ratio of exploiting biased or high-temperature ensembles to accelerate rare-event sampling. TRAM does not depend on any rate model in addition to the widely used Markov state model approximation, but uses only fundamental relations such as detailed balance and binless reweighting of configurations between ensembles. Previous methods, including the multistate Bennett acceptance ratio, discrete TRAM, and Markov state models are special cases and can be derived from the TRAM equations. TRAM is demonstrated by efficiently computing MEMMs in cases where other estimators break down, including the full thermodynamics and rare-event kinetics from high-dimensional simulation data of an all-atom protein-ligand binding model.

Multiensemble Markov models of molecular thermodynamics and kinetics

PubMed Central

Wu, Hao; Paul, Fabian; Noé, Frank

2016-01-01

We introduce the general transition-based reweighting analysis method (TRAM), a statistically optimal approach to integrate both unbiased and biased molecular dynamics simulations, such as umbrella sampling or replica exchange. TRAM estimates a multiensemble Markov model (MEMM) with full thermodynamic and kinetic information at all ensembles. The approach combines the benefits of Markov state models—clustering of high-dimensional spaces and modeling of complex many-state systems—with those of the multistate Bennett acceptance ratio of exploiting biased or high-temperature ensembles to accelerate rare-event sampling. TRAM does not depend on any rate model in addition to the widely used Markov state model approximation, but uses only fundamental relations such as detailed balance and binless reweighting of configurations between ensembles. Previous methods, including the multistate Bennett acceptance ratio, discrete TRAM, and Markov state models are special cases and can be derived from the TRAM equations. TRAM is demonstrated by efficiently computing MEMMs in cases where other estimators break down, including the full thermodynamics and rare-event kinetics from high-dimensional simulation data of an all-atom protein–ligand binding model. PMID:27226302

Simulation Modelling in Healthcare: An Umbrella Review of Systematic Literature Reviews.

PubMed

Salleh, Syed; Thokala, Praveen; Brennan, Alan; Hughes, Ruby; Booth, Andrew

2017-09-01

Numerous studies examine simulation modelling in healthcare. These studies present a bewildering array of simulation techniques and applications, making it challenging to characterise the literature. The aim of this paper is to provide an overview of the level of activity of simulation modelling in healthcare and the key themes. We performed an umbrella review of systematic literature reviews of simulation modelling in healthcare. Searches were conducted of academic databases (JSTOR, Scopus, PubMed, IEEE, SAGE, ACM, Wiley Online Library, ScienceDirect) and grey literature sources, enhanced by citation searches. The articles were included if they performed a systematic review of simulation modelling techniques in healthcare. After quality assessment of all included articles, data were extracted on numbers of studies included in each review, types of applications, techniques used for simulation modelling, data sources and simulation software. The search strategy yielded a total of 117 potential articles. Following sifting, 37 heterogeneous reviews were included. Most reviews achieved moderate quality rating on a modified AMSTAR (A Measurement Tool used to Assess systematic Reviews) checklist. All the review articles described the types of applications used for simulation modelling; 15 reviews described techniques used for simulation modelling; three reviews described data sources used for simulation modelling; and six reviews described software used for simulation modelling. The remaining reviews either did not report or did not provide enough detail for the data to be extracted. Simulation modelling techniques have been used for a wide range of applications in healthcare, with a variety of software tools and data sources. The number of reviews published in recent years suggest an increased interest in simulation modelling in healthcare.

Perspective on the reactions between F- and CH3CH2F: the free energy landscape of the E2 and SN2 reaction channels.

PubMed

Ensing, Bernd; Klein, Michael L

2005-05-10

Recently, we computed the 3D free energy surface of the base-induced elimination reaction between F(-) and CH(3)CH(2)F by using a powerful technique within Car-Parrinello molecular dynamics simulation. Here, the set of three order parameters is expanded to six, which allows the study of the competing elimination and substitution reactions simultaneously. The power of the method is exemplified by the exploration of the six-dimensional free energy landscape, sampling, and mapping out the eight stable states as well as the connecting bottlenecks. The free energy profile and barrier along the E2 and S(N)2 reaction channels are refined by using umbrella sampling. The two mechanisms do not share a common "E2C-like" transition state. Comparison with the zero temperature profiles shows a particularly significant entropy contribution to the S(N)2 channel.

Conformational free energies of methyl-α-L-iduronic and methyl-β-D-glucuronic acids in water

NASA Astrophysics Data System (ADS)

Babin, Volodymyr; Sagui, Celeste

2010-03-01

We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a nonequilibrium umbrella sampling method, in this case, the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the weighted histogram analysis technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of α-L-iduronic acid and its C5 epimer β-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.

Exploiting Lipid Permutation Symmetry to Compute Membrane Remodeling Free Energies.

PubMed

Bubnis, Greg; Risselada, Herre Jelger; Grubmüller, Helmut

2016-10-28

A complete physical description of membrane remodeling processes, such as fusion or fission, requires knowledge of the underlying free energy landscapes, particularly in barrier regions involving collective shape changes, topological transitions, and high curvature, where Canham-Helfrich (CH) continuum descriptions may fail. To calculate these free energies using atomistic simulations, one must address not only the sampling problem due to high free energy barriers, but also an orthogonal sampling problem of combinatorial complexity stemming from the permutation symmetry of identical lipids. Here, we solve the combinatorial problem with a permutation reduction scheme to map a structural ensemble into a compact, nondegenerate subregion of configuration space, thereby permitting straightforward free energy calculations via umbrella sampling. We applied this approach, using a coarse-grained lipid model, to test the CH description of bending and found sharp increases in the bending modulus for curvature radii below 10 nm. These deviations suggest that an anharmonic bending term may be required for CH models to give quantitative energetics of highly curved states.

Conformational free energies of methyl-alpha-L-iduronic and methyl-beta-D-glucuronic acids in water.

PubMed

Babin, Volodymyr; Sagui, Celeste

2010-03-14

We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a nonequilibrium umbrella sampling method, in this case, the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the weighted histogram analysis technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of alpha-L-iduronic acid and its C5 epimer beta-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.

Information Behavior and Information Practice: Reviewing the "Umbrella Concepts" of Information-Seeking Studies

ERIC Educational Resources Information Center

Savolainen, Reijo

2007-01-01

Information behavior and information practice, two major concepts denoting the general ways in which people deal with information, are analyzed. Because of their general nature, they may be conceived of as umbrella concepts drawing on "umbrella discourses" with similar names. Information behavior is currently the dominating umbrella concept, while…

Ecological neighborhoods as a framework for umbrella species selection

USGS Publications Warehouse

Stuber, Erica F.; Fontaine, Joseph J.

2018-01-01

Umbrella species are typically chosen because they are expected to confer protection for other species assumed to have similar ecological requirements. Despite its popularity and substantial history, the value of the umbrella species concept has come into question because umbrella species chosen using heuristic methods, such as body or home range size, are not acting as adequate proxies for the metrics of interest: species richness or population abundance in a multi-species community for which protection is sought. How species associate with habitat across ecological scales has important implications for understanding population size and species richness, and therefore may be a better proxy for choosing an umbrella species. We determined the spatial scales of ecological neighborhoods important for predicting abundance of 8 potential umbrella species breeding in Nebraska using Bayesian latent indicator scale selection in N-mixture models accounting for imperfect detection. We compare the conservation value measured as collective avian abundance under different umbrella species selected following commonly used criteria and selected based on identifying spatial land cover characteristics within ecological neighborhoods that maximize collective abundance. Using traditional criteria to select an umbrella species resulted in sub-maximal expected collective abundance in 86% of cases compared to selecting an umbrella species based on land cover characteristics that maximized collective abundance directly. We conclude that directly assessing the expected quantitative outcomes, rather than ecological proxies, is likely the most efficient method to maximize the potential for conservation success under the umbrella species concept.

Investigations of Takeout proteins' ligand binding and release mechanism using molecular dynamics simulation.

PubMed

Zhang, Huijing; Yu, Hui; Zhao, Xi; Liu, Xiaoguang; Feng, Xianli; Huang, Xuri

2017-05-01

Takeout (To) proteins exist in a diverse range of insect species. They are involved in many important processes of insect physiology and behaviors. As the ligand carriers, To proteins can transport the small molecule to the target tissues. However, ligand release mechanism of To proteins is unclear so far. In this contribution, the process and pathway of the ligand binding and release are revealed by conventional molecular dynamics simulation, steered molecular dynamics simulation and umbrella sampling methods. Our results show that the α4-side of the protein is the unique gate for the ligand binding and release. The structural analysis confirms that the internal cavity of the protein has high rigidity, which is in accordance with the recent experimental results. By using the potential of mean force calculations in combination with residue cross correlation calculation, we concluded that the binding between the ligand and To proteins is a process of conformational selection. Furthermore, the conformational changes of To proteins and the hydrophobic interactions both are the key factors for ligand binding and release.

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.

Selection of multiple umbrella species for functional and taxonomic diversity to represent urban biodiversity.

PubMed

Sattler, T; Pezzatti, G B; Nobis, M P; Obrist, M K; Roth, T; Moretti, M

2014-04-01

Surrogates, such as umbrella species, are commonly used to reduce the complexity of quantifying biodiversity for conservation purposes. The presence of umbrella species is often indicative of high taxonomic diversity; however, functional diversity is now recognized as an important metric for biodiversity and thus should be considered when choosing umbrella species. We identified umbrella species associated with high taxonomic and functional biodiversity in urban areas in Switzerland. We analyzed 39,752 individuals of 574 animal species from 96 study plots and 1397 presences of 262 plant species from 58 plots. Thirty-one biodiversity measures of 7 taxonomic groups (plants, spiders, bees, ground beetles, lady bugs, weevils and birds) were included in within- and across-taxa analyses. Sixteen measures were taxonomical (species richness and species diversity), whereas 15 were functional (species traits including mobility, resource use, and reproduction). We used indicator value analysis to identify umbrella species associated with single or multiple biodiversity measures. Many umbrella species were indicators of high biodiversity within their own taxonomic group (from 33.3% in weevils to 93.8% in birds), to a lesser extent they were indicators across taxa. Principal component analysis revealed that umbrella species for multiple measures of biodiversity represented different aspects of biodiversity, especially with respect to measures of taxonomic and functional diversity. Thus, even umbrella species for multiple measures of biodiversity were complementary in the biodiversity aspects they represented. Thus, the choice of umbrella species based solely on taxonomic diversity is questionable and may not represent biodiversity comprehensively. Our results suggest that, depending on conservation priorities, managers should choose multiple and complementary umbrella species to assess the state of biodiversity. © 2013 Society for Conservation Biology.

Thermodynamics of coupled protein adsorption and stability using hybrid Monte Carlo simulations.

PubMed

Zhong, Ellen D; Shirts, Michael R

2014-05-06

A better understanding of changes in protein stability upon adsorption can improve the design of protein separation processes. In this study, we examine the coupling of the folding and the adsorption of a model protein, the B1 domain of streptococcal protein G, as a function of surface attraction using a hybrid Monte Carlo (HMC) approach with temperature replica exchange and umbrella sampling. In our HMC implementation, we are able to use a molecular dynamics (MD) time step that is an order of magnitude larger than in a traditional MD simulation protocol and observe a factor of 2 enhancement in the folding and unfolding rate. To demonstrate the convergence of our systems, we measure the travel of our order parameter the fraction of native contacts between folded and unfolded states throughout the length of our simulations. Thermodynamic quantities are extracted with minimum statistical variance using multistate reweighting between simulations at different temperatures and harmonic distance restraints from the surface. The resultant free energies, enthalpies, and entropies of the coupled unfolding and absorption processes are in qualitative agreement with previous experimental and computational observations, including entropic stabilization of the adsorbed, folded state relative to the bulk on surfaces with low attraction.

Modeling of Oligosaccharides within Glycoproteins from Free-Energy Landscapes

PubMed Central

2017-01-01

In spite of the abundance of glycoproteins in biological processes, relatively little three-dimensional structural data is available for glycan structures. Here, we study the structure and flexibility of the vast majority of mammalian oligosaccharides appearing in N- and O-glycosylated proteins using a bottom up approach. We report the conformational free-energy landscapes of all relevant glycosidic linkages as obtained from local elevation simulations and subsequent umbrella sampling. To the best of our knowledge, this represents the first complete conformational library for the construction of N- and O-glycan structures. Next, we systematically study the effect of neighboring residues, by extensively simulating all relevant trisaccharides and one tetrasaccharide. This allows for an unprecedented comparison of disaccharide linkages in large oligosaccharides. With a small number of exceptions, the conformational preferences in the larger structures are very similar as in the disaccharides. This, finally, allows us to suggest several efficient approaches to construct complete N- and O-glycans on glycoproteins, as exemplified on two relevant examples. PMID:28816453

Enhanced Molecular Dynamics Methods Applied to Drug Design Projects.

PubMed

Ziada, Sonia; Braka, Abdennour; Diharce, Julien; Aci-Sèche, Samia; Bonnet, Pascal

2018-01-01

Nobel Laureate Richard P. Feynman stated: "[…] everything that living things do can be understood in terms of jiggling and wiggling of atoms […]." The importance of computer simulations of macromolecules, which use classical mechanics principles to describe atom behavior, is widely acknowledged and nowadays, they are applied in many fields such as material sciences and drug discovery. With the increase of computing power, molecular dynamics simulations can be applied to understand biological mechanisms at realistic timescales. In this chapter, we share our computational experience providing a global view of two of the widely used enhanced molecular dynamics methods to study protein structure and dynamics through the description of their characteristics, limits and we provide some examples of their applications in drug design. We also discuss the appropriate choice of software and hardware. In a detailed practical procedure, we describe how to set up, run, and analyze two main molecular dynamics methods, the umbrella sampling (US) and the accelerated molecular dynamics (aMD) methods.

GDP Release Preferentially Occurs on the Phosphate Side in Heterotrimeric G-proteins

PubMed Central

Louet, Maxime; Martinez, Jean; Floquet, Nicolas

2012-01-01

After extra-cellular stimulation of G-Protein Coupled Receptors (GPCRs), GDP/GTP exchange appears as the key, rate limiting step of the intracellular activation cycle of heterotrimeric G-proteins. Despite the availability of a large number of X-ray structures, the mechanism of GDP release out of heterotrimeric G-proteins still remains unknown at the molecular level. Starting from the available X-ray structure, extensive unconstrained/constrained molecular dynamics simulations were performed on the complete membrane-anchored Gi heterotrimer complexed to GDP, for a total simulation time overcoming 500 ns. By combining Targeted Molecular Dynamics (TMD) and free energy profiles reconstruction by umbrella sampling, our data suggest that the release of GDP was much more favored on its phosphate side. Interestingly, upon the forced extraction of GDP on this side, the whole protein encountered large, collective motions in perfect agreement with those we described previously including a domain to domain motion between the two ras-like and helical sub-domains of Gα. PMID:22829757

Free energy surfaces for the interaction of D-glucose with planar aromatic groups in aqueous solution

NASA Astrophysics Data System (ADS)

Wohlert, Jakob; Schnupf, Udo; Brady, John W.

2010-10-01

Multidimensional potentials of mean force for the interactions in aqueous solution of both anomers of D-glucopyranose with two planar aromatic molecules, indole and para-methyl-phenol, have been calculated using molecular dynamics simulations with umbrella sampling and were subsequently used to estimate binding free energies. Indole and para-methyl-phenol serve as models for the side chains of the amino acids tryptophan and tyrosine, respectively. In all cases, a weak affinity between the glucose molecules and the flat aromatic surfaces was found. The global minimum for these interactions was found to be for the case when the pseudoplanar face of β-D-glucopyranose is stacked against the planar surfaces of the aromatic residues. The calculated binding free energies are in good agreement with both experiment and previous simulations. The multidimensional free energy maps suggest a mechanism that could lend kinetic stability to the complexes formed by sugars bound to sugar-binding proteins.

Exploring transition pathway and free-energy profile of large-scale protein conformational change by combining normal mode analysis and umbrella sampling molecular dynamics.

PubMed

Wang, Jinan; Shao, Qiang; Xu, Zhijian; Liu, Yingtao; Yang, Zhuo; Cossins, Benjamin P; Jiang, Hualiang; Chen, Kaixian; Shi, Jiye; Zhu, Weiliang

2014-01-09

Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38α kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38α leads to a large change in free-energy barrier (ΔΔG ≈ 7 kcal/mol), promoting the transition from DFG-in to DFG-out conformation (induced fit mechanism). Moreover, the effect of the protonation of D168 on the conformational change of p38α is also studied, which reduces the free-energy difference between the two functional states of p38α and thus further facilitates the conformational interconversion. Therefore, the present study suggests that the detailed mechanism of ligand binding and the associated conformational transition is not uniform for all kinds of proteins but correlated to their respective biological functions.

Excited state free energy calculations of Cy3 in different environments

NASA Astrophysics Data System (ADS)

Sawangsang, Pilailuk; Buranachai, Chittanon; Punwong, Chutintorn

2015-05-01

Cy3, a cyanine dye, is one of the most widely used dyes in investigating the structure and dynamics of biomolecules by means of fluorescence methods. However, Cy3 fluorescence emission is strongly competed by trans-cis isomerization, whose efficiency is dictated by the isomerization energy barrier and the environment of Cy3. The fluorescence quantum yield of Cy3 is very low when the dye is free in homogeneous solution but it is considerably enhanced in an environment that rigidifies the structure, e.g. when it is attached to a DNA strand. In this work, the barriers for isomerization on the excited state of free Cy3, and Cy3 attached to single- and double-stranded DNA in methanol, are presented. The free energy and subsequently the isomerization barrier calculations are performed using the umbrella sampling technique with the weighted histogram analysis method. The hybrid quantum mechanics/molecular mechanics (QM/MM) approach is employed to provide the potential energy surfaces for the excited state dynamics simulations in umbrella sampling. The semiempirical floating occupation molecular orbital configuration interaction method is used for electronic excited state calculations of the QM region (Cy3). From the free energy calculations, the barrier of Cy3 attached to the single-stranded DNA is highest, in agreement with previously reported experimental results. This is likely due to the stacking interaction between Cy3 and DNA. Such a stacking interaction is likely associated with steric hindrance that prevents the rotation around the conjugated bonds of Cy3. If Cy3 experiences high steric hindrance, it has a higher isomerization barrier and thus the efficiency of fluorescence emission increases.

Transition-Tempered Metadynamics Is a Promising Tool for Studying the Permeation of Drug-like Molecules through Membranes.

PubMed

Sun, Rui; Dama, James F; Tan, Jeffrey S; Rose, John P; Voth, Gregory A

2016-10-11

Metadynamics is an important enhanced sampling technique in molecular dynamics simulation to efficiently explore potential energy surfaces. The recently developed transition-tempered metadynamics (TTMetaD) has been proven to converge asymptotically without sacrificing exploration of the collective variable space in the early stages of simulations, unlike other convergent metadynamics (MetaD) methods. We have applied TTMetaD to study the permeation of drug-like molecules through a lipid bilayer to further investigate the usefulness of this method as applied to problems of relevance to medicinal chemistry. First, ethanol permeation through a lipid bilayer was studied to compare TTMetaD with nontempered metadynamics and well-tempered metadynamics. The bias energies computed from various metadynamics simulations were compared to the potential of mean force calculated from umbrella sampling. Though all of the MetaD simulations agree with one another asymptotically, TTMetaD is able to predict the most accurate and reliable estimate of the potential of mean force for permeation in the early stages of the simulations and is robust to the choice of required additional parameters. We also show that using multiple randomly initialized replicas allows convergence analysis and also provides an efficient means to converge the simulations in shorter wall times and, more unexpectedly, in shorter CPU times; splitting the CPU time between multiple replicas appears to lead to less overall error. After validating the method, we studied the permeation of a more complicated drug-like molecule, trimethoprim. Three sets of TTMetaD simulations with different choices of collective variables were carried out, and all converged within feasible simulation time. The minimum free energy paths showed that TTMetaD was able to predict almost identical permeation mechanisms in each case despite significantly different definitions of collective variables.

Free energies from dynamic weighted histogram analysis using unbiased Markov state model.

PubMed

Rosta, Edina; Hummer, Gerhard

2015-01-13

The weighted histogram analysis method (WHAM) is widely used to obtain accurate free energies from biased molecular simulations. However, WHAM free energies can exhibit significant errors if some of the biasing windows are not fully equilibrated. To account for the lack of full equilibration, we develop the dynamic histogram analysis method (DHAM). DHAM uses a global Markov state model to obtain the free energy along the reaction coordinate. A maximum likelihood estimate of the Markov transition matrix is constructed by joint unbiasing of the transition counts from multiple umbrella-sampling simulations along discretized reaction coordinates. The free energy profile is the stationary distribution of the resulting Markov matrix. For this matrix, we derive an explicit approximation that does not require the usual iterative solution of WHAM. We apply DHAM to model systems, a chemical reaction in water treated using quantum-mechanics/molecular-mechanics (QM/MM) simulations, and the Na(+) ion passage through the membrane-embedded ion channel GLIC. We find that DHAM gives accurate free energies even in cases where WHAM fails. In addition, DHAM provides kinetic information, which we here use to assess the extent of convergence in each of the simulation windows. DHAM may also prove useful in the construction of Markov state models from biased simulations in phase-space regions with otherwise low population.

Perspective on the reactions between F– and CH3CH2F: The free energy landscape of the E2 and SN2 reaction channels

PubMed Central

Ensing, Bernd; Klein, Michael L.

2005-01-01

Recently, we computed the 3D free energy surface of the base-induced elimination reaction between F– and CH3CH2F by using a powerful technique within Car–Parrinello molecular dynamics simulation. Here, the set of three order parameters is expanded to six, which allows the study of the competing elimination and substitution reactions simultaneously. The power of the method is exemplified by the exploration of the six-dimensional free energy landscape, sampling, and mapping out the eight stable states as well as the connecting bottlenecks. The free energy profile and barrier along the E2 and SN2 reaction channels are refined by using umbrella sampling. The two mechanisms do not share a common “E2C-like” transition state. Comparison with the zero temperature profiles shows a particularly significant entropy contribution to the SN2 channel. PMID:15863622

Convergence and Efficiency of Adaptive Importance Sampling Techniques with Partial Biasing

NASA Astrophysics Data System (ADS)

Fort, G.; Jourdain, B.; Lelièvre, T.; Stoltz, G.

2018-04-01

We propose a new Monte Carlo method to efficiently sample a multimodal distribution (known up to a normalization constant). We consider a generalization of the discrete-time Self Healing Umbrella Sampling method, which can also be seen as a generalization of well-tempered metadynamics. The dynamics is based on an adaptive importance technique. The importance function relies on the weights (namely the relative probabilities) of disjoint sets which form a partition of the space. These weights are unknown but are learnt on the fly yielding an adaptive algorithm. In the context of computational statistical physics, the logarithm of these weights is, up to an additive constant, the free-energy, and the discrete valued function defining the partition is called the collective variable. The algorithm falls into the general class of Wang-Landau type methods, and is a generalization of the original Self Healing Umbrella Sampling method in two ways: (i) the updating strategy leads to a larger penalization strength of already visited sets in order to escape more quickly from metastable states, and (ii) the target distribution is biased using only a fraction of the free-energy, in order to increase the effective sample size and reduce the variance of importance sampling estimators. We prove the convergence of the algorithm and analyze numerically its efficiency on a toy example.

Surface polarity of beta-HMX crystal and the related adhesive forces with Estane binder.

PubMed

Yang, Lu

2008-12-02

Here I present the results on the study of surface properties of beta-HMX crystal utilizing molecular dynamics simulations. The surface polarity of three principal crystal surfaces, (011), (010), and (110), is investigated by measuring the water contact angles. The calculated contact angles are in excellent agreement with the values measured by experiment and show that the surface polarity of three crystal surfaces are different. The free energies and forces of detaching an Estane chain (with and without surrounding nitroplasticizer molecules) from the three principal crystal surfaces are also calculated using the umbrella sampling method. I find that the force for Estane detachment increases with the increasing HMX surface polarity. In addition, my results show that the nitroplasticizer also plays an important role in the adhesion between Estane and HMX surfaces.

Computational Fluid Dynamics Simulation of Flows in an Oxidation Ditch Driven by a New Surface Aerator.

PubMed

Huang, Weidong; Li, Kun; Wang, Gan; Wang, Yingzhe

2013-11-01

In this article, we present a newly designed inverse umbrella surface aerator, and tested its performance in driving flow of an oxidation ditch. Results show that it has a better performance in driving the oxidation ditch than the original one with higher average velocity and more uniform flow field. We also present a computational fluid dynamics model for predicting the flow field in an oxidation ditch driven by a surface aerator. The improved momentum source term approach to simulate the flow field of the oxidation ditch driven by an inverse umbrella surface aerator was developed and validated through experiments. Four kinds of turbulent models were investigated with the approach, including the standard k - ɛ model, RNG k - ɛ model, realizable k - ɛ model, and Reynolds stress model, and the predicted data were compared with those calculated with the multiple rotating reference frame approach (MRF) and sliding mesh approach (SM). Results of the momentum source term approach are in good agreement with the experimental data, and its prediction accuracy is better than MRF, close to SM. It is also found that the momentum source term approach has lower computational expenses, is simpler to preprocess, and is easier to use.

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

Heinemann, Thomas, E-mail: thomas.heinemann@tu-berlin.de; Klapp, Sabine H. L., E-mail: klapp@physik.tu-berlin.de; Palczynski, Karol, E-mail: karol.palczynski@helmholtz-berlin.de

We present an approach for calculating coarse-grained angle-resolved effective pair potentials for uniaxial molecules. For integrating out the intramolecular degrees of freedom we apply umbrella sampling and steered dynamics techniques in atomistically-resolved molecular dynamics (MD) computer simulations. Throughout this study we focus on disk-like molecules such as coronene. To develop the methods we focus on integrating out the van der Waals and intramolecular interactions, while electrostatic charge contributions are neglected. The resulting coarse-grained pair potential reveals a strong temperature and angle dependence. In the next step we fit the numerical data with various Gay-Berne-like potentials to be used in moremore » efficient simulations on larger scales. The quality of the resulting coarse-grained results is evaluated by comparing their pair and many-body structure as well as some thermodynamic quantities self-consistently to the outcome of atomistic MD simulations of many-particle systems. We find that angle-resolved potentials are essential not only to accurately describe crystal structures but also for fluid systems where simple isotropic potentials start to fail already for low to moderate packing fractions. Further, in describing these states it is crucial to take into account the pronounced temperature dependence arising in selected pair configurations due to bending fluctuations.« less

Multiscale Molecular Dynamics Simulations of Model Hydrophobically Modified Ethylene Oxide Urethane Micelles.

PubMed

Yuan, Fang; Larson, Ronald G

2015-09-24

The flower-like micelles of various aggregation numbers of a model hydrophobically modified ethylene oxide urethane (HEUR) molecule, C16E45C16, and their corresponding starlike micelles, containing the surfactants C16E22 and C16E23, were studied by atomistic and coarse-grained molecular dynamic (MD) simulations. We used free energies from umbrella sampling to calculate the size distribution of micelle sizes and the average time for escape of a hydrophobic group from the micelle. Using the coarse-grained MARTINI force field, the most probable size of the model HEUR molecule was thereby determined to be about 80 hydrophobes per micelle and the average hydrophobe escape time to be about 0.1 s, both of which are consistent with previous experimental studies. Atomistic simulations reveal that hydrogen bond formation and the mean lifetime of hydration waters of the poly(ethylene oxide) (or PEO) groups are location-dependent in the HEUR micelle, with PEO groups immediately adjacent to the C16 groups forming the fewest hydrogen bonds with water and having hydration waters with longer lifetimes than those of the PEO groups located further away from the C16 groups.

Probing the Energy Landscape of Activation Gating of the Bacterial Potassium Channel KcsA

PubMed Central

Linder, Tobias; de Groot, Bert L.; Stary-Weinzinger, Anna

2013-01-01

The bacterial potassium channel KcsA, which has been crystallized in several conformations, offers an ideal model to investigate activation gating of ion channels. In this study, essential dynamics simulations are applied to obtain insights into the transition pathways and the energy profile of KcsA pore gating. In agreement with previous hypotheses, our simulations reveal a two phasic activation gating process. In the first phase, local structural rearrangements in TM2 are observed leading to an intermediate channel conformation, followed by large structural rearrangements leading to full opening of KcsA. Conformational changes of a highly conserved phenylalanine, F114, at the bundle crossing region are crucial for the transition from a closed to an intermediate state. 3.9 µs umbrella sampling calculations reveal that there are two well-defined energy barriers dividing closed, intermediate, and open channel states. In agreement with mutational studies, the closed state was found to be energetically more favorable compared to the open state. Further, the simulations provide new insights into the dynamical coupling effects of F103 between the activation gate and the selectivity filter. Investigations on individual subunits support cooperativity of subunits during activation gating. PMID:23658510

Perforation of the right aortic valve cusp: complication of ventricular septal defect closure with a modified Rashkind umbrella.

PubMed

Vogel, M; Rigby, M L; Shore, D

1996-01-01

An 18-month-old boy with a perimembranous ventricular septal defect (VSD) had undergone transcatheter closure of the defect with a modified 17 mm Rashkind umbrella device at age 4 months (weight 3.8 kg). The clinical signs of a VSD persisted, and he developed aortic incompetence, first detected 5 months after the procedure, which progressed from mild to moderate. A three-dimensional echocardiographic study demonstrated that one of the four arms holding the umbrella was protruding into the aortic valve and had perforated the right aortic valve cusp. This diagnosis was confirmed at subsequent surgery. Surgical repair of the perforated right aortic valve leaflet was necessary. The umbrella was adherent to the tricuspid valve and could not be removed. Instead it was left in situ, but three of the stainless steel arms were cut off. When umbrella closure of a perimembranous VSD is undertaken, the close proximity of part of the distal umbrella to the aortic valve can lead to aortic regurgitation.

Spectral gap optimization of order parameters for sampling complex molecular systems

PubMed Central

Tiwary, Pratyush; Berne, B. J.

2016-01-01

In modern-day simulations of many-body systems, much of the computational complexity is shifted to the identification of slowly changing molecular order parameters called collective variables (CVs) or reaction coordinates. A vast array of enhanced-sampling methods are based on the identification and biasing of these low-dimensional order parameters, whose fluctuations are important in driving rare events of interest. Here, we describe a new algorithm for finding optimal low-dimensional CVs for use in enhanced-sampling biasing methods like umbrella sampling, metadynamics, and related methods, when limited prior static and dynamic information is known about the system, and a much larger set of candidate CVs is specified. The algorithm involves estimating the best combination of these candidate CVs, as quantified by a maximum path entropy estimate of the spectral gap for dynamics viewed as a function of that CV. The algorithm is called spectral gap optimization of order parameters (SGOOP). Through multiple practical examples, we show how this postprocessing procedure can lead to optimization of CV and several orders of magnitude improvement in the convergence of the free energy calculated through metadynamics, essentially giving the ability to extract useful information even from unsuccessful metadynamics runs. PMID:26929365

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.

Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations.

PubMed

Zhao, Sufang; Zhu, Jingyu; Xu, Lei; Jin, Jian

2017-06-01

Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase which is widely involved in cell signaling and controls a broad number of cellular functions. GSK3 contains α and β isoforms, and GSK3β has received more attention and becomes an attractive drug target for the treatment of several diseases. The binding pocket of cyclin-dependent kinase 2 (CDK2) shares high sequence identity to that of GSK3β, and therefore, the design of highly selective inhibitors toward GSK3β remains a big challenge. In this study, a computational strategy, which combines molecular docking, molecular dynamics simulations, free energy calculations, and umbrella sampling simulations, was employed to explore the binding mechanisms of two selective inhibitors to GSK3β and CDK2. The simulation results highlighted the key residues critical for GSK3β selectivity. It was observed that although GSK3β and CDK2 share the conserved ATP-binding pockets, some different residues have significant contributions to protein selectivity. This study provides valuable information for understanding the GSK3β-selective binding mechanisms and the rational design of selective GSK3β inhibitors. © 2016 John Wiley & Sons A/S.

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

2016-03-01

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.

78 FR 9066 - Endangered and Threatened Wildlife and Plants; Enhancement of Survival Permit Application; Draft...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-07

... impacts to the human environment from the proposed Umbrella CCAA and alternatives to the action. DATES..., State, and local governments: Draft Greater Sage-grouse Umbrella Candidate Conservation Agreement with Assurances for Wyoming Ranch Management (Umbrella CCAA), and Draft Environment Assessment of the Greater Sage...

Exploring Flexibility of Progesterone Receptor Ligand Binding Domain Using Molecular Dynamics

PubMed Central

Zheng, Liangzhen; Mu, Yuguang

2016-01-01

Progesterone receptor (PR), a member of nuclear receptor (NR) superfamily, plays a vital role for female reproductive tissue development, differentiation and maintenance. PR ligand, such as progesterone, induces conformation changes in PR ligand binding domain (LBD), thus mediates subsequent gene regulation cascades. PR LBD may adopt different conformations upon an agonist or an antagonist binding. These different conformations would trigger distinct transcription events. Therefore, the dynamics of PR LBD would be of general interest to biologists for a deep understanding of its structure-function relationship. However, no apo-form (non-ligand bound) of PR LBD model has been proposed either by experiments or computational methods so far. In this study, we explored the structural dynamics of PR LBD using molecular dynamics simulations and advanced sampling tools in both ligand-bound and the apo-forms. Resolved by the simulation study, helix 11, helix 12 and loop 895–908 (the loop between these two helices) are quite flexible in antagonistic conformation. Several residues, such as Arg899 and Glu723, could form salt-bridging interaction between helix 11 and helix 3, and are important for the PR LBD dynamics. And we also propose that helix 12 in apo-form PR LBD, not like other NR LBDs, such as human estrogen receptor α (ERα) LBD, may not adopt a totally extended conformation. With the aid of umbrella sampling and metadynamics simulations, several stable conformations of apo-form PR LBD have been sampled, which may work as critical structural models for further large scale virtual screening study to discover novel PR ligands for therapeutic application. PMID:27824891

Accurate calculation of conformational free energy differences in explicit water: the confinement-solvation free energy approach.

PubMed

Esque, Jeremy; Cecchini, Marco

2015-04-23

The calculation of the free energy of conformation is key to understanding the function of biomolecules and has attracted significant interest in recent years. Here, we present an improvement of the confinement method that was designed for use in the context of explicit solvent MD simulations. The development involves an additional step in which the solvation free energy of the harmonically restrained conformers is accurately determined by multistage free energy perturbation simulations. As a test-case application, the newly introduced confinement/solvation free energy (CSF) approach was used to compute differences in free energy between conformers of the alanine dipeptide in explicit water. The results are in excellent agreement with reference calculations based on both converged molecular dynamics and umbrella sampling. To illustrate the general applicability of the method, conformational equilibria of met-enkephalin (5 aa) and deca-alanine (10 aa) in solution were also analyzed. In both cases, smoothly converged free-energy results were obtained in agreement with equilibrium sampling or literature calculations. These results demonstrate that the CSF method may provide conformational free-energy differences of biomolecules with small statistical errors (below 0.5 kcal/mol) and at a moderate computational cost even with a full representation of the solvent.

Computational Approach to Explore the B/A Junction Free Energy in DNA.

PubMed

Kulkarni, Mandar; Mukherjee, Arnab

2016-01-04

Protein-DNA interactions induce conformational changes in DNA such as B- to A-form transitions at a local level. Such transitions are associated with a junction free energy cost at the boundary of two different conformations in a DNA molecule. In this study, we performed umbrella sampling simulations to find the free energy values of the B-A transition at the dinucleotide and trinucleotide level of DNA. Using a combination of dinucleotide and trinucleotide free energy costs obtained from simulations, we calculated the B/A junction free energy. Our study shows that the B/A junction free energy is 0.52 kcal mol(-1) for the A-philic GG step and 1.59 kcal mol(-1) for the B-philic AA step. This observation is in agreement with experimentally derived values. After excluding junction effects, we obtained an absolute free energy cost for the B- to A-form conversion for all the dinucleotide steps. These absolute free energies may be used for predicting the propensity of structural transitions in DNA. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways.

PubMed

Heinz, Leonard P; Kopec, Wojciech; de Groot, Bert L; Fink, Rainer H A

2018-05-02

The ryanodine receptor 1 is a large calcium ion channel found in mammalian skeletal muscle. The ion channel gained a lot of attention recently, after multiple independent authors published near-atomic cryo electron microscopy data. Taking advantage of the unprecedented quality of structural data, we performed molecular dynamics simulations on the entire ion channel as well as on a reduced model. We calculated potentials of mean force for Ba 2+ , Ca 2+ , Mg 2+ , K + , Na + and Cl - ions using umbrella sampling to identify the key residues involved in ion permeation. We found two main binding sites for the cations, whereas the channel is strongly repulsive for chloride ions. Furthermore, the data is consistent with the model that the receptor achieves its ion selectivity by over-affinity for divalent cations in a calcium-block-like fashion. We reproduced the experimental conductance for potassium ions in permeation simulations with applied voltage. The analysis of the permeation paths shows that ions exit the pore via multiple pathways, which we suggest to be related to the experimental observation of different subconducting states.

A Smoluchowski model of crystallization dynamics of small colloidal clusters

NASA Astrophysics Data System (ADS)

Beltran-Villegas, Daniel J.; Sehgal, Ray M.; Maroudas, Dimitrios; Ford, David M.; Bevan, Michael A.

2011-10-01

We investigate the dynamics of colloidal crystallization in a 32-particle system at a fixed value of interparticle depletion attraction that produces coexisting fluid and solid phases. Free energy landscapes (FELs) and diffusivity landscapes (DLs) are obtained as coefficients of 1D Smoluchowski equations using as order parameters either the radius of gyration or the average crystallinity. FELs and DLs are estimated by fitting the Smoluchowski equations to Brownian dynamics (BD) simulations using either linear fits to locally initiated trajectories or global fits to unbiased trajectories using Bayesian inference. The resulting FELs are compared to Monte Carlo Umbrella Sampling results. The accuracy of the FELs and DLs for modeling colloidal crystallization dynamics is evaluated by comparing mean first-passage times from BD simulations with analytical predictions using the FEL and DL models. While the 1D models accurately capture dynamics near the free energy minimum fluid and crystal configurations, predictions near the transition region are not quantitatively accurate. A preliminary investigation of ensemble averaged 2D order parameter trajectories suggests that 2D models are required to capture crystallization dynamics in the transition region.

Nucleus-size pinning for determination of nucleation free-energy barriers and nucleus geometry

NASA Astrophysics Data System (ADS)

Sharma, Abhishek K.; Escobedo, Fernando A.

2018-05-01

Classical Nucleation Theory (CNT) has recently been used in conjunction with a seeding approach to simulate nucleation phenomena at small-to-moderate supersaturation conditions when large free-energy barriers ensue. In this study, the conventional seeding approach [J. R. Espinosa et al., J. Chem. Phys. 144, 034501 (2016)] is improved by a novel, more robust method to estimate nucleation barriers. Inspired by the interfacial pinning approach [U. R. Pedersen, J. Chem. Phys. 139, 104102 (2013)] used before to determine conditions where two phases coexist, the seed of the incipient phase is pinned to a preselected size to iteratively drive the system toward the conditions where the seed becomes a critical nucleus. The proposed technique is first validated by estimating the critical nucleation conditions for the disorder-to-order transition in hard spheres and then applied to simulate and characterize the highly non-trivial (prolate) morphology of the critical crystal nucleus in hard gyrobifastigia. A generalization of CNT is used to account for nucleus asphericity and predict nucleation free-energy barriers for gyrobifastigia. These predictions of nuclei shape and barriers are validated by independent umbrella sampling calculations.

Variational Identification of Markovian Transition States

NASA Astrophysics Data System (ADS)

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

2017-07-01

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

Search for the source of an apparent interfacial resistance to mass transfer of CnEm surfactants to the water/oil interface.

PubMed

Huston, Kyle J; Kiemen, Ashley; Larson, Ronald G

2018-06-12

Experiments have shown that relaxation of oil/water interfacial tension by adsorption of alkyl ethoxylate surfactants from water onto an oil droplet is delayed relative to diffusion-controlled adsorption. We examine possible causes of this delay, and we show that several are implausible. We find that re-dissolution of the surfactant in the oil droplet cannot explain the apparent interfacial resistance at short times, because the interface will preferentially fill before any such re-dissolution occurs. We also perform umbrella sampling with molecular dynamics simulation and do not find any evidence of a free energy barrier or low-diffusivity zone near the interface. Nor do we find evidence from simulation that pre-micellar aggregation slows diffusion enough to cause the observed resistance to interfacial adsorption. We are therefore unable to pinpoint the cause of the resistance, but we suggest that "dead time" associated with the experimental method could be responsible - specifically a local depletion of surfactant by the ejected droplet when creating the fresh interface between the oil and water.

Energetics of Glutamate Binding to an Ionotropic Glutamate Receptor.

PubMed

Yu, Alvin; Lau, Albert Y

2017-11-22

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are responsible for the majority of excitatory transmission at the synaptic cleft. Mechanically speaking, agonist binding to the ligand binding domain (LBD) activates the receptor by triggering a conformational change that is transmitted to the transmembrane region, opening the ion channel pore. We use fully atomistic molecular dynamics simulations to investigate the binding process in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, an iGluR subtype. The string method with swarms of trajectories was applied to calculate the possible pathways glutamate traverses during ligand binding. Residues peripheral to the binding cleft are found to metastably bind the ligand prior to ligand entry into the binding pocket. Umbrella sampling simulations were performed to compute the free energy barriers along the binding pathways. The calculated free energy profiles demonstrate that metastable interactions contribute substantially to the energetics of ligand binding and form local minima in the overall free energy landscape. Protein-ligand interactions at sites outside of the orthosteric agonist-binding site may serve to lower the transition barriers of the binding process.

A thermodynamic study of Abeta(16-21) dissociation from a fibril using computer simulations

NASA Astrophysics Data System (ADS)

Dias, Cristiano; Mahmoudinobar, Farbod; Su, Zhaoqian

Here, I will discuss recent all-atom molecular dynamics simulations with explicit water in which we studied the thermodynamic properties of Abeta(16-21) dissociation from an amyloid fibril. Changes in thermodynamics quantities, e.g., entropy, enthalpy, and volume, are computed from the temperature dependence of the free-energy computed using the umbrella sampling method. We find similarities and differences between the thermodynamics of peptide dissociation and protein unfolding. Similarly to protein unfolding, Abeta(16-21) dissociation is characterized by an unfavorable change in enthalpy, a favorable change in the entropic energy, and an increase in the heat capacity. A main difference is that peptide dissociation is characterized by a weak enthalpy-entropy compensation. We characterize dock and lock states of the peptide based on the solvent accessible surface area. The Lennard-Jones energy of the system is observed to increase continuously in lock and dock states as the peptide dissociates. The electrostatic energy increases in the lock state and it decreases in the dock state as the peptide dissociates. These results will be discussed as well as their implication for fibril growth.

When BVD doesn't look like BVD

USDA-ARS?s Scientific Manuscript database

Due to the sheer number of different clinical presentations existing under the BVD umbrella, diagnosing BVD based on clinical signs is not advisable. Thus diagnosis relies upon testing of samples in diagnostic laboratories. In the US, most of the diagnostic effort has been focused on identifying a...

Radioactivity in three species of eastern Mediterranean jellyfish.

PubMed

Mamish, S; Al-Masri, M S; Durgham, H

2015-11-01

Activity concentrations of (137)Cs, (40)K, (210)Po, (210)Pb, (234)U and (238)U were determined in umbrella and oral arms of three widely distributed jellyfish species; namely Rhopilema nomadica Galil, 1990, Aurelia aurita Linne, 1758 and Aequorea forskalea Péron & Lesueur, 1810 collected from February 2011 to January 2012 in four sampling locations along the Syrian coast (Eastern Mediterranean Sea). The results have shown significant variations in radionuclides activity concentrations amongst the species. The average activity concentrations of (40)K, (210)Po, (210)Pb, (234)U and (238)U in the umbrella of R. nomadica species were higher than the average activity concentrations in the umbrella of A. aurita species by about 3.2, 1.4, 1.8, 3.2 and 3.2 folds, and A. forskalea species by about 45.5, 15.4, 19, 7.4 and 7.6 folds, respectively. The average activity concentrations of (40)K, (210)Po, (210)Pb, (234)U and (238)U in oral arms of R. nomadica species were higher than the average activity concentrations in oral arms of A. aurita species by about 3.8, 1.7, 1.9, 2.8 and 2.9 folds, respectively. (137)Cs activity concentrations were below the detection limit in all measured samples. In addition, activity concentrations of (137)Cs, (40)K, (210)Po, (210)Pb, (234)U and (238)U were also determined in 44 surface seawater samples and the activity concentrations ranged between 10.6 and 11.9 Bq l(-1) for (40)K, 1.1 and 1.4 mBq l(-1) for (210)Po, 0.5 and 0.7 mBq l(-1) for (210)Pb, 40.8 and 44.5 mBq l(-1) for (234)U, and 36.9 and 38.4 mBq l(-1) for (238)U, while (137)Cs activity concentrations were below the detection limit in all measured samples. Moreover, the umbrella and oral arms readily accumulated (40)K, (210)Po, (210)Pb, (234)U and (238)U above ambient seawater levels in the sequence of (210)Po > (210)Pb > (4) K > (234)U and (238)U. Concentration ratio (CR) values were relatively high for (210)Po and (210)Pb and reached 10(3) and 10(2), respectively for the jellyfish R. nomadica species compared to A. aurita and A. forskalea species. Therefore, R. nomadica can be used as biomonitor for these two radionuclides in the Eastern Mediterranean Sea. However, the obtained data can be considered the first reported baseline values for radioactivity in jellyfish. Copyright © 2015 Elsevier Ltd. All rights reserved.

Selectivity trend of gas separation through nanoporous graphene

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

Liu, Hongjun; Chen, Zhongfang; Dai, Sheng

2015-04-15

By means of molecular dynamics (MD) simulations, we demonstrate that porous graphene can efficiently separate gases according to their molecular sizes. The flux sequence from the classical MD simulation is H{sub 2}>CO{sub 2}≫N{sub 2}>Ar>CH{sub 4}, which generally follows the trend in the kinetic diameters. This trend is also confirmed from the fluxes based on the computed free energy barriers for gas permeation using the umbrella sampling method and kinetic theory of gases. Both brute-force MD simulations and free-energy calcualtions lead to the flux trend consistent with experiments. Case studies of two compositions of CO{sub 2}/N{sub 2} mixtures further demonstrate themore » separation capability of nanoporous graphene. - Graphical abstract: Classical molecular dynamics simulations show the flux trend of H{sub 2}>CO{sub 2}≫N{sub 2}>Ar>CH{sub 4} for their permeation through a porous graphene, in excellent agreement with a recent experiment. - Highlights: • Classical MD simulations show the flux trend of H{sub 2}>CO{sub 2}≫N{sub 2}>Ar>CH{sub 4} for their permeation through a porous graphene. • Free energy calculations yield permeation barriers for those gases. • Selectivities for several gas pairs are estimated from the free-energy barriers and the kinetic theory of gases. • The selectivity trend is in excellent agreement with a recent experiment.« less

Mechanism of mRNA-STAR domain interaction: Molecular dynamics simulations of Mammalian Quaking STAR protein.

PubMed

Sharma, Monika; Anirudh, C R

2017-10-03

STAR proteins are evolutionary conserved mRNA-binding proteins that post-transcriptionally regulate gene expression at all stages of RNA metabolism. These proteins possess conserved STAR domain that recognizes identical RNA regulatory elements as YUAAY. Recently reported crystal structures show that STAR domain is composed of N-terminal QUA1, K-homology domain (KH) and C-terminal QUA2, and mRNA binding is mediated by KH-QUA2 domain. Here, we present simulation studies done to investigate binding of mRNA to STAR protein, mammalian Quaking protein (QKI). We carried out conventional MD simulations of STAR domain in presence and absence of mRNA, and studied the impact of mRNA on the stability, dynamics and underlying allosteric mechanism of STAR domain. Our unbiased simulations results show that presence of mRNA stabilizes the overall STAR domain by reducing the structural deviations, correlating the 'within-domain' motions, and maintaining the native contacts information. Absence of mRNA not only influenced the essential modes of motion of STAR domain, but also affected the connectivity of networks within STAR domain. We further explored the dissociation of mRNA from STAR domain using umbrella sampling simulations, and the results suggest that mRNA binding to STAR domain occurs in multi-step: first conformational selection of mRNA backbone conformations, followed by induced fit mechanism as nucleobases interact with STAR domain.

Theory and simulation of ion conduction in the pentameric GLIC channel.

PubMed

Zhu, Fangqiang; Hummer, Gerhard

2012-10-09

GLIC is a bacterial member of the large family of pentameric ligand-gated ion channels. To study ion conduction through GLIC and other membrane channels, we combine the one-dimensional potential of mean force for ion passage with a Smoluchowski diffusion model, making it possible to calculate single-channel conductance in the regime of low ion concentrations from all-atom molecular dynamics (MD) simulations. We then perform MD simulations to examine sodium ion conduction through the GLIC transmembrane pore in two systems with different bulk ion concentrations. The ion potentials of mean force, calculated from umbrella sampling simulations with Hamiltonian replica exchange, reveal a major barrier at the hydrophobic constriction of the pore. The relevance of this barrier for ion transport is confirmed by a committor function that rises sharply in the barrier region. From the free evolution of Na(+) ions starting at the barrier top, we estimate the effective diffusion coefficient in the barrier region, and subsequently calculate the conductance of the pore. The resulting diffusivity compares well with the position-dependent ion diffusion coefficient obtained from restrained simulations. The ion conductance obtained from the diffusion model agrees with the value determined via a reactive-flux rate calculation. Our results show that the conformation in the GLIC crystal structure, with an estimated conductance of ~1 picosiemens at 140 mM ion concentration, is consistent with a physiologically open state of the channel.

Conformational properties of glucose-based disaccharides investigated using molecular dynamics simulations with local elevation umbrella sampling.

PubMed

Perić-Hassler, Lovorka; Hansen, Halvor S; Baron, Riccardo; Hünenberger, Philippe H

2010-08-16

Explicit-solvent molecular dynamics (MD) simulations of the 11 glucose-based disaccharides in water at 300K and 1bar are reported. The simulations were carried out with the GROMOS 45A4 force-field and the sampling along the glycosidic dihedral angles phi and psi was artificially enhanced using the local elevation umbrella sampling (LEUS) method. The trajectories are analyzed in terms of free-energy maps, stable and metastable conformational states (relative free energies and estimated transition timescales), intramolecular H-bonds, single molecule configurational entropies, and agreement with experimental data. All disaccharides considered are found to be characterized either by a single stable (overwhelmingly populated) state ((1-->n)-linked disaccharides with n=1, 2, 3, or 4) or by two stable (comparably populated and differing in the third glycosidic dihedral angle omega ; gg or gt) states with a low interconversion barrier ((1-->6)-linked disaccharides). Metastable (anti-phi or anti-psi) states are also identified with relative free energies in the range of 8-22 kJ mol(-1). The 11 compounds can be classified into four families: (i) the alpha(1-->1)alpha-linked disaccharide trehalose (axial-axial linkage) presents no metastable state, the lowest configurational entropy, and no intramolecular H-bonds; (ii) the four alpha(1-->n)-linked disaccharides (n=1, 2, 3, or 4; axial-equatorial linkage) present one metastable (anti-psi) state, an intermediate configurational entropy, and two alternative intramolecular H-bonds; (iii) the four beta(1-->n)-linked disaccharides (n=1, 2, 3, or 4; equatorial-equatorial linkage) present two metastable (anti-phi and anti-psi) states, an intermediate configurational entropy, and one intramolecular H-bond; (iv) the two (1-->6)-linked disaccharides (additional glycosidic dihedral angle) present no (isomaltose) or a pair of (gentiobiose) metastable (anti-phi) states, the highest configurational entropy, and no intramolecular H-bonds. The observed conformational preferences appear to be dictated by four main driving forces (ring conformational preferences, exo-anomeric effect, steric constraints, and possible presence of a third glycosidic dihedral angle), leaving a secondary role to intramolecular H-bonding and specific solvation effects. In spite of the weak conformational driving force attributed to solvent-exposed H-bonds in water (highly polar protic solvent), intramolecular H-bonds may still have a significant influence on the physico-chemical properties of the disaccharide by decreasing its hydrophilicity. Along with previous work, the results also complete the suggestion of a spectrum of approximate transition timescales for carbohydrates up to the disaccharide level, namely: approximately 30 ps (hydroxyl groups), approximately 1 ns (free lactol group, free hydroxymethyl groups, glycosidic dihedral angleomega in (1-->6)-linked disaccharides), approximately 10 ns to 2 micros (ring conformation, glycosidic dihedral angles phi and psi). The calculated average values of the glycosidic torsional angles agree well with the available experimental data, providing validation for the force-field and simulation methodology employed. Copyright 2010 Elsevier Ltd. All rights reserved.

Miscibility at the immiscible liquid/liquid interface: A molecular dynamics study of thermodynamics and mechanism

NASA Astrophysics Data System (ADS)

Karnes, John J.; Benjamin, Ilan

2018-01-01

Molecular dynamics simulations are used to study the dissolution of water into an adjacent, immiscible organic liquid phase. Equilibrium thermodynamic and structural properties are calculated during the transfer of water molecule(s) across the interface using umbrella sampling. The net free energy of transfer agrees reasonably well with experimental solubility values. We find that water molecules "prefer" to transfer into the adjacent phase one-at-a-time, without co-transfer of the hydration shell, as in the case of evaporation. To study the dynamics and mechanism of transfer of water to liquid nitrobenzene, we collected over 400 independent dissolution events. Analysis of these trajectories suggests that the transfer of water is facilitated by interfacial protrusions of the water phase into the organic phase, where one water molecule at the tip of the protrusion enters the organic phase by the breakup of a single hydrogen bond.

Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations.

PubMed

Sgrignani, Jacopo; Grazioso, Giovanni; De Amici, Marco

2016-09-13

The fast and constant development of drug resistant bacteria represents a serious medical emergency. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this work, we investigated, at the atomistic level, the mechanisms of hydrolysis of Meropenem by OXA-23, a class D β-lactamase, combining unbiased classical molecular dynamics and umbrella sampling simulations with classical force field-based and quantum mechanics/molecular mechanics potentials. Our calculations provide a detailed structural and dynamic picture of the molecular steps leading to the formation of the Meropenem-OXA-23 covalent adduct, the subsequent hydrolysis, and the final release of the inactive antibiotic. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements, validating the expected reaction path.

Effect of tension and curvature on the chemical potential of lipids in lipid aggregates.

PubMed

Grafmüller, Andrea; Lipowsky, Reinhard; Knecht, Volker

2013-01-21

Understanding the factors that influence the free energy of lipids in bilayer membranes is an essential step toward understanding exchange processes of lipids between membranes. In general, both lipid composition and membrane geometry can affect lipid exchange rates between bilayer membranes. Here, the free energy change ΔG(des) for the desorption of dipalmitoyl-phosphatidylcholine (DPPC) lipids from different lipid aggregates has been computed using molecular dynamics simulations and umbrella sampling. The value of ΔG(des) is found to depend strongly on the local properties of the aggregate, in that both tension and curvature lead to an increase in ΔG(des). A detailed analysis shows that the increased desorption free energy for tense bilayers arises from the increased conformational entropy of the lipid tails, which reduces the favorable component -TΔS(L) of the desorption free energy.

Adaptively biased molecular dynamics for free energy calculations

NASA Astrophysics Data System (ADS)

Babin, Volodymyr; Roland, Christopher; Sagui, Celeste

2008-04-01

We present an adaptively biased molecular dynamics (ABMD) method for the computation of the free energy surface of a reaction coordinate using nonequilibrium dynamics. The ABMD method belongs to the general category of umbrella sampling methods with an evolving biasing potential and is inspired by the metadynamics method. The ABMD method has several useful features, including a small number of control parameters and an O(t ) numerical cost with molecular dynamics time t. The ABMD method naturally allows for extensions based on multiple walkers and replica exchange, where different replicas can have different temperatures and/or collective variables. This is beneficial not only in terms of the speed and accuracy of a calculation, but also in terms of the amount of useful information that may be obtained from a given simulation. The workings of the ABMD method are illustrated via a study of the folding of the Ace-GGPGGG-Nme peptide in a gaseous and solvated environment.

Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach.

PubMed

Aromataris, Edoardo; Fernandez, Ritin; Godfrey, Christina M; Holly, Cheryl; Khalil, Hanan; Tungpunkom, Patraporn

2015-09-01

With the increase in the number of systematic reviews available, a logical next step to provide decision makers in healthcare with the evidence they require has been the conduct of reviews of existing systematic reviews. Syntheses of existing systematic reviews are referred to by many different names, one of which is an umbrella review. An umbrella review allows the findings of reviews relevant to a review question to be compared and contrasted. An umbrella review's most characteristic feature is that this type of evidence synthesis only considers for inclusion the highest level of evidence, namely other systematic reviews and meta-analyses. A methodology working group was formed by the Joanna Briggs Institute to develop methodological guidance for the conduct of an umbrella review, including diverse types of evidence, both quantitative and qualitative. The aim of this study is to describe the development and guidance for the conduct of an umbrella review. Discussion and testing of the elements of methods for the conduct of an umbrella review were held over a 6-month period by members of a methodology working group. The working group comprised six participants who corresponded via teleconference, e-mail and face-to-face meeting during this development period. In October 2013, the methodology was presented in a workshop at the Joanna Briggs Institute Convention. Workshop participants, review authors and methodologists provided further testing, critique and feedback on the proposed methodology. This study describes the methodology and methods developed for the conduct of an umbrella review that includes published systematic reviews and meta-analyses as the analytical unit of the review. Details are provided regarding the essential elements of an umbrella review, including presentation of the review question in a Population, Intervention, Comparator, Outcome format, nuances of the inclusion criteria and search strategy. A critical appraisal tool with 10 questions to help assess risk of bias in systematic reviews and meta-analyses was also developed and tested. Relevant details to extract from included reviews and how to best present the findings of both quantitative and qualitative systematic reviews in a reader friendly format are provided. Umbrella reviews provide a ready means for decision makers in healthcare to gain a clear understanding of a broad topic area. The umbrella review methodology described here is the first to consider reviews that report other than quantitative evidence derived from randomized controlled trials. The methodology includes an easy to use and informative summary of evidence table to readily provide decision makers with the available, highest level of evidence relevant to the question posed.

Position paper: Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol.

PubMed

van den Heuvel-Eibrink, Marry M; Hol, Janna A; Pritchard-Jones, Kathy; van Tinteren, Harm; Furtwängler, Rhoikos; Verschuur, Arnauld C; Vujanic, Gordan M; Leuschner, Ivo; Brok, Jesper; Rübe, Christian; Smets, Anne M; Janssens, Geert O; Godzinski, Jan; Ramírez-Villar, Gema L; de Camargo, Beatriz; Segers, Heidi; Collini, Paola; Gessler, Manfred; Bergeron, Christophe; Spreafico, Filippo; Graf, Norbert

2017-12-01

The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP-RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP-RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP-RTSG best available treatment standard.

Computational Fluid Dynamics Simulation of Flows in an Oxidation Ditch Driven by a New Surface Aerator

PubMed Central

Huang, Weidong; Li, Kun; Wang, Gan; Wang, Yingzhe

2013-01-01

Abstract In this article, we present a newly designed inverse umbrella surface aerator, and tested its performance in driving flow of an oxidation ditch. Results show that it has a better performance in driving the oxidation ditch than the original one with higher average velocity and more uniform flow field. We also present a computational fluid dynamics model for predicting the flow field in an oxidation ditch driven by a surface aerator. The improved momentum source term approach to simulate the flow field of the oxidation ditch driven by an inverse umbrella surface aerator was developed and validated through experiments. Four kinds of turbulent models were investigated with the approach, including the standard k−ɛ model, RNG k−ɛ model, realizable k−ɛ model, and Reynolds stress model, and the predicted data were compared with those calculated with the multiple rotating reference frame approach (MRF) and sliding mesh approach (SM). Results of the momentum source term approach are in good agreement with the experimental data, and its prediction accuracy is better than MRF, close to SM. It is also found that the momentum source term approach has lower computational expenses, is simpler to preprocess, and is easier to use. PMID:24302850

Sun Protection by Beach Umbrella vs Sunscreen With a High Sun Protection Factor: A Randomized Clinical Trial.

PubMed

Ou-Yang, Hao; Jiang, Lily I; Meyer, Karen; Wang, Steve Q; Farberg, Aaron S; Rigel, Darrell S

2017-03-01

Sun-protective behavior affects skin cancer prevention. Shade works by physically shielding skin from direct harmful UV rays; however, skin may still remain exposed to reflected and indirect UV rays. There is no current standard metric to evaluate shade for its effectiveness in sun protection, and there is insufficient clinical evidence that a beach umbrella alone can provide adequate sun protection. To directly measure sunburn protection offered by a standard beach umbrella compared with that provided by sunscreen with a high sun protection factor under actual use conditions. A single-center, evaluator-blinded, randomized clinical study was conducted from August 13 to 15, 2014, in Lake Lewisville, Texas (elevation, 159 m above sea level), among 81 participants with Fitzpatrick skin types I (n = 1), II (n = 42), and III (n = 38). Participants were randomly assigned to 2 groups: 1 using only a beach umbrella, and the other using only sunscreen with a sun protection factor of 100. All participants remained at a sunny beach for 3½ hours at midday. Clinical sunburn evaluation of each individual for all exposed body sites was conducted 22 to 24 hours after sun exposure. The shade provided by a beach umbrella or protection provided by sunscreen with a sun protection factor of 100. Sunburn on all exposed body sites 22 to 24 hours after sun exposure. Among the 81 participants (25 male and 56 female; mean [SD] age, 41 [16] years) for all body sites evaluated (face, back of neck, upper chest, arms, and legs), the umbrella group showed a statistically significant increase in clinical sunburn scores compared with baseline and had higher postexposure global scores than the sunscreen group (0.75 vs 0.05; P < .001). There was a total of 142 sunburn incidences in the umbrella group vs 17 in the sunscreen group. Thirty-two of the 41 participants (78%) in the umbrella group showed erythema in 1 or more sites vs 10 of the 40 participants (25%) in the sunscreen group (P < .001). Neither umbrella nor sunscreen alone completely prevented sunburn. A beach umbrella alone may not provide sufficient protection for extended UV exposure. It is important to educate the public that combining multiple sun protection measures may be needed to achieve optimal protection. isrctn.org Identifier: ISRCTN19177299.

Optimal updating magnitude in adaptive flat-distribution sampling

NASA Astrophysics Data System (ADS)

Zhang, Cheng; Drake, Justin A.; Ma, Jianpeng; Pettitt, B. Montgomery

2017-11-01

We present a study on the optimization of the updating magnitude for a class of free energy methods based on flat-distribution sampling, including the Wang-Landau (WL) algorithm and metadynamics. These methods rely on adaptive construction of a bias potential that offsets the potential of mean force by histogram-based updates. The convergence of the bias potential can be improved by decreasing the updating magnitude with an optimal schedule. We show that while the asymptotically optimal schedule for the single-bin updating scheme (commonly used in the WL algorithm) is given by the known inverse-time formula, that for the Gaussian updating scheme (commonly used in metadynamics) is often more complex. We further show that the single-bin updating scheme is optimal for very long simulations, and it can be generalized to a class of bandpass updating schemes that are similarly optimal. These bandpass updating schemes target only a few long-range distribution modes and their optimal schedule is also given by the inverse-time formula. Constructed from orthogonal polynomials, the bandpass updating schemes generalize the WL and Langfeld-Lucini-Rago algorithms as an automatic parameter tuning scheme for umbrella sampling.

Optimal updating magnitude in adaptive flat-distribution sampling.

PubMed

Zhang, Cheng; Drake, Justin A; Ma, Jianpeng; Pettitt, B Montgomery

2017-11-07

We present a study on the optimization of the updating magnitude for a class of free energy methods based on flat-distribution sampling, including the Wang-Landau (WL) algorithm and metadynamics. These methods rely on adaptive construction of a bias potential that offsets the potential of mean force by histogram-based updates. The convergence of the bias potential can be improved by decreasing the updating magnitude with an optimal schedule. We show that while the asymptotically optimal schedule for the single-bin updating scheme (commonly used in the WL algorithm) is given by the known inverse-time formula, that for the Gaussian updating scheme (commonly used in metadynamics) is often more complex. We further show that the single-bin updating scheme is optimal for very long simulations, and it can be generalized to a class of bandpass updating schemes that are similarly optimal. These bandpass updating schemes target only a few long-range distribution modes and their optimal schedule is also given by the inverse-time formula. Constructed from orthogonal polynomials, the bandpass updating schemes generalize the WL and Langfeld-Lucini-Rago algorithms as an automatic parameter tuning scheme for umbrella sampling.

Metadynamics convergence law in a multidimensional system

NASA Astrophysics Data System (ADS)

Crespo, Yanier; Marinelli, Fabrizio; Pietrucci, Fabio; Laio, Alessandro

2010-05-01

Metadynamics is a powerful sampling technique that uses a nonequilibrium history-dependent process to reconstruct the free-energy surface as a function of the relevant collective variables s . In Bussi [Phys. Rev. Lett. 96, 090601 (2006)] it is proved that, in a Langevin process, metadynamics provides an unbiased estimate of the free energy F(s) . We here study the convergence properties of this approach in a multidimensional system, with a Hamiltonian depending on several variables. Specifically, we show that in a Monte Carlo metadynamics simulation of an Ising model the time average of the history-dependent potential converge to F(s) with the same law of an umbrella sampling performed in optimal conditions (i.e., with a bias exactly equal to the negative of the free energy). Remarkably, after a short transient, the error becomes approximately independent on the filling speed, showing that even in out-of-equilibrium conditions metadynamics allows recovering an accurate estimate of F(s) . These results have been obtained introducing a functional form of the history-dependent potential that avoids the onset of systematic errors near the boundaries of the free-energy landscape.

Metadynamics convergence law in a multidimensional system.

PubMed

Crespo, Yanier; Marinelli, Fabrizio; Pietrucci, Fabio; Laio, Alessandro

2010-05-01

Metadynamics is a powerful sampling technique that uses a nonequilibrium history-dependent process to reconstruct the free-energy surface as a function of the relevant collective variables s . In Bussi [Phys. Rev. Lett. 96, 090601 (2006)] it is proved that, in a Langevin process, metadynamics provides an unbiased estimate of the free energy F(s) . We here study the convergence properties of this approach in a multidimensional system, with a Hamiltonian depending on several variables. Specifically, we show that in a Monte Carlo metadynamics simulation of an Ising model the time average of the history-dependent potential converge to F(s) with the same law of an umbrella sampling performed in optimal conditions (i.e., with a bias exactly equal to the negative of the free energy). Remarkably, after a short transient, the error becomes approximately independent on the filling speed, showing that even in out-of-equilibrium conditions metadynamics allows recovering an accurate estimate of F(s) . These results have been obtained introducing a functional form of the history-dependent potential that avoids the onset of systematic errors near the boundaries of the free-energy landscape.

Gregg T. Beckham | NREL

Science.gov Websites

Molecular Dynamics, and a suite of free energy methods such as MD Umbrella Sampling, Equilibrium Path chain on the crystal surface, and the degree of crystallinity in the substrate. We have used free energy shows the free energy results for edge, middle, and corner chains for all four types of cellulose. All

Angle-resolved effective potentials for disk-shaped molecules

NASA Astrophysics Data System (ADS)

Heinemann, Thomas; Palczynski, Karol; Dzubiella, Joachim; Klapp, Sabine H. L.

2014-12-01

We present an approach for calculating coarse-grained angle-resolved effective pair potentials for uniaxial molecules. For integrating out the intramolecular degrees of freedom we apply umbrella sampling and steered dynamics techniques in atomistically-resolved molecular dynamics (MD) computer simulations. Throughout this study we focus on disk-like molecules such as coronene. To develop the methods we focus on integrating out the van der Waals and intramolecular interactions, while electrostatic charge contributions are neglected. The resulting coarse-grained pair potential reveals a strong temperature and angle dependence. In the next step we fit the numerical data with various Gay-Berne-like potentials to be used in more efficient simulations on larger scales. The quality of the resulting coarse-grained results is evaluated by comparing their pair and many-body structure as well as some thermodynamic quantities self-consistently to the outcome of atomistic MD simulations of many-particle systems. We find that angle-resolved potentials are essential not only to accurately describe crystal structures but also for fluid systems where simple isotropic potentials start to fail already for low to moderate packing fractions. Further, in describing these states it is crucial to take into account the pronounced temperature dependence arising in selected pair configurations due to bending fluctuations.

How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study

PubMed Central

2015-01-01

Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born–Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition–elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman’s phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman. PMID:24786171

Molecular dynamics simulation study of the "stay or leave" problem for two magnesium ions in gene transcription.

PubMed

Wu, Shaogui

2017-06-01

Two magnesium ions play important roles in nucleotide addition cycle (NAC) of gene transcription. However, at the end of each NAC, why does one ion stay in the active site while the other ion leaves with product pyrophosphate (PP i )? This problem still remains obscure. In this work, we studied the problem using all-atom molecular dynamics simulation combined with steered molecular dynamics and umbrella sampling simulation methods. Our simulations reveal that although both ions are located in the active site after chemistry, their detailed positions are not symmetrical, leading to their different forces from surrounding groups. One ion makes weaker contacts with PP i than the whole protein. Hence, PP i release is less likely to take it away. The other one forms tighter contacts with PP i relative to the protein. The formed (Mg 2+ -PP i ) 2- complex is found to break the contacts with surrounding protein residues one by one so as to dissociate from the active site. This effectively avoids the coexistence of two ions in the active site after PP i release and guarantees a reasonable Mg 2+ ion number in the active site for the next NAC. The observations from this work can provide valuable information for comprehensively understanding the molecular mechanism of transcription. Proteins 2017; 85:1002-1007. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Non-arrhenius behavior in the unfolding of a short, hydrophobic alpha-helix. Complementarity of molecular dynamics and lattice model simulations.

PubMed

Collet, Olivier; Chipot, Christophe

2003-05-28

The unfolding of the last, C-terminal residue of AcNH(2)-(l-Leu)(11)-NHMe in its alpha-helical form has been investigated by measuring the variation of free energy involved in the alpha(R) to beta conformational transition. These calculations were performed using large-scale molecular dynamics simulations in conjunction with the umbrella sampling method. For different temperatures ranging from 280 to 370 K, the free energy of activation was estimated. Concurrently, unfolding simulations of a homopolypeptide formed by twelve hydrophobic residues were carried out, employing a three-dimensional lattice model description of the peptide, with a temperature-dependent interaction potential. Using a Monte Carlo approach, the lowest free energy conformation, an analogue of a right-handed alpha-helix, was determined in the region where the peptide chain is well ordered. The free energy barrier separating this state from a distinct, compact conformation, analogue to a beta-strand, was determined over a large enough range of temperatures. The results of these molecular dynamics and lattice model simulations are consistent and indicate that the kinetics of the unfolding of a hydrophobic peptide exhibits a non-Arrhenius behavior closely related to the temperature dependence of the hydrophobic effect. These results further illuminate the necessity to include a temperature dependence in potential energy functions designed for coarse-grained models of proteins.

Transition between B-DNA and Z-DNA: free energy landscape for the B-Z junction propagation.

PubMed

Lee, Juyong; Kim, Yang-Gyun; Kim, Kyeong Kyu; Seok, Chaok

2010-08-05

Canonical, right-handed B-DNA can be transformed into noncanonical, left-handed Z-DNA in vitro at high salt concentrations or in vivo under physiological conditions. The molecular mechanism of this drastic conformational transition is still unknown despite numerous studies. Inspired by the crystal structure of a B-Z junction and the previous zipper model, we show here, with the aid of molecular dynamics simulations, that a stepwise propagation of a B-Z junction is a highly probable pathway for the B-Z transition. In this paper, the movement of a B-Z junction by a two-base-pair step in a double-strand nonamer, [d(GpCpGpCpGpCpGpCpG)](2), is considered. Targeted molecular dynamics simulations and umbrella sampling for this transition resulted in a transition pathway with a free energy barrier of 13 kcal/mol. This barrier is much more favorable than those obtained from previous atomistic simulations that lead to concerted transitions of the whole strands. The free energy difference between B-DNA and Z-DNA evaluated from our simulation is 0.9 kcal/mol per dinucleotide unit, which is consistent with previous experiments. The current computation thus strongly supports the proposal that the B-Z transition involves a relatively fast extension of B-DNA or Z-DNA by sequential propagation of B-Z junctions once nucleation of junctions is established.

Peace umbrella, a vague policy and checkered past. Research report

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

Biszak, G.A.

1997-03-01

With the break-up of the former Soviet Union, the United Nations Security Council enjoyed a greater consensus among its members in confronting aggression and participation in humanitarian and peace operations. Deploying significant military forces under the peace umbrella at the beginning of this decade was highly unlikely. However, since 1990, 25 deployments have been conducted with the majority falling under the peace umbrella. This paper analyzes current national and military strategy in regards to the peace umbrella, specifically peace enforcement, military doctrine, and the case of Somalia. In addition, this paper looks at doctrine and directives that currently guide deploymentmore » of forces and the potential for future peace operations.« less

Recipes for free energy calculations in biomolecular systems.

PubMed

Moradi, Mahmoud; Babin, Volodymyr; Sagui, Celeste; Roland, Christopher

2013-01-01

During the last decade, several methods for sampling phase space and calculating various free energies in biomolecular systems have been devised or refined for molecular dynamics (MD) simulations. Thus, state-of-the-art methodology and the ever increasing computer power allow calculations that were forbidden a decade ago. These calculations, however, are not trivial as they require knowledge of the methods, insight into the system under study, and, quite often, an artful combination of different methodologies in order to avoid the various traps inherent in an unknown free energy landscape. In this chapter, we illustrate some of these concepts with two relatively simple systems, a sugar ring and proline oligopeptides, whose free energy landscapes still offer considerable challenges. In order to explore the configurational space of these systems, and to surmount the various free energy barriers, we combine three complementary methods: a nonequilibrium umbrella sampling method (adaptively biased MD, or ABMD), replica-exchange molecular dynamics (REMD), and steered molecular dynamics (SMD). In particular, ABMD is used to compute the free energy surface of a set of collective variables; REMD is used to improve the performance of ABMD, to carry out sampling in space complementary to the collective variables, and to sample equilibrium configurations directly; and SMD is used to study different transition mechanisms.

CR@BaSO4: an acid rain-indicating material.

PubMed

Gao, Hong-Wen; Xu, Xin-Hui

2011-12-28

The CR@BaSO(4) hybrid was synthesized, characterized and used as an acid rain-indicating (ARI) material. A painted ARI umbrella was discolored after exposure to simulated acid rain of pH 5 or less and returned to the initial color after the rain stopped. Such a functionalized material may make acid rain visual to remind people in real-time. This journal is © The Royal Society of Chemistry 2011

Open-Source Integrated Design-Analysis Environment For Nuclear Energy Advanced Modeling & Simulation Final Scientific/Technical Report

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

O'Leary, Patrick

The framework created through the Open-Source Integrated Design-Analysis Environment (IDAE) for Nuclear Energy Advanced Modeling & Simulation grant has simplify and democratize advanced modeling and simulation in the nuclear energy industry that works on a range of nuclear engineering applications. It leverages millions of investment dollars from the Department of Energy's Office of Nuclear Energy for modeling and simulation of light water reactors and the Office of Nuclear Energy's research and development. The IDEA framework enhanced Kitware’s Computational Model Builder (CMB) while leveraging existing open-source toolkits and creating a graphical end-to-end umbrella guiding end-users and developers through the nuclear energymore » advanced modeling and simulation lifecycle. In addition, the work deliver strategic advancements in meshing and visualization for ensembles.« less

Restrained Proton Indicator in Combined Quantum-Mechanics/Molecular-Mechanics Dynamics Simulations of Proton Transfer through a Carbon Nanotube.

PubMed

Duster, Adam W; Lin, Hai

2017-09-14

Recently, a collective variable "proton indicator" was purposed for tracking an excess proton solvated in bulk water in molecular dynamics simulations. In this work, we demonstrate the feasibility of utilizing the position of this proton indicator as a reaction coordinate to model an excess proton migrating through a hydrophobic carbon nanotube in combined quantum-mechanics/molecular-mechanics simulations. Our results indicate that applying a harmonic restraint to the proton indicator in the bulk solvent near the nanotube pore entrance leads to the recruitment of water molecules into the pore. This is consistent with an earlier study that employed a multistate empirical valence bond potential and a different representation (center of excess charge) of the proton. We attribute this water recruitment to the delocalized nature of the solvated proton, which prefers to be in high-dielectric bulk solvent. While water recruitment into the pore is considered an artifact in the present simulations (because of the artificially imposed restraint on the proton), if the proton were naturally restrained, it could assist in building water wires prior to proton transfer through the pore. The potential of mean force for a proton translocation through the water-filled pore was computed by umbrella sampling, where the bias potentials were applied to the proton indicator. The free energy curve and barrier heights agree reasonably with those in the literature. The results suggest that the proton indicator can be used as a reaction coordinate in simulations of proton transport in confined environments.

Evidence-Based Practice Guidelines for Fetal Alcohol Spectrum Disorder and Literacy and Learning

ERIC Educational Resources Information Center

Mitten, H. Rae

2013-01-01

Evidence-based Practice Guidelines for Fetal Alcohol Spectrum Disorder (FASD) and Literacy and Learning are derived from an inductive analysis of qualitative data collected in field research. FASD is the umbrella term for a spectrum of neurocognitive and physical disabilities caused by prenatal exposure to alcohol. Data from a sample of N=150 was…

Evidence-Based Practice Guidelines for Fetal Alcohol Spectrum Disorder and Literacy and Learning

ERIC Educational Resources Information Center

Mitten, H. Rae

2013-01-01

Evidence-based Practice Guidelines for Fetal Alcohol Spectrum Disorder (FASD) and Literacy and Learning are derived from an inductive analysis of qualitative data collected in field research. FASD is the umbrella term for a spectrum of neurocognitive and physical disabilities caused by prenatal exposure to alcohol. Data from a sample of N =150 was…

Analysis of the interactions between GMF and Arp2/3 complex in two binding sites by molecular dynamics simulation.

PubMed

Popinako, A; Antonov, M; Dibrova, D; Chemeris, A; Sokolova, O S

2018-02-05

The Arp2/3 complex plays a key role in nucleating actin filaments branching. The glia maturation factor (GMF) competes with activators for interacting with the Arp2/3 complex and initiates the debranching of actin filaments. In this study, we performed a comparative analysis of interactions between GMF and the Arp2/3 complex and identified new amino acid residues involved in GMF binding to the Arp2/3 complex at two separate sites, revealed by X-ray and single particle EM techniques. Using molecular dynamics simulations we demonstrated the quantitative and qualitative changes in hydrogen bonds upon binding with GMF. We identified the specific amino acid residues in GMF and Arp2/3 complex that stabilize the interactions and estimated the mean force profile for the GMF using umbrella sampling. Phylogenetic and structural analyses of the recently defined GMF binding site on the Arp3 subunit indicate a new mechanism for Arp2/3 complex inactivation that involves interactions between the Arp2/3 complex and GMF at two binding sites. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of hydrophobic and dipole-dipole interactions on the conformational transitions of a model polypeptide

NASA Astrophysics Data System (ADS)

Mu, Yan; Gao, Yi Qin

2007-09-01

We studied the effects of hydrophobicity and dipole-dipole interactions between the nearest-neighbor amide planes on the secondary structures of a model polypeptide by calculating the free energy differences between different peptide structures. The free energy calculations were performed with low computational costs using the accelerated Monte Carlo simulation (umbrella sampling) method, with a bias-potential method used earlier in our accelerated molecular dynamics simulations. It was found that the hydrophobic interaction enhances the stability of α helices at both low and high temperatures but stabilizes β structures only at high temperatures at which α helices are not stable. The nearest-neighbor dipole-dipole interaction stabilizes β structures under all conditions, especially in the low temperature region where α helices are the stable structures. Our results indicate clearly that the dipole-dipole interaction between the nearest neighboring amide planes plays an important role in determining the peptide structures. Current research provides a more unified and quantitative picture for understanding the effects of different forms of interactions on polypeptide structures. In addition, the present model can be extended to describe DNA/RNA, polymer, copolymer, and other chain systems.

Computing the Free Energy along a Reaction Coordinate Using Rigid Body Dynamics.

PubMed

Tao, Peng; Sodt, Alexander J; Shao, Yihan; König, Gerhard; Brooks, Bernard R

2014-10-14

The calculations of potential of mean force along complex chemical reactions or rare events pathways are of great interest because of their importance for many areas in chemistry, molecular biology, and material science. The major difficulty for free energy calculations comes from the great computational cost for adequate sampling of the system in high-energy regions, especially close to the reaction transition state. Here, we present a method, called FEG-RBD, in which the free energy gradients were obtained from rigid body dynamics simulations. Then the free energy gradients were integrated along a reference reaction pathway to calculate free energy profiles. In a given system, the reaction coordinates defining a subset of atoms (e.g., a solute, or the quantum mechanics (QM) region of a quantum mechanics/molecular mechanics simulation) are selected to form a rigid body during the simulation. The first-order derivatives (gradients) of the free energy with respect to the reaction coordinates are obtained through the integration of constraint forces within the rigid body. Each structure along the reference reaction path is separately subjected to such a rigid body simulation. The individual free energy gradients are integrated along the reference pathway to obtain the free energy profile. Test cases provided demonstrate both the strengths and weaknesses of the FEG-RBD method. The most significant benefit of this method comes from the fast convergence rate of the free energy gradient using rigid-body constraints instead of restraints. A correction to the free energy due to approximate relaxation of the rigid-body constraint is estimated and discussed. A comparison with umbrella sampling using a simple test case revealed the improved sampling efficiency of FEG-RBD by a factor of 4 on average. The enhanced efficiency makes this method effective for calculating the free energy of complex chemical reactions when the reaction coordinate can be unambiguously defined by a small subset of atoms within the system.

Computing the Free Energy along a Reaction Coordinate Using Rigid Body Dynamics

PubMed Central

2015-01-01

The calculations of potential of mean force along complex chemical reactions or rare events pathways are of great interest because of their importance for many areas in chemistry, molecular biology, and material science. The major difficulty for free energy calculations comes from the great computational cost for adequate sampling of the system in high-energy regions, especially close to the reaction transition state. Here, we present a method, called FEG-RBD, in which the free energy gradients were obtained from rigid body dynamics simulations. Then the free energy gradients were integrated along a reference reaction pathway to calculate free energy profiles. In a given system, the reaction coordinates defining a subset of atoms (e.g., a solute, or the quantum mechanics (QM) region of a quantum mechanics/molecular mechanics simulation) are selected to form a rigid body during the simulation. The first-order derivatives (gradients) of the free energy with respect to the reaction coordinates are obtained through the integration of constraint forces within the rigid body. Each structure along the reference reaction path is separately subjected to such a rigid body simulation. The individual free energy gradients are integrated along the reference pathway to obtain the free energy profile. Test cases provided demonstrate both the strengths and weaknesses of the FEG-RBD method. The most significant benefit of this method comes from the fast convergence rate of the free energy gradient using rigid-body constraints instead of restraints. A correction to the free energy due to approximate relaxation of the rigid-body constraint is estimated and discussed. A comparison with umbrella sampling using a simple test case revealed the improved sampling efficiency of FEG-RBD by a factor of 4 on average. The enhanced efficiency makes this method effective for calculating the free energy of complex chemical reactions when the reaction coordinate can be unambiguously defined by a small subset of atoms within the system. PMID:25328492

The relationship between childhood body weight and dental caries experience: an umbrella systematic review protocol.

PubMed

Carson, Susan J; Abuhaloob, Lamis; Richards, Derek; Hector, Mark P; Freeman, Ruth

2017-10-25

Obesity and dental caries are global public health problems which can impact in childhood and throughout the life course. In simple terms, childhood dental caries and body weight are linked via the common risk factor of diet. An association between dental caries and obesity has been described in a number of studies and reviews. However, similarly, a relationship has also been noted between low body weight and caries experience in children. This protocol will provide the framework for an umbrella review to address the following question: Does the available evidence support a relationship between dental caries experience and body weight in the child population? This review protocol outlines the process to carry out an umbrella systematic review which will synthesise previous reviews of childhood dental caries experience and body weight. An umbrella review methodology will be used to examine the methodological and reporting quality of existing reviews. The final umbrella review aims to aggregate the available evidence in order to provide a summary for policymakers and to inform healthcare interventions. PROSPERO CRD42016047304.

High-Grade Urothelial Carcinoma on Urine Cytology Resembling Umbrella Cells.

PubMed

Renshaw, Andrew A; Gould, Edwin W

2018-01-01

High-grade urothelial carcinoma (UC) cells have many appearances on urine cytology, but according to The Paris System, they can be easily distinguished from umbrella cells. We aimed to define the incidence and appearance of high-grade UC cells that resemble umbrella cells in Cytospin preparations on urine cytology. Cytospin preparations from 331 cases with biopsy follow-up (230 benign/low-grade and 101 malignant [22 carcinoma in situ, 52 papillary, 19 invasive UC, 8 other] cases) were reviewed. A total of 18 cases with malignant cells resembling umbrella cells were identified (17.8% of the malignant cases) and were the only type of malignant cell in 3% of the cases. Two patterns were identified. Tumor cells were either identifiable by at least 20 abnormal cells which were large, had abundant cytoplasm but an elevated nuclear-to-cytoplasmic ratio, and markedly enlarged, round-to-elongated nucleoli, or else rare cells with abundant cytoplasm but obviously malignant nuclei. Cells without nucleoli or obviously malignant nuclei were not specific. Malignant cells resembling umbrella cells can be seen in up to 17% of urine cytology specimens. © 2017 S. Karger AG, Basel.

Transcatheter Closure of Bilateral Multiple Huge Pulmonary Arteriovenous Malformations with Homemade Double-Umbrella Occluders

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

Zhong Hongshan, E-mail: zhonghongshan@hotmail.com; Xu Ke; Shao Haibo

2008-07-15

A 28-year-old man underwent successful transcatheter occlusion of three huge pulmonary arteriovenous malformations (PAVMs) using homemade double-umbrella occluders and stainless steel coils. Thoracic CT with three-dimensional reconstruction and pulmonary angiography were used for treatment planning and follow-up. The diameters of the feeding vessels were 11 mm, 13 mm, and 14 mm, respectively. This report demonstrates the novel design and utility of the double-umbrella occluder, an alternative tool for treatment of large PAVMs.

29. Umbrella sheds behind South Station. Boston, Suffolk Co., MA. ...

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

29. Umbrella sheds behind South Station. Boston, Suffolk Co., MA. Sec. 4116, MP 229.50. - Northeast Railroad Corridor, Amtrak Route between RI/MA State Line & South Station, Boston, Suffolk County, MA

Kirkwood-Buff integrals of finite systems: shape effects

NASA Astrophysics Data System (ADS)

Dawass, Noura; Krüger, Peter; Simon, Jean-Marc; Vlugt, Thijs J. H.

2018-06-01

The Kirkwood-Buff (KB) theory provides an important connection between microscopic density fluctuations in liquids and macroscopic properties. Recently, Krüger et al. derived equations for KB integrals for finite subvolumes embedded in a reservoir. Using molecular simulation of finite systems, KB integrals can be computed either from density fluctuations inside such subvolumes, or from integrals of radial distribution functions (RDFs). Here, based on the second approach, we establish a framework to compute KB integrals for subvolumes with arbitrary convex shapes. This requires a geometric function w(x) which depends on the shape of the subvolume, and the relative position inside the subvolume. We present a numerical method to compute w(x) based on Umbrella Sampling Monte Carlo (MC). We compute KB integrals of a liquid with a model RDF for subvolumes with different shapes. KB integrals approach the thermodynamic limit in the same way: for sufficiently large volumes, KB integrals are a linear function of area over volume, which is independent of the shape of the subvolume.

Locking the Active Conformation of c-Src Kinase through the Phosphorylation of the Activation Loop

PubMed Central

Meng, Yilin; Roux, Benoît

2013-01-01

Molecular dynamics umbrella sampling simulations are used to compare the relative stability of the active conformation of the catalytic domain of c-Src kinase while the tyrosine 416 in the activation loop (A-loop) is either unphosphorylated or phosphorylated. When the A-loop is unphosphorylated, there is considerable flexiblity of the kinase. While the active conformation of the kinase is not forbidden and can be visited transiently, it is not the predominant state. This is consistent with the view that c-Src displays some catalytic activity even when the A-loop is unphosphorylated. In contrast, phosphorylation of the A-loop contributes to stabilize several structural features that are critical for catalysis, such as the hydrophobic regulatory spine, the HRD motif, and the electrostatic switch. In summary, the free energy landscape calculations demonstrate that phosphorylation of tyrosine 416 in the A-loop essentially “locks” the kinase into its catalytically competent conformation. PMID:24103328

Theoretical and Experimental Study of Inclusion Complexes of β-Cyclodextrins with Chalcone and 2',4'-Dihydroxychalcone.

PubMed

Sancho, Matias I; Andujar, Sebastian; Porasso, Rodolfo D; Enriz, Ricardo D

2016-03-31

The inclusion complexes formed by chalcone and 2',4'-dihydroxychalcone with β-cyclodextrin have been studied combining experimental (phase solubility diagrams, Fourier transform infrared spectroscopy) and molecular modeling (molecular dynamics, quantum mechanics/molecular mechanics calculations) techniques. The formation constants of the complexes were determined at different temperatures, and the thermodynamic parameters of the process were obtained. The inclusion of chalcone in β-cyclodextrin is an exothermic process, while the inclusion of 2',4'-dihydroxychalcone is endothermic. Free energy profiles, derived from umbrella sampling using molecular dynamics simulations, were constructed to analyze the binding affinity and the complexation reaction at a molecular level. Hybrid QM/MM calculations were also employed to obtain a better description of the energetic and structural aspects of the complexes. The intermolecular interactions that stabilize both inclusion complexes were characterized by means of quantum atoms in molecules theory and reduce density gradient method. The calculated interactions were experimentally observed using FTIR.

Amino acids at water-vapor interfaces: surface activity and orientational ordering.

PubMed

Vöhringer-Martinez, Esteban; Toro-Labbé, Alejandro

2010-10-14

The surface activity and orientational ordering of amino acids at water-vapor interfaces were studied with molecular dynamics simulations in combination with thermodynamic integration and umbrella sampling. Asparagine, representing amino acids with polar side chains, displays no surface activity. Tryptophan, in contrast, with its hydrophobic indole ring as side chain unveils a free energy minimum at the water-vapor interface, which lies 6 kJ/mol under the hydration free energy. To study the orientational ordering of tryptophan along the interface, the order parameter was calculated. At the free energy minimum and at the Gibbs dividing surface, the order parameter reveals a parallel alignment of the indole ring with the water surface exposing the π-system to electrophiles in the hydrophobic phase and indicating polarization dependent spectroscopy. In the vicinity of this position a perpendicular orientation is obtained. The surface excess, calculated from the potential of mean force along the interface, is in excellent agreement with experimental measurements.

Molecular conformation of linear alkane molecules: From gas phase to bulk water through the interface

NASA Astrophysics Data System (ADS)

Murina, Ezequiel L.; Fernández-Prini, Roberto; Pastorino, Claudio

2017-08-01

We studied the behavior of long chain alkanes (LCAs) as they were transferred from gas to bulk water, through the liquid-vapor interface. These systems were studied using umbrella sampling molecular dynamics simulation and we have calculated properties like free energy profiles, molecular orientation, and radius of gyration of the LCA molecules. The results show changes in conformation of the solutes along the path. LCAs adopt pronounced molecular orientations and the larger ones extend appreciably when partially immersed in the interface. In bulk water, their conformations up to dodecane are mainly extended. However, larger alkanes like eicosane present a more stable collapsed conformation as they approach bulk water. We have characterized the more probable configurations in all interface and bulk regions. The results obtained are of interest for the study of biomatter processes requiring the transfer of hydrophobic matter, especially chain-like molecules like LCAs, from gas to bulk aqueous systems through the interface.

Molecular simulation of CO chemisorption on Co(0001) in presence of supercritical fluid solvent: A potential of mean force study

NASA Astrophysics Data System (ADS)

Asiaee, Alireza; Benjamin, Kenneth M.

2016-08-01

For several decades, heterogeneous catalytic processes have been improved through utilizing supercritical fluids (SCFs) as solvents. While numerous experimental studies have been established across a range of chemistries, such as oxidation, pyrolysis, amination, and Fischer-Tropsch synthesis, still there is little fundamental, molecular-level information regarding the role of the SCF on elementary heterogeneous catalytic steps. In this study, the influence of hexane solvent on the adsorption of carbon monoxide on Co(0001), as the first step in the reaction mechanism of many processes involving syngas conversion, is probed. Simulations are performed at various bulk hexane densities, ranging from ideal gas conditions (no SCF hexane) to various near- and super-critical hexane densities. For this purpose, both density functional theory and molecular dynamics simulations are employed to determine the adsorption energy and free energy change during CO chemisorption. Potential of mean force calculations, utilizing umbrella sampling and the weighted histogram analysis method, provide the first commentary on SCF solvent effects on the energetic aspects of the chemisorption process. Simulation results indicate an enhanced stability of CO adsorption on the catalyst surface in the presence of supercritical hexane within the reduced pressure range of 1.0-1.5 at a constant temperature of 523 K. Furthermore, it is shown that the maximum stability of CO in the adsorbed state as a function of supercritical hexane density at 523 K nearly coincides with the maximum isothermal compressibility of bulk hexane at this temperature.

Free energy calculations along entropic pathways. I. Homogeneous vapor-liquid nucleation for atomic and molecular systems

NASA Astrophysics Data System (ADS)

Desgranges, Caroline; Delhommelle, Jerome

2016-11-01

Using the entropy S as a reaction coordinate, we determine the free energy barrier associated with the formation of a liquid droplet from a supersaturated vapor for atomic and molecular fluids. For this purpose, we develop the μ V T -S simulation method that combines the advantages of the grand-canonical ensemble, that allows for a direct evaluation of the entropy, and of the umbrella sampling method, that is well suited to the study of an activated process like nucleation. Applying this approach to an atomic system such as Ar allows us to test the method. The results show that the μ V T -S method gives the correct dependence on supersaturation of the height of the free energy barrier and of the size of the critical droplet, when compared to predictions from the classical nucleation theory and to previous simulation results. In addition, it provides insight into the relation between the entropy and droplet formation throughout this process. An additional advantage of the μ V T -S approach is its direct transferability to molecular systems, since it uses the entropy of the system as the reaction coordinate. Applications of the μ V T -S simulation method to N2 and CO2 are presented and discussed in this work, showing the versatility of the μ V T -S approach.

Defining and evaluating the umbrella species concept for conserving and restoring landscape connectivity.

PubMed

Breckheimer, Ian; Haddad, Nick M; Morris, William F; Trainor, Anne M; Fields, William R; Jobe, R Todd; Hudgens, Brian R; Moody, Aaron; Walters, Jeffrey R

2014-12-01

Conserving or restoring landscape connectivity between patches of breeding habitat is a common strategy to protect threatened species from habitat fragmentation. By managing connectivity for some species, usually charismatic vertebrates, it is often assumed that these species will serve as conservation umbrellas for other species. We tested this assumption by developing a quantitative method to measure overlap in dispersal habitat of 3 threatened species-a bird (the umbrella), a butterfly, and a frog-inhabiting the same fragmented landscape. Dispersal habitat was determined with Circuitscape, which was parameterized with movement data collected for each species. Despite differences in natural history and breeding habitat, we found substantial overlap in the spatial distributions of areas important for dispersal of this suite of taxa. However, the intuitive umbrella species (the bird) did not have the highest overlap with other species in terms of the areas that supported connectivity. Nevertheless, we contend that when there are no irreconcilable differences between the dispersal habitats of species that cohabitate on the landscape, managing for umbrella species can help conserve or restore connectivity simultaneously for multiple threatened species with different habitat requirements. © 2014 Society for Conservation Biology.

Free energy barriers to evaporation of water in hydrophobic confinement.

PubMed

Sharma, Sumit; Debenedetti, Pablo G

2012-11-08

We use umbrella sampling Monte Carlo and forward and reverse forward flux sampling (FFS) simulation techniques to compute the free energy barriers to evaporation of water confined between two hydrophobic surfaces separated by nanoscopic gaps, as a function of the gap width, at 1 bar and 298 K. The evaporation mechanism for small (1 × 1 nm(2)) surfaces is found to be fundamentally different from that for large (3 × 3 nm(2)) surfaces. In the latter case, the evaporation proceeds via the formation of a gap-spanning tubular cavity. The 1 × 1 nm(2) surfaces, in contrast, are too small to accommodate a stable vapor cavity. Accordingly, the associated free energy barriers correspond to the formation of a critical-sized cavity for sufficiently large confining surfaces, and to complete emptying of the gap region for small confining surfaces. The free energy barriers to evaporation were found to be of O(20kT) for 14 Å gaps, and to increase by approximately ~5kT with every 1 Å increase in the gap width. The entropy contribution to the free energy of evaporation was found to be independent of the gap width.

Hybrid quantum and classical methods for computing kinetic isotope effects of chemical reactions in solutions and in enzymes.

PubMed

Gao, Jiali; Major, Dan T; Fan, Yao; Lin, Yen-Lin; Ma, Shuhua; Wong, Kin-Yiu

2008-01-01

A method for incorporating quantum mechanics into enzyme kinetics modeling is presented. Three aspects are emphasized: 1) combined quantum mechanical and molecular mechanical methods are used to represent the potential energy surface for modeling bond forming and breaking processes, 2) instantaneous normal mode analyses are used to incorporate quantum vibrational free energies to the classical potential of mean force, and 3) multidimensional tunneling methods are used to estimate quantum effects on the reaction coordinate motion. Centroid path integral simulations are described to make quantum corrections to the classical potential of mean force. In this method, the nuclear quantum vibrational and tunneling contributions are not separable. An integrated centroid path integral-free energy perturbation and umbrella sampling (PI-FEP/UM) method along with a bisection sampling procedure was summarized, which provides an accurate, easily convergent method for computing kinetic isotope effects for chemical reactions in solution and in enzymes. In the ensemble-averaged variational transition state theory with multidimensional tunneling (EA-VTST/MT), these three aspects of quantum mechanical effects can be individually treated, providing useful insights into the mechanism of enzymatic reactions. These methods are illustrated by applications to a model process in the gas phase, the decarboxylation reaction of N-methyl picolinate in water, and the proton abstraction and reprotonation process catalyzed by alanine racemase. These examples show that the incorporation of quantum mechanical effects is essential for enzyme kinetics simulations.

The Flatstent versus the conventional umbrella devices in the percutaneous closure of patent foramen ovale.

PubMed

Aral, Mert; Mullen, Michael

2015-05-01

Patent foramen ovale (PFO) has been associated with paradoxical embolism leading to stroke/transient ischemic attack, migraine, and neurological decompression sickness. In search for the optimal device that would achieve effective clinical closure with minimal complications, a better device selection based on PFO anatomy and improvements in device design is needed. The Flatstent is a new device designed to treat the highly prevalent long-tunnel PFOs from within, minimizing the amount of material left behind in an attempt to reduce device-related complications. The objective is to compare the safety and efficacy of the novel Flatstent versus the conventional umbrella devices in the transcatheter closure of PFO in a nonrandomized, retrospective, single-center study. Between March 2010 and March 2013, 88 patients underwent PFO closure at The Heart Hospital, London with either the novel Flatstent or one of the four conventionally used umbrella devices (GORE Helex Septal Occluder, Occlutech Figulla Flex, Biostar Septal Occluder, and Amplatzer PFO Occluder) depending on their PFO anatomy. Patients were then evaluated with contrast transthoracic echocardiography (TTE) and/or transoesophageal echocardiography (TOE) at 6 weeks and 1 year after the procedure. The residual shunt and complication rates between the Flatstent and umbrella devices were compared. The Flatstent was used in 27 patients (30.7%), whereas 61 patients (69.3%) received one of the four umbrella devices. Primary efficacy point of clinical closure defined as grade 0 or grade 1; residual shunt was achieved in 81.3% in the Flatstent cohort and 80.3% in the umbrella device group at 6 weeks follow-up. At 1 year, the clinical closure rates reached 92.6 and 91.8%. There were two device embolizations, one in each cohort during the immediate postoperative period (<24 hrs), with successful retrieval. One patient in the umbrella device group developed transient atrial fibrillation, which was controlled medically. Event recurrence rate was 0% at 1 year. No difference was found in closure or complication rates between the Flatstent and the umbrella devices. With appropriate preassessment of the PFO anatomy, the Flatstent works as a safe and effective method of treating the PFO from within the tunnel, especially in those with long-tunnel PFOs. Longer follow-up is needed to establish superiority. © 2014 Wiley Periodicals, Inc.

Molecular Dynamics Studies of Overbased Detergents on a Water Surface.

PubMed

Bodnarchuk, M S; Dini, D; Heyes, D M; Breakspear, A; Chahine, S

2017-07-25

Molecular dynamics (MD) simulations are reported of model overbased detergent nanoparticles on a model water surface which mimic their behavior on a Langmuir trough or large water droplet in engine oil. The simulations predict that the structure of the nanoparticle on a water surface is different to when it is immersed in a bulk hydrophobic solvent. The surfactant tails are partly directed out of the water, while the carbonate core maximizes its extent of contact with the water. Umbrella sampling calculations of the potential of mean force between two particles showed that they are associated with varying degrees with a maximum binding free energy of ca. 10 k B T for the salicylate stabilized particle, ca. 8 k B T for a sulfurized alkyl phenate stabilized particle, and ca. 5 k B T for a sulfonate stabilized particle. The differences in the strength of attraction depend on the proximity of nearest approach and the energy penalty associated with the disruption of the hydration shell of water molecules around the calcium carbonate core when the two particles approach. This is greatest for the sulfonate particle, which partially loses the surfactant ions to the solution, and least for the salicylate, which forms the weakest water "cage". The particles are separated by a water hydration layer, even at the point of closest approach.

Umbrella occlusion of persistent arterial duct in children under two years.

PubMed Central

Gatzoulis, M A; Rigby, M L; Redington, A N

1994-01-01

OBJECTIVE--To assess the use of trans-catheter occlusion of a persistent arterial duct in symptomatic children < 2 years of age. DESIGN--Descriptive study of selected, non-randomised infants with persistent arterial duct who underwent attempted umbrella occlusion. SETTING--Tertiary referral centre. PATIENTS--Between June 1990 and April 1993, 29 young children with a symptomatic persistent arterial duct underwent attempted transcatheter occlusion. Their age ranged from 1.5 to 23 months, with the youngest infant weighing 2.9 kg. The diagnosis was established before operation in all patients by cross sectional echocardiography. INTERVENTION--Transcatheter occlusion of a haemodynamically important persistent arterial duct was performed with the Rashkind ductal umbrella. In the past year the front loading technique has been used to place the 12 mm umbrella through a 6 F (French) sheath and the 17 mm device through a 8 F sheath so extending the indications for their use. RESULTS--Umbrellas were successfully placed in 25 (86.2%) infants and there was symptomatic improvement in all. There were no deaths or severe complications. The four failures occurred early in the series. They were caused by kinking of the 11 F sheath in two cases and embolisation into the left pulmonary artery in one case. The procedure was abandoned in the fourth case because of a large duct. Only three of the 25 patients had small residual shunts at one year follow up (all with 17 mm devices) but no stenosis or turbulence was noted in any of the patients. CONCLUSION--The transcatheter occlusion of persistent arterial duct in young children with symptoms is a safe alternative to surgery. The new front loading umbrella technique enables successful ductal closure in even smaller infants than earlier devices. Images PMID:7833196

Non-target effects on songbirds from habitat manipulation for Greater Sage-Grouse: Implications for the umbrella species concept

USGS Publications Warehouse

Carlisle, Jason D.; Chalfoun, Anna D.; Smith, Kurt T.; Beck, Jeffery L.

2018-01-01

The “umbrella species” concept is a conservation strategy in which creating and managing reserve areas to meet the needs of one species is thought to benefit other species indirectly. Broad-scale habitat protections on behalf of an umbrella species are assumed to benefit co-occurring taxa, but targeted management actions to improve local habitat suitability for the umbrella species may produce unintended effects on other species. Our objective was to quantify the effects of a common habitat treatment (mowing of big sagebrush [Artemisia tridentata]) intended to benefit a high-profile umbrella species (Greater Sage-Grouse [Centrocercus urophasianus]) on 3 sympatric songbird species of concern. We used a before–after control-impact experimental design spanning 3 yr in Wyoming, USA, to quantify the effect of mowing on the abundance, nest-site selection, nestling condition, and nest survival of 2 sagebrush-obligate songbirds (Brewer's Sparrow [Spizella breweri] and Sage Thrasher [Oreoscoptes montanus]) and one open-habitat generalist songbird (Vesper Sparrow [Pooecetes gramineus]). Mowing was associated with lower abundance of Brewer's Sparrows and Sage Thrashers but higher abundance of Vesper Sparrows. We found no Brewer's Sparrows or Sage Thrashers nesting in the mowed footprint posttreatment, which suggests complete loss of nesting habitat for these species. Mowing was associated with higher nestling condition and nest survival for Vesper Sparrows but not for the sagebrush-obligate species. Management prescriptions that remove woody biomass within a mosaic of intact habitat may be tolerated by sagebrush-obligate songbirds but are likely more beneficial for open-habitat generalist species. By definition, umbrella species conservation entails habitat protections at broad spatial scales. We caution that habitat manipulations to benefit Greater Sage-Grouse could negatively affect nontarget species of conservation concern if implemented across large spatial extents.

Optimization of antioxidant activity by response surface methodology in hydrolysates of jellyfish (Rhopilema esculentum) umbrella collagen.

PubMed

Zhuang, Yong-liang; Zhao, Xue; Li, Ba-fang

2009-08-01

To optimize the hydrolysis conditions to prepare hydrolysates of jellyfish umbrella collagen with the highest hydroxyl radical scavenging activity, collagen extracted from jellyfish umbrella was hydrolyzed with trypsin, and response surface methodology (RSM) was applied. The optimum conditions obtained from experiments were pH 7.75, temperature (T) 48.77 degrees C, and enzyme-to-substrate ratio ([E]/[S]) 3.50%. The analysis of variance in RSM showed that pH and [E]/[S] were important factors that significantly affected the process (P<0.05 and P<0.01, respectively). The hydrolysates of jellyfish umbrella collagen were fractionated by high performance liquid chromatography (HPLC), and three fractions (HF-1>3000 Da, 1000 Da

Optimization of antioxidant activity by response surface methodology in hydrolysates of jellyfish (Rhopilema esculentum) umbrella collagen*

PubMed Central

Zhuang, Yong-liang; Zhao, Xue; Li, Ba-fang

2009-01-01

To optimize the hydrolysis conditions to prepare hydrolysates of jellyfish umbrella collagen with the highest hydroxyl radical scavenging activity, collagen extracted from jellyfish umbrella was hydrolyzed with trypsin, and response surface methodology (RSM) was applied. The optimum conditions obtained from experiments were pH 7.75, temperature (T) 48.77 °C, and enzyme-to-substrate ratio ([E]/[S]) 3.50%. The analysis of variance in RSM showed that pH and [E]/[S] were important factors that significantly affected the process (P<0.05 and P<0.01, respectively). The hydrolysates of jellyfish umbrella collagen were fractionated by high performance liquid chromatography (HPLC), and three fractions (HF-1>3000 Da, 1000 Da

Molecular simulation of CO chemisorption on Co(0001) in presence of supercritical fluid solvent: A potential of mean force study

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

Asiaee, Alireza; Benjamin, Kenneth M., E-mail: kenneth.benjamin@sdsmt.edu

2016-08-28

For several decades, heterogeneous catalytic processes have been improved through utilizing supercritical fluids (SCFs) as solvents. While numerous experimental studies have been established across a range of chemistries, such as oxidation, pyrolysis, amination, and Fischer-Tropsch synthesis, still there is little fundamental, molecular-level information regarding the role of the SCF on elementary heterogeneous catalytic steps. In this study, the influence of hexane solvent on the adsorption of carbon monoxide on Co(0001), as the first step in the reaction mechanism of many processes involving syngas conversion, is probed. Simulations are performed at various bulk hexane densities, ranging from ideal gas conditions (nomore » SCF hexane) to various near- and super-critical hexane densities. For this purpose, both density functional theory and molecular dynamics simulations are employed to determine the adsorption energy and free energy change during CO chemisorption. Potential of mean force calculations, utilizing umbrella sampling and the weighted histogram analysis method, provide the first commentary on SCF solvent effects on the energetic aspects of the chemisorption process. Simulation results indicate an enhanced stability of CO adsorption on the catalyst surface in the presence of supercritical hexane within the reduced pressure range of 1.0–1.5 at a constant temperature of 523 K. Furthermore, it is shown that the maximum stability of CO in the adsorbed state as a function of supercritical hexane density at 523 K nearly coincides with the maximum isothermal compressibility of bulk hexane at this temperature.« less

Exploring resistance mechanisms of HCV NS3/4A protease mutations to MK5172: insight from molecular dynamics simulations and free energy calculations.

PubMed

Guan, Yan; Sun, Huiyong; Pan, Peichen; Li, Youyong; Li, Dan; Hou, Tingjun

2015-09-01

Mutations at a number of key positions (Ala156, Asp168 and Arg155) of the HCV NS3/4A protease can induce medium to high resistance to MK5172. The emergence of the resistant mutations seriously compromises the antiviral therapy efficacy to hepatitis C. In this study, molecular dynamics (MD) simulations, free energy calculations and free energy decomposition were used to explore the interaction profiles of MK5172 with the wild-type (WT) and four mutated (R155K, D168A, D168V and A156T) HCV NS3/4A proteases. The binding free energies predicted by Molecular Mechanics/Generalized Born Solvent Area (MM/GBSA) are consistent with the trend of the experimental drug resistance data. The free energy decomposition analysis shows that the resistant mutants may change the protein-MK5172 interaction profiles, resulting in the unbalanced energetic distribution amongst the catalytic triad, the strand 135-139 and the strand 154-160. Moreover, umbrella sampling (US) simulations were employed to elucidate the unbinding processes of MK5172 from the active pockets of the WT HCV NS3/4A protease and the four mutants. The US simulations demonstrate that the dissociation pathways of MK5172 escaping from the binding pockets of the WT and mutants are quite different, and it is quite possible that MK5172 will be harder to get access to the correct binding sites of the mutated proteases, thereafter leading to drug resistance.

Mechanism of the αβ Conformational Change in F1-ATPase after ATP Hydrolysis: Free-Energy Simulations

PubMed Central

Ito, Yuko; Ikeguchi, Mitsunori

2015-01-01

One of the motive forces for F1-ATPase rotation is the conformational change of the catalytically active β subunit due to closing and opening motions caused by ATP binding and hydrolysis, respectively. The closing motion is accomplished in two steps: the hydrogen-bond network around ATP changes and then the entire structure changes via B-helix sliding, as shown in our previous study. Here, we investigated the opening motion induced by ATP hydrolysis using all-atom free-energy simulations, combining the nudged elastic band method and umbrella sampling molecular-dynamics simulations. Because hydrolysis requires residues in the α subunit, the simulations were performed with the αβ dimer. The results indicate that the large-scale opening motion is also achieved by the B-helix sliding (in the reverse direction). However, the sliding mechanism is different from that of ATP binding because sliding is triggered by separation of the hydrolysis products ADP and Pi. We also addressed several important issues: 1), the timing of the product Pi release; 2), the unresolved half-closed β structure; and 3), the ADP release mechanism. These issues are fundamental for motor function; thus, the rotational mechanism of the entire F1-ATPase is also elucidated through this αβ study. During the conformational change, conserved residues among the ATPase proteins play important roles, suggesting that the obtained mechanism may be shared with other ATPase proteins. When combined with our previous studies, these results provide a comprehensive view of the β-subunit conformational change that drives the ATPase. PMID:25564855

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

PubMed

Jani, Vinod; Sonavane, Uddhavesh; Joshi, Rajendra

2016-07-01

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

Transcatheter umbrella closure of valvular and paravalvular leaks.

PubMed

Hourihan, M; Perry, S B; Mandell, V S; Keane, J F; Rome, J J; Bittl, J A; Lock, J E

1992-11-15

Our aim was to adapt the technique of transcatheter umbrella closure of intracardiac defects for closure of valvular and paravalvular defects. The double-umbrella device developed by Rashkind and Cuaso has been safely and effectively delivered across a host of intracardiac defects, but transcatheter closure of valvular and paravalvular leaks has not been reported. Between February 1987 and September 1990, eight patients who were believed to be poor operative candidates were taken to the catheterization laboratory for transcatheter double-umbrella closure of a valvular or a paravalvular leak. Four patients had a paravalvular leak around a prosthetic aortic valve. The other four patients had a valvular leak: one patient with a regurgitant native aortic valve after a Stansel procedure and three patients with a regurgitant porcine valve in a left ventricular apex to descending aorta conduit. Placement of a double-umbrella device was attempted in seven of the eight patients and was successful in all seven. Device placement was not attempted in one patient because of the crescentic shape of his defect. Two patients required two devices for each closure; the other five required only one device each. Angiography, performed on six patients after device closure, demonstrated that three patients had a completely occluded defect, two had trivial residual flow and one patient had mild residual flow through the device. All significant complications occurred in one patient who had hemolysis and oliguria that resolved when the initial umbrella was replaced by a larger device. In addition, two devices migrated to the patient's pulmonary arteries but were retrieved in the catheterization laboratory without difficulty. No other early or late complications occurred in 21 to 50 months of follow-up. Of the four patients with a paravalvular leak, the one who did not receive a device died at operation, one patient died at operation for an associated defect (in the operating room the umbrella was found securely in place across the paraaortic defect) and two patients are clinically well at home after 21 and 32 months, respectively. Of the four patients with closure of a valvular leak, one patient remains well at home 50 months later, one patient died at operation for associated defects and two patients had additional successful surgical treatment and remain well 29 months after device placement. Transcatheter umbrella closure appears to be a reasonable alternative for closure of a valvular or paravalvular leak in patients who are poor operative candidates.

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

Ngo, Van; Wang, Yibo; Haas, Stephan

Crystal structures of several bacterial Na v channels have been recently published and molecular dynamics simulations of ion permeation through these channels are consistent with many electrophysiological properties of eukaryotic channels. Bacterial Na v channels have been characterized as functionally asymmetric, and the mechanism of this asymmetry has not been clearly understood. To address this question, we combined non-equilibrium simulation data with two-dimensional equilibrium unperturbed landscapes generated by umbrella sampling and Weighted Histogram Analysis Methods for multiple ions traversing the selectivity filter of bacterial Na vAb channel. This approach provided new insight into the mechanism of selective ion permeation inmore » bacterial Nav channels. The non-equilibrium simulations indicate that two or three extracellular K + ions can block the entrance to the selectivity filter of Na vAb in the presence of applied forces in the inward direction, but not in the outward direction. The block state occurs in an unstable local minimum of the equilibrium unperturbed free-energy landscape of two K+ ions that can be ‘locked’ in place bymodest applied forces. In contrast to K +, three Na + ions move favorably through the selectivity filter together as a unit in a loose “knock-on” mechanism of permeation in both inward and outward directions, and there is no similar local minimum in the two-dimensional free-energy landscape of two Na + ions for a block state. The useful work predicted by the non-equilibrium simulations that is required to break the K + block is equivalent to large applied potentials experimentally measured for two bacterial Na v channels to induce inward currents of K + ions. Here, these results illustrate how inclusion of non-equilibrium factors in the simulations can provide detailed information about mechanisms of ion selectivity that is missing from mechanisms derived from either crystal structures or equilibrium unperturbed free-energy landscapes.« less

Molecular mechanisms responsible for hydrate anti-agglomerant performance.

PubMed

Phan, Anh; Bui, Tai; Acosta, Erick; Krishnamurthy, Pushkala; Striolo, Alberto

2016-09-28

Steered and equilibrium molecular dynamics simulations were employed to study the coalescence of a sI hydrate particle and a water droplet within a hydrocarbon mixture. The size of both the hydrate particle and the water droplet is comparable to that of the aqueous core in reverse micelles. The simulations were repeated in the presence of various quaternary ammonium chloride surfactants. We investigated the effects due to different groups on the quaternary head group (e.g. methyl vs. butyl groups), as well as different hydrophobic tail lengths (e.g. n-hexadecyl vs. n-dodecyl tails) on the surfactants' ability to prevent coalescence. Visual inspection of sequences of simulation snapshots indicates that when the water droplet is not covered by surfactants it is more likely to approach the hydrate particle, penetrate the protective surfactant film, reach the hydrate surface, and coalesce with the hydrate than when surfactants are present on both surfaces. Force-distance profiles obtained from steered molecular dynamics simulations and free energy profiles obtained from umbrella sampling suggest that surfactants with butyl tripods on the quaternary head group and hydrophobic tails with size similar to the solvent molecules can act as effective anti-agglomerants. These results qualitatively agree with macroscopic experimental observations. The simulation results provide additional insights, which could be useful in flow assurance applications: the butyl tripod provides adhesion between surfactants and hydrates; when the length of the surfactant tail is compatible with that of the hydrocarbon in the liquid phase a protective film can form on the hydrate; however, once a molecularly thin chain of water molecules forms through the anti-agglomerant film, connecting the water droplet and the hydrate, water flows to the hydrate and coalescence is inevitable.

On the ambiguity of conformational states: A B&S-LEUS simulation study of the helical conformations of decaalanine in water

NASA Astrophysics Data System (ADS)

Bieler, Noah S.; Hünenberger, Philippe H.

2015-04-01

Estimating the relative stabilities of different conformational states of a (bio-)molecule using molecular dynamics simulations involves two challenging problems: the conceptual problem of how to define the states of interest and the technical problem of how to properly sample these states, along with achieving a sufficient number of interconversion transitions. In this study, the two issues are addressed in the context of a decaalanine peptide in water, by considering the 310-, α-, and π-helical states. The simulations rely on the ball-and-stick local-elevation umbrella-sampling (B&S-LEUS) method. In this scheme, the states are defined as hyperspheres (balls) in a (possibly high dimensional) collective-coordinate space and connected by hypercylinders (sticks) to ensure transitions. A new object, the pipe, is also introduced here to handle curvilinear pathways. Optimal sampling within the so-defined space is ensured by confinement and (one-dimensional) memory-based biasing potentials associated with the three different kinds of objects. The simulation results are then analysed in terms of free energies using reweighting, possibly relying on two distinct sets of collective coordinates for the state definition and analysis. The four possible choices considered for these sets are Cartesian coordinates, hydrogen-bond distances, backbone dihedral angles, or pairwise sums of successive backbone dihedral angles. The results concerning decaalanine underline that the concept of conformational state may be extremely ambiguous, and that its tentative absolute definition as a free-energy basin remains subordinated to the choice of a specific analysis space. For example, within the force-field employed and depending on the analysis coordinates selected, the 310-helical state may refer to weakly overlapping collections of conformations, differing by as much as 25 kJ mol-1 in terms of free energy. As another example, the π-helical state appears to correspond to a free-energy basin for three choices of analysis coordinates, but to be unstable with the fourth one. The problem of conformational-state definition may become even more intricate when comparison with experiment is involved, where the state definition relies on spectroscopic or functional observables.

On the ambiguity of conformational states: A B&S-LEUS simulation study of the helical conformations of decaalanine in water.

PubMed

Bieler, Noah S; Hünenberger, Philippe H

2015-04-28

Estimating the relative stabilities of different conformational states of a (bio-)molecule using molecular dynamics simulations involves two challenging problems: the conceptual problem of how to define the states of interest and the technical problem of how to properly sample these states, along with achieving a sufficient number of interconversion transitions. In this study, the two issues are addressed in the context of a decaalanine peptide in water, by considering the 310-, α-, and π-helical states. The simulations rely on the ball-and-stick local-elevation umbrella-sampling (B&S-LEUS) method. In this scheme, the states are defined as hyperspheres (balls) in a (possibly high dimensional) collective-coordinate space and connected by hypercylinders (sticks) to ensure transitions. A new object, the pipe, is also introduced here to handle curvilinear pathways. Optimal sampling within the so-defined space is ensured by confinement and (one-dimensional) memory-based biasing potentials associated with the three different kinds of objects. The simulation results are then analysed in terms of free energies using reweighting, possibly relying on two distinct sets of collective coordinates for the state definition and analysis. The four possible choices considered for these sets are Cartesian coordinates, hydrogen-bond distances, backbone dihedral angles, or pairwise sums of successive backbone dihedral angles. The results concerning decaalanine underline that the concept of conformational state may be extremely ambiguous, and that its tentative absolute definition as a free-energy basin remains subordinated to the choice of a specific analysis space. For example, within the force-field employed and depending on the analysis coordinates selected, the 310-helical state may refer to weakly overlapping collections of conformations, differing by as much as 25 kJ mol(-1) in terms of free energy. As another example, the π-helical state appears to correspond to a free-energy basin for three choices of analysis coordinates, but to be unstable with the fourth one. The problem of conformational-state definition may become even more intricate when comparison with experiment is involved, where the state definition relies on spectroscopic or functional observables.

Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds Along Two Different Reaction Pathways: Implica-tions for Engineering Bioscavengers

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

Wymore, Troy W; Langan, Paul; Smith, Jeremy C

Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ( bioscavengers ) is an emerging prophylactic approach to diminishing their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical (QM/MM) umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalentmore » intermediate. P F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily due to the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed -propeller folds for more efficient degradation of OP compounds.« less

Predicting kinetic nanocrystal shapes through multi-scale theory and simulation: Polyvinylpyrrolidone-mediated growth of Ag nanocrystals

NASA Astrophysics Data System (ADS)

Balankura, Tonnam; Qi, Xin; Zhou, Ya; Fichthorn, Kristen A.

2016-10-01

In the shape-controlled synthesis of colloidal Ag nanocrystals, structure-directing agents, particularly polyvinylpyrrolidone (PVP), are known to be a key additive in making nanostructures with well-defined shapes. Although many Ag nanocrystals have been successfully synthesized using PVP, the mechanism by which PVP actuates shape control remains elusive. Here, we present a multi-scale theoretical framework for kinetic Wulff shape predictions that accounts for the chemical environment, which we used to probe the kinetic influence of the adsorbed PVP film. Within this framework, we use umbrella-sampling molecular dynamics simulations to calculate the potential of mean force and diffusion coefficient profiles of Ag atom deposition onto Ag(100) and Ag(111) in ethylene glycol solution with surface-adsorbed PVP. We use these profiles to calculate the mean-first passage times and implement extensive Brownian dynamics simulations, which allows the kinetic effects to be quantitatively evaluated. Our results show that PVP films can regulate the flux of Ag atoms to be greater towards Ag(111) than Ag(100). PVP's preferential binding towards Ag(100) over Ag(111) gives PVP its flux-regulating capabilities through the lower free-energy barrier of Ag atoms to cross the lower-density PVP film on Ag(111) and enhanced Ag trapping by the extended PVP film on Ag(111). Under kinetic control, {100}-faceted nanocrystals will be formed when the Ag flux is greater towards Ag(111). The predicted kinetic Wulff shapes are in agreement with the analogous experimental system.

Study of hydrogen-molecule guests in type II clathrate hydrates using a force-matched potential model parameterised from ab initio molecular dynamics

NASA Astrophysics Data System (ADS)

Burnham, Christian J.; Futera, Zdenek; English, Niall J.

2018-03-01

The force-matching method has been applied to parameterise an empirical potential model for water-water and water-hydrogen intermolecular interactions for use in clathrate-hydrate simulations containing hydrogen guest molecules. The underlying reference simulations constituted ab initio molecular dynamics (AIMD) of clathrate hydrates with various occupations of hydrogen-molecule guests. It is shown that the resultant model is able to reproduce AIMD-derived free-energy curves for the movement of a tagged hydrogen molecule between the water cages that make up the clathrate, thus giving us confidence in the model. Furthermore, with the aid of an umbrella-sampling algorithm, we calculate barrier heights for the force-matched model, yielding the free-energy barrier for a tagged molecule to move between cages. The barrier heights are reasonably large, being on the order of 30 kJ/mol, and are consistent with our previous studies with empirical models [C. J. Burnham and N. J. English, J. Phys. Chem. C 120, 16561 (2016) and C. J. Burnham et al., Phys. Chem. Chem. Phys. 19, 717 (2017)]. Our results are in opposition to the literature, which claims that this system may have very low barrier heights. We also compare results to that using the more ad hoc empirical model of Alavi et al. [J. Chem. Phys. 123, 024507 (2005)] and find that this model does very well when judged against the force-matched and ab initio simulation data.

Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds along Two Different Reaction Pathways: Implications for Engineering Bioscavengers

PubMed Central

2015-01-01

Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents (“bioscavengers”) is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P–F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds. PMID:24720808

Force and Stress along Simulated Dissociation Pathways of Cucurbituril-Guest Systems.

PubMed

Velez-Vega, Camilo; Gilson, Michael K

2012-03-13

The field of host-guest chemistry provides computationally tractable yet informative model systems for biomolecular recognition. We applied molecular dynamics simulations to study the forces and mechanical stresses associated with forced dissociation of aqueous cucurbituril-guest complexes with high binding affinities. First, the unbinding transitions were modeled with constant velocity pulling (steered dynamics) and a soft spring constant, to model atomic force microscopy (AFM) experiments. The computed length-force profiles yield rupture forces in good agreement with available measurements. We also used steered dynamics with high spring constants to generate paths characterized by a tight control over the specified pulling distance; these paths were then equilibrated via umbrella sampling simulations and used to compute time-averaged mechanical stresses along the dissociation pathways. The stress calculations proved to be informative regarding the key interactions determining the length-force profiles and rupture forces. In particular, the unbinding transition of one complex is found to be a stepwise process, which is initially dominated by electrostatic interactions between the guest's ammoniums and the host's carbonyl groups, and subsequently limited by the extraction of the guest's bulky bicyclooctane moiety; the latter step requires some bond stretching at the cucurbituril's extraction portal. Conversely, the dissociation of a second complex with a more slender guest is mainly driven by successive electrostatic interactions between the different guest's ammoniums and the host's carbonyl groups. The calculations also provide information on the origins of thermodynamic irreversibilities in these forced dissociation processes.

Reflective Practice in Healthcare Education: An Umbrella Review

ERIC Educational Resources Information Center

Fragkos, Konstantinos C.

2016-01-01

Reflection in healthcare education is an emerging topic with many recently published studies and reviews. This current systematic review of reviews (umbrella review) of this field explores the following aspects: which definitions and models are currently in use; how reflection impacts design, evaluation, and assessment; and what future challenges…

Thermodynamics of Micelle Formation and Membrane Fusion Modulate Antimicrobial Lipopeptide Activity

PubMed Central

Lin, Dejun; Grossfield, Alan

2015-01-01

Antimicrobial lipopeptides (AMLPs) are antimicrobial drug candidates that preferentially target microbial membranes. One class of AMLPs, composed of cationic tetrapeptides attached to an acyl chain, have minimal inhibitory concentrations in the micromolar range against a range of bacteria and fungi. Previously, we used coarse-grained molecular dynamics simulations and free energy methods to study the thermodynamics of their interaction with membranes in their monomeric state. Here, we extended the study to the biologically relevant micellar state, using, to our knowledge, a novel reaction coordinate based on hydrophobic contacts. Using umbrella sampling along this reaction coordinate, we identified the critical transition states when micelles insert into membranes. The results indicate that the binding of these AMLP micelles to membranes is thermodynamically favorable, but in contrast to the monomeric case, there are significant free energy barriers. The height of these free energy barriers depends on the membrane composition, suggesting that the AMLPs’ ability to selectively target bacterial membranes may be as much kinetic as thermodynamic. This mechanism highlights the importance of considering oligomeric state in solution as criterion when optimizing peptides or lipopeptides as antibiotic leads. PMID:26287627

Under the Whole Language Umbrella: Many Cultures, Many Voices.

ERIC Educational Resources Information Center

Flurkey, Alan D., Ed.; Meyer, Richard J., Ed.

Originally presented at the second annual Whole Language Umbrella Conference, the 18 essays in this book address the three related themes of identity, responsibility, and practice. The essays in the book discuss how whole language is defined, and how its practitioners come to define themselves; how whole language teachers act upon their identities…

Identification of Regime Transitions in Umbrella Cloud Growth for Short- and Long-Lived Eruptions

NASA Astrophysics Data System (ADS)

Pouget, S.; Bursik, M. I.; Johnson, C. G.; Hogg, A. J.; Sparks, R. S. J.; Phillips, J.

2014-12-01

The ability to characterize the transition between fluid dynamic regimes in an umbrella cloud as it spreads as a gravity current is important for volcanologists and atmospheric scientists. It would allow a better understanding of how ash behaves and spreads in the atmosphere and therefore better estimate the location and propagation of the ash during an eruption. We tested a new gravity current model that allows us to study the transition from one flow regime to another in data plume growth data from several eruptions. It was found that previous asymptotic models of umbrella cloud growth only treat one part of the evolution of the cloud. The new model allows for the study of the duration of different regimes and the timing of transitions during growth of the umbrella cloud. It was found, by testing the effect of the different input parameters of the model, that the duration of release from the volcanic source has a larger impact than the drag force and the initial radius of the intrusion on the initial and downwind spreading.

Evaluation of Selected New York City Umbrella Programs, 1974-1975 School Year.

ERIC Educational Resources Information Center

Fordham Univ., Bronx, NY. Inst. for Research and Evaluation.

An evaluation of twelve different New York City Umbrella Programs coordinated in New York City public schools during the 1974-1975 school year is contained in this document. This report presents a description and evaluation of these programs, together with the major findings. The programs were implemented in the following areas: (1) tutoring in…

Greater sage-grouse as an umbrella species for sagebrush-associated vertebrates.

Treesearch

Mary M. Rowland; Michael J. Wisdom; Lowell Suring; Cara W. Meinke

2006-01-01

Widespread degradation of the sagebrush ecosystem in the western United States, including the invasion of cheatgrass, has prompted resource managers to consider a variety of approaches to restore and conserve habitats for sagebrush-associated species. One such approach involves the use of greater sage-grouse, a species of prominent conservation interest, as an umbrella...

What regulates the catalytic activities in AGE catalysis? An answer from quantum mechanics/molecular mechanics simulations.

PubMed

Zhang, Yulai; Zhang, Hongxing; Zheng, Qingchuan

2017-12-06

The AGE superfamily (AGEs) is made up of kinds of isomerase which are very important both physiologically and industrially. One of the most intriguing aspects of AGEs has to do with the mechanism that regulates their activities in single conserved active pocket. In order to clarify the relationship among single conserved active pocket and two activities in AGEs, results for the epimerization activity catalyzed by RaCE and the isomerization activity catalyzed by SeYihS were obtained by using QM/MM umbrella sampling simulations and 2D-FES calculations. Our results show that both of them have similar enzyme-substrate combination mode for inner pyranose ring in single conserved active pocket even though they have different substrate specificity. This means that the pathways of ring opening catalyzed by them are similar. However, one non-conserved residue (Leu183 in RaCE, Met175 in SeYihS) in the active site, which has different steric hindrance, causes a small but effective change in the direction of ring opening in stage 1. And then this change will induce a fundamentally different catalytic activity for RaCE and SeYihS in stage 2. Our results give a novel viewpoint about the regulatory mechanism between CE and YihS in AGEs, and may be helpful for further experiments of rational enzyme design based on the (α/α) 6 -barrel basic scaffold.

A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases

NASA Astrophysics Data System (ADS)

Rashid, M. Harunur; Huq, Redwan; Tanner, Mark R.; Chhabra, Sandeep; Khoo, Keith K.; Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra; Pennington, Michael W.; Beeton, Christine; Kuyucak, Serdar; Norton, Raymond S.

2014-03-01

HsTX1 toxin, from the scorpion Heterometrus spinnifer, is a 34-residue, C-terminally amidated peptide cross-linked by four disulfide bridges. Here we describe new HsTX1 analogues with an Ala, Phe, Val or Abu substitution at position 14. Complexes of HsTX1 with the voltage-gated potassium channels Kv1.3 and Kv1.1 were created using docking and molecular dynamics simulations, then umbrella sampling simulations were performed to construct the potential of mean force (PMF) of the ligand and calculate the corresponding binding free energy for the most stable configuration. The PMF method predicted that the R14A mutation in HsTX1 would yield a > 2 kcal/mol gain for the Kv1.3/Kv1.1 selectivity free energy relative to the wild-type peptide. Functional assays confirmed the predicted selectivity gain for HsTX1[R14A] and HsTX1[R14Abu], with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold for Kv1.3 over Kv1.1. This remarkable potency and selectivity for Kv1.3, which is significantly up-regulated in activated effector memory cells in humans, suggest that these analogues represent valuable leads in the development of therapeutics for autoimmune diseases.

Investigating Hydrophilic Pores in Model Lipid Bilayers using Molecular Simulations: Correlating Bilayer Properties with Pore Formation Thermodynamics

PubMed Central

Hu, Yuan; Sinha, Sudipta Kumar

2015-01-01

Cell-penetrating and antimicrobial peptides show remarkable ability to translocate across physiological membranes. Along with factors such as electric potential induced-perturbations of membrane structure and surface tension effects, experiments invoke pore-like membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a non-trivial free energy cost, thus necessitating consideration of the factors associated with pore formation and attendant free energetics. Due to experimental and modeling challenges related to the long timescales of the translocation process, we use umbrella-sampling molecular dynamics simulations with a lipid-density based order parameter to investigate membrane pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of head-groups, charge states, acyl chain lengths and saturation. We probe the dependence of pore-formation barriers on area per lipid, lipid bilayer thickness, membrane bending rigidities in three different lipid classes. The pore formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. Pore formation free energy is higher in peptide-lipid systems relative to the peptide-free lipid systems due to penalties to maintain solvation of charged hydrophilic solutes within the membrane environment. PMID:25614183

Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics.

PubMed

Hu, Yuan; Sinha, Sudipta Kumar; Patel, Sandeep

2015-06-23

Cell-penetrating and antimicrobial peptides show a remarkable ability to translocate across physiological membranes. Along with factors such as electric-potential-induced perturbations of membrane structure and surface tension effects, experiments invoke porelike membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a nontrivial free-energy cost, thus necessitating a consideration of the factors associated with pore formation and the attendant free energies. Because of experimental and modeling challenges related to the long time scales of the translocation process, we use umbrella sampling molecular dynamics simulations with a lipid-density-based order parameter to investigate membrane-pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of headgroups, charge states, acyl chain lengths, and saturation. We probe the dependence of pore-formation barriers on the area per lipid, lipid bilayer thickness, and membrane bending rigidities in three different lipid classes. The pore-formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. The pore-formation free energy is higher in peptide-lipid systems than in peptide-free lipid systems due to penalties to maintain the solvation of charged hydrophilic solutes within the membrane environment.

The interfacial energetics of the oil molecules interactions with shale media using molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Zhang, Z.; Wang, J.

2017-12-01

Characterizing the behavior of oil molecules in nanopore is vital to the understanding of geochemistry of hydrocarbon-bearing fluid in ultra-tight source rocks, such as shale. The heterogeneous nature of hydrocarbon system of nanoscale complicates experimental studies of oil / shale interfacial interaction. Therefore, to gain mechanistic understanding of the interplay of oil molecules in rock nanopore, molecular dynamics simulations have been applied to study the interactions of polar and non-polar oil on both calcite and kerogen surfaces. The effect of surface wetting, oil polarity, and temperature on the Gibbs free energy of adsorption have been investigated. The free energy, entropy, and enthalpy profiles have been calculated using advanced molecular dynamics method: umbrella sampling. In agreement with experiment, 1) surface with adsorbed water layer significantly reduces the oil adsorption energy on kerogen and turns the calcite surface to highly oil-repellent; 2) polar oil has overall stronger adsorption free energy than that of non-polar oil on both non-wetted calcite and kerogen surface; 3) organic interface (e.g. kerogen) exhibits stronger adsorption of oil molecules compared to inorganic one (e.g. calcite). The finding of this study indicates that oil displacement in nanopores can be enhanced by promoting the water adsorption on surface and reducing the polarity of oil on both inorganic and organic interfaces.

Urothelial cells in smears from cervix uteri

PubMed Central

Palaoro, Luis Alberto; Guerra, Fernando; Angeleri, Anabela; Palamas, Marta; Melba, Sardi-Segovia; Rocher, Adriana Esther

2012-01-01

Objectives: To establish the cytological criteria to identify the urothelial cells in cervical smears in order to avoid mistakes in the cytological diagnosis. Materials and Methods: Cervical smears from 34 post menopausal women with vesicovaginal fistulas, advanced bladder prolapse and genital erosive lichen planes (vulvar kraurosis) (Group 1) and transitional cell metaplasia of the cervix (TCM, Group 2) were stained with Papanicolaou technique. The cervical samples were taken during the routine annual examination for prevention of the uterine cancer. Results: The smears of cervix from Group 1 showed urothelial cells from the three layers of the transitional epithelium. The umbrella cells are the bigger ones with relatively large nuclei. Frequently, they are multinucleated with single or multiple nucleoli and a typical “frothy” cytoplasm (cytoplasmic vacuoles). The cells of the Group 2 showed nuclei with oval to spindled shapes, some tapered ends, less cytoplasm than squamous metaplastic cells, powdery chromatin, small nucleoli and nuclear grooves. Conclusions: The umbrella cells may be mistaken for dysplastic cells originating in low grade squamous intraepithelial lesions lesions (LSILs) due to their nuclear and cytoplasm sizes. Therefore, it is important to know the possibility of their appearance in the cervical smears, especially in post menopausal patients in order to avoid a false diagnosis of an intraepithelial lesion. It is unlikely that deeper cells of urothelium would be confused with high grade squamous intraepithelial lesion (HSIL) cells. However, their presence might be a reason of mistake in the diagnosis. TCM is an under-recognized metaplastic phenomenon of the cervix and vagina, which is a mimicker of high-grade squamous intraepithelial lesion. The differential characteristic between umbrella cells, cells from TCM and the deeper urothelial cells, and LSIL and HSIL are detailed in the present paper. PMID:22438615

Challenges in molecular simulation of homogeneous ice nucleation

NASA Astrophysics Data System (ADS)

Brukhno, Andrey V.; Anwar, Jamshed; Davidchack, Ruslan; Handel, Richard

2008-12-01

We address the problem of recognition and growth of ice nuclei in simulation of supercooled bulk water. Bond orientation order parameters based on the spherical harmonics analysis are shown to be ineffective when applied to ice nucleation. Here we present an alternative method which robustly differentiates between hexagonal and cubic ice forms. The method is based on accumulation of the maximum projection of bond orientations onto a set of predetermined vectors, where different terms can contribute with opposite signs with the result that the irrelevant or incompatible molecular arrangements are damped out. We also introduce an effective cluster size by assigning a quality weight to each molecule in an ice-like cluster. We employ our cluster analysis in Monte Carlo simulation of homogeneous ice formation. Replica-exchange umbrella sampling is used for biasing the growth of the largest cluster and calculating the associated free energy barrier. Our results suggest that the ice formation can be seen as a two-stage process. Initially, short tetrahedrally arranged threads and rings are present; these become correlated and form a diffuse ice-genic network. Later, hydrogen bond arrangements within the amorphous ice-like structure gradually settle down and simultaneously 'tune-up' nearby water molecules. As a result, a well-shaped ice core emerges and spreads throughout the system. The process is very slow and diverse owing to the rough energetic landscape and sluggish molecular motion in supercooled water, while large configurational fluctuations are needed for crystallization to occur. In the small systems studied so far the highly cooperative molecular rearrangements eventually lead to a relatively fast percolation of the forming ice structure through the periodic boundaries, which inevitably affects the simulation results.

Free-Energy Landscape of Reverse tRNA Translocation through the Ribosome Analyzed by Electron Microscopy Density Maps and Molecular Dynamics Simulations

PubMed Central

Ishida, Hisashi; Matsumoto, Atsushi

2014-01-01

To understand the mechanism of reverse tRNA translocation in the ribosome, all-atom molecular dynamics simulations of the ribosome-tRNAs-mRNA-EFG complex were performed. The complex at the post-translocational state was directed towards the translocational and pre-translocational states by fitting the complex into cryo-EM density maps. Between a series of the fitting simulations, umbrella sampling simulations were performed to obtain the free-energy landscape. Multistep structural changes, such as a ratchet-like motion and rotation of the head of the small subunit were observed. The free-energy landscape showed that there were two main free-energy barriers: one between the post-translocational and intermediate states, and the other between the pre-translocational and intermediate states. The former corresponded to a clockwise rotation, which was coupled to the movement of P-tRNA over the P/E-gate made of G1338, A1339 and A790 in the small subunit. The latter corresponded to an anticlockwise rotation of the head, which was coupled to the location of the two tRNAs in the hybrid state. This indicates that the coupled motion of the head rotation and tRNA translocation plays an important role in opening and closing of the P/E-gate during the ratchet-like movement in the ribosome. Conformational change of EF-G was interpreted to be the result of the combination of the external motion by L12 around an axis passing near the sarcin-ricin loop, and internal hinge-bending motion. These motions contributed to the movement of domain IV of EF-G to maintain its interaction with A/P-tRNA. PMID:24999999

Free-energy landscape of reverse tRNA translocation through the ribosome analyzed by electron microscopy density maps and molecular dynamics simulations.

PubMed

Ishida, Hisashi; Matsumoto, Atsushi

2014-01-01

To understand the mechanism of reverse tRNA translocation in the ribosome, all-atom molecular dynamics simulations of the ribosome-tRNAs-mRNA-EFG complex were performed. The complex at the post-translocational state was directed towards the translocational and pre-translocational states by fitting the complex into cryo-EM density maps. Between a series of the fitting simulations, umbrella sampling simulations were performed to obtain the free-energy landscape. Multistep structural changes, such as a ratchet-like motion and rotation of the head of the small subunit were observed. The free-energy landscape showed that there were two main free-energy barriers: one between the post-translocational and intermediate states, and the other between the pre-translocational and intermediate states. The former corresponded to a clockwise rotation, which was coupled to the movement of P-tRNA over the P/E-gate made of G1338, A1339 and A790 in the small subunit. The latter corresponded to an anticlockwise rotation of the head, which was coupled to the location of the two tRNAs in the hybrid state. This indicates that the coupled motion of the head rotation and tRNA translocation plays an important role in opening and closing of the P/E-gate during the ratchet-like movement in the ribosome. Conformational change of EF-G was interpreted to be the result of the combination of the external motion by L12 around an axis passing near the sarcin-ricin loop, and internal hinge-bending motion. These motions contributed to the movement of domain IV of EF-G to maintain its interaction with A/P-tRNA.

Insight into resistance mechanism of anaplastic lymphoma kinase to alectinib and JH-VIII-157-02 caused by G1202R solvent front mutation.

PubMed

Wang, Han; Wang, Yao; Guo, Wentao; Du, Bin; Huang, Xiaobing; Wu, Riping; Yang, Baoyu; Lin, Xiaoyan; Wu, Yilan

2018-01-01

Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation. Molecular docking, conventional molecular dynamics (MD) simulations, free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principles of the binding preferences of alectinib and JH-VIII-157-02 toward ALK WT and the ALK G1202R (ALK G1202R ) mutation. JH-VIII-157-02 has similar binding affinities to both ALK WT and ALK G1202R whereas it has has a much lower binding affinity for alectinib to ALK G1202R . Analysis of individual energy terms indicate the major variation involves the van der Waals and entropy terms. Structural analysis reveals that the conformational change of the ATP-binding glycine-rich loop was primarily responsible for the alectinib resistance, not JH-VIII-157-02. In addition, US simulations prove JH-VIII-157-02 has similar dissociative processes from both ALK WT and ALK G1202R , while alectinib is more easily dissociated from ALK G1202R than from ALK WT , thus indicating lesser residence time. Both the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation in ALK resistance.

Insight into resistance mechanism of anaplastic lymphoma kinase to alectinib and JH-VIII-157-02 caused by G1202R solvent front mutation

PubMed Central

Wang, Han; Wang, Yao; Guo, Wentao; Du, Bin; Huang, Xiaobing; Wu, Riping; Yang, Baoyu; Lin, Xiaoyan; Wu, Yilan

2018-01-01

Background Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation. Methods Molecular docking, conventional molecular dynamics (MD) simulations, free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principles of the binding preferences of alectinib and JH-VIII-157-02 toward ALKWT and the ALK G1202R (ALKG1202R) mutation. Results JH-VIII-157-02 has similar binding affinities to both ALKWT and ALKG1202R whereas it has has a much lower binding affinity for alectinib to ALKG1202R. Analysis of individual energy terms indicate the major variation involves the van der Waals and entropy terms. Structural analysis reveals that the conformational change of the ATP-binding glycine-rich loop was primarily responsible for the alectinib resistance, not JH-VIII-157-02. In addition, US simulations prove JH-VIII-157-02 has similar dissociative processes from both ALKWT and ALKG1202R, while alectinib is more easily dissociated from ALKG1202R than from ALKWT, thus indicating lesser residence time. Conclusion Both the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation in ALK resistance. PMID:29785088

Quality Assurance and Evaluation through Brazilian Lenses: An Exploration into the Validity of Umbrella Concepts

ERIC Educational Resources Information Center

Centeno, Vera G.; Kauko, Jaakko; Candido, Helena H. D.

2018-01-01

In our present research we address the question of whether it is valid to apply the Quality Assurance and Evaluation (QAE) umbrella concept, which was formulated to explain new phenomena in European educational governance, to similar developments in Brazilian basic education. This led us to reflect on the possible pitfalls and potential strengths…

Minimally Invasive Surgical Device for Precise Application of Bioadhesives to Prevent iPPROM.

PubMed

Devaud, Yannick Robert; Züger, Silvia; Zimmermann, Roland; Ehrbar, Martin; Ochsenbein-Kölble, Nicole

2018-06-19

The benefits of endoscopic fetal surgery are deteriorated by the high risk of iatrogenic preterm prelabor rupture of fetal membranes (iPPROM). While previous studies have reported good sealing candidates to prevent membrane rupture, the delivery of these materials to the location of membrane puncture remains unsolved. We describe an approach to apply sealing materials onto the amnion through the fetoscopy port. We developed a device composed of an umbrella-shaped polyester coated nitinol mesh and an applicator. The spontaneously unfolding umbrella is pushed through the port, pulled against the amnion, and glued onto the amnion defect site. We tested the adhesion strength of multiple glues and tested the feasibility and reproducibility of this fetal membrane sealing approach in an ex vivo model. The umbrella unfolded and was well positioned in all tests (n = 18). When applied via the fetoscopy port, umbrellas were successfully glued onto the fetal membrane, and all of them completely covered the defect (n = 5). The mean time needed for the whole procedure was 3 min. This study is a proof of concept presenting a potential future solution for the precise local application of bioadhesives for the prevention of iPPROM. © 2018 S. Karger AG, Basel.

Geological support for the Umbrella Effect as a link between geomagnetic field and climate

PubMed Central

Kitaba, Ikuko; Hyodo, Masayuki; Nakagawa, Takeshi; Katoh, Shigehiro; Dettman, David L.; Sato, Hiroshi

2017-01-01

The weakening of the geomagnetic field causes an increase in galactic cosmic ray (GCR) flux. Some researchers argue that enhanced GCR flux might lead to a climatic cooling by increasing low cloud formation, which enhances albedo (umbrella effect). Recent studies have reported geological evidence for a link between weakened geomagnetic field and climatic cooling. However, more work is needed on the mechanism of this link, including whether the umbrella effect is playing a central role. In this research, we present new geological evidence that GCR flux change had a greater impact on continental climate than on oceanic climate. According to pollen data from Osaka Bay, Japan, the decrease in temperature of the Siberian air mass was greater than that of the Pacific air mass during geomagnetic reversals in marine isotope stages (MIS) 19 and 31. Consequently, the summer land-ocean temperature gradient was smaller, and the summer monsoon was weaker. Greater terrestrial cooling indicates that a reduction of insolation is playing a key role in the link between the weakening of the geomagnetic field and climatic cooling. The most likely candidate for the mechanism seems to be the increased albedo of the umbrella effect. PMID:28091595

Geological support for the Umbrella Effect as a link between geomagnetic field and climate.

PubMed

Kitaba, Ikuko; Hyodo, Masayuki; Nakagawa, Takeshi; Katoh, Shigehiro; Dettman, David L; Sato, Hiroshi

2017-01-16

The weakening of the geomagnetic field causes an increase in galactic cosmic ray (GCR) flux. Some researchers argue that enhanced GCR flux might lead to a climatic cooling by increasing low cloud formation, which enhances albedo (umbrella effect). Recent studies have reported geological evidence for a link between weakened geomagnetic field and climatic cooling. However, more work is needed on the mechanism of this link, including whether the umbrella effect is playing a central role. In this research, we present new geological evidence that GCR flux change had a greater impact on continental climate than on oceanic climate. According to pollen data from Osaka Bay, Japan, the decrease in temperature of the Siberian air mass was greater than that of the Pacific air mass during geomagnetic reversals in marine isotope stages (MIS) 19 and 31. Consequently, the summer land-ocean temperature gradient was smaller, and the summer monsoon was weaker. Greater terrestrial cooling indicates that a reduction of insolation is playing a key role in the link between the weakening of the geomagnetic field and climatic cooling. The most likely candidate for the mechanism seems to be the increased albedo of the umbrella effect.

Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

PubMed

Campbell, Jared M; Bateman, Emma; Peters, Micah Dj; Bowen, Joanne M; Keefe, Dorothy M; Stephenson, Matthew D

2016-03-01

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.

A molecular dynamics study of slow base flipping in DNA using conformational flooding.

PubMed

Bouvier, Benjamin; Grubmüller, Helmut

2007-08-01

Individual DNA bases are known to be able to flip out of the helical stack, providing enzymes with access to the genetic information otherwise hidden inside the helix. Consequently, base flipping is a necessary first step to many more complex biological processes such as DNA transcription or replication. Much remains unknown about this elementary step, despite a wealth of experimental and theoretical studies. From the theoretical point of view, the involved timescale of milliseconds or longer requires the use of enhanced sampling techniques. In contrast to previous theoretical studies employing umbrella sampling along a predefined flipping coordinate, this study attempts to induce flipping without prior knowledge of the pathway, using information from a molecular dynamics simulation of a B-DNA fragment and the conformational flooding method. The relevance to base flipping of the principal components of the simulation is assayed, and a combination of modes optimally related to the flipping of the base through either helical groove is derived for each of the two bases of the central guanine-cytosine basepair. By applying an artificial flooding potential along these collective coordinates, the flipping mechanism is accelerated to within the scope of molecular dynamics simulations. The associated free energy surface is found to feature local minima corresponding to partially flipped states, particularly relevant to flipping in isolated DNA; further transitions from these minima to the fully flipped conformation are accelerated by additional flooding potentials. The associated free energy profiles feature similar barrier heights for both bases and pathways; the flipped state beyond is a broad and rugged attraction basin, only a few kcal/mol higher in energy than the closed conformation. This result diverges from previous works but echoes some aspects of recent experimental findings, justifying the need for novel approaches to this difficult problem: this contribution represents a first step in this direction. Important structural factors involved in flipping, both local (sugar-phosphate backbone dihedral angles) and global (helical axis bend), are also identified.

Is Liberal Studies a Political Instrument in the Secondary School Curriculum? Lessons from the Umbrella Movement in Post-Colonial Hong Kong

ERIC Educational Resources Information Center

Fung, Dennis Chun-Lok; Lui, Wai-Mei

2017-01-01

This paper examines whether Hong Kong teachers and students perceived Liberal Studies and its ongoing curriculum review as politically driven during and after the Umbrella Movement, a large-scale civil disobedience campaign that took place in September 2014. The findings presented herein show that both groups disagreed with the claim that Liberal…

Numerical Simulation of Atomization in Nozzle Injection Flow

NASA Astrophysics Data System (ADS)

Fan, Qinyin; Guo, Chenhai; Takagi, Tosimi; Narumiya, Kikuo; Hattori, Hiroshi

At the initial stage of injection, the injection flow has not yet broken up and in a range of small atmosphere pressure (16˜500KPa), the tip of the injection flow always forms a shape of mushroom. [1] [2] Moreover, the umbrella of the mushroom is always very big and its root is always very thin, especially when the atmosphere pressure is relatively low (88KPa, or 100mmHg). These phenomena are not known popularly and the reason of mushroom formation is not clear. In this paper, with the MARS method for simulating free surface, analysis of injection flow is practiced. The phenomena are reproduced and the reason is cleared that the formation of the mushroom is induced by the momentum exchange between the injection fuel flow with very high speed and the very complex flow of the air.

Umbrellas can work under water: Using threatened species as indicator and management surrogates can improve coastal conservation

NASA Astrophysics Data System (ADS)

Gilby, Ben L.; Olds, Andrew D.; Connolly, Rod M.; Yabsley, Nicholas A.; Maxwell, Paul S.; Tibbetts, Ian R.; Schoeman, David S.; Schlacher, Thomas A.

2017-12-01

Species surrogates, the use of particular species to index habitat condition or to represent ecological assemblages are commonly identified in many ecosystems, but are less tested, and therefore less employed in estuaries. Estuaries provide important ecosystem goods (e.g. harvestable species) and services (e.g. carbon processing, coastal armouring), but require protection from multiple human activities, meaning that finding surrogates for estuarine condition or faunal assemblages is a significant knowledge gap. In this study, we test the efficacy of the threatened estuary ray Hemitrygon fluviorum, as a suitable indicator of ecosystem condition and management umbrella surrogate species for conservation prioritisation and monitoring purposes within estuaries. We surveyed fish assemblages and ray presence at ten sites within each of 22 estuaries in southeast Queensland, Australia, using one hour deployments of baited video arrays. We then tested for correlations between ray presence, a series of environmental variables considered important to ecosystem management within estuaries (i.e. testing rays as indicator species), and the co-occurring fish species (i.e. testing rays as umbrella species). Estuary rays function as both umbrella species and ecological indicators of habitat status in subtropical Australian estuaries. As umbrellas, ray occurrence concords with elevated species richness. As ecological indicators, ray distribution concords with habitats of good water quality (especially low turbidity) and more natural vegetation remaining in the catchment. These results highlight the potential for other threatened aquatic vertebrates that are both readily detectable and that are reliable proxies for ecosystems status to be become useful management tools in estuaries. The protection of such large, threatened species in coastal seascapes allows managers to address multiple targets for conservation, especially; (1) protecting species of conservation concern; (2) maintaining diversity; and (3) protecting optimal habitats by better placing reserves.

Experimental Investigation of the Performance of Image Registration and De-aliasing Algorithms

DTIC Science & Technology

2009-09-01

spread function In the literature these types of algorithms are sometimes hcluded under the broad umbrella of superresolution . However, in the current...We use one of these patterns to visually demonstrate successful de-aliasing 15. SUBJECT TERMS Image de-aliasing Superresolution Microscanning Image...undersampled point spread function. In the literature these types of algorithms are sometimes included under the broad umbrella of superresolution . However, in

Reaction mechanism of Ru(II) piano-stool complexes: umbrella sampling QM/MM MD study.

PubMed

Futera, Zdeněk; Burda, Jaroslav V

2014-07-15

Biologically relevant interactions of piano-stool ruthenium(II) complexes with ds-DNA are studied in this article by hybrid quantum mechanics-molecular mechanics (QM/MM) computational technique. The whole reaction mechanism is divided into three phases: (i) hydration of the [Ru(II) (η(6) -benzene)(en)Cl](+) complex, (ii) monoadduct formation between the resulting aqua-Ru(II) complex and N7 position of one of the guanines in the ds-DNA oligomer, and (iii) formation of the intrastrand Ru(II) bridge (cross-link) between two adjacent guanines. Free energy profiles of all the reactions are explored by QM/MM MD umbrella sampling approach where the Ru(II) complex and two guanines represent a quantum core, which is described by density functional theory methods. The combined QM/MM scheme is realized by our own software, which was developed to couple several quantum chemical programs (in this study Gaussian 09) and Amber 11 package. Calculated free energy barriers of the both ruthenium hydration and Ru(II)-N7(G) DNA binding process are in good agreement with experimentally measured rate constants. Then, this method was used to study the possibility of cross-link formation. One feasible pathway leading to Ru(II) guanine-guanine cross-link with synchronous releasing of the benzene ligand is predicted. The cross-linking is an exergonic process with the energy barrier lower than for the monoadduct reaction of Ru(II) complex with ds-DNA. Copyright © 2014 Wiley Periodicals, Inc.

Longitudinal Patterns and Predictors of Depression Trajectories Related to the 2014 Occupy Central/Umbrella Movement in Hong Kong

PubMed Central

Li, Tom K.; Pang, Herbert; Chan, Brandford H. Y.; Kawachi, Ichiro; Viswanath, Kasisomayajula; Schooling, Catherine Mary; Leung, Gabriel Matthew

2017-01-01

Objectives. To examine the longitudinal patterns and predictors of depression trajectories before, during, and after Hong Kong’s 2014 Occupy Central/Umbrella Movement. Methods. In a prospective study, between March 2009 and November 2015, we interviewed 1170 adults randomly sampled from the population-representative FAMILY Cohort. We used the Patient Health Questionnaire-9 to assess depressive symptoms and probable major depression. We investigated pre-event and time-varying predictors of depressive symptoms. Results. We identified 4 trajectories: resistant (22.6% of sample), resilient (37.0%), mild depressive symptoms (32.5%), and persistent moderate depression (8.0%). Baseline predictors that appeared to protect against persistent moderate depression included higher household income (odds ratio [OR] = 0.18; 95% confidence interval [CI] = 0.06, 0.56), greater psychological resilience (OR = 0.63; 95% CI = 0.48, 0.82), more family harmony (OR = 0.68; 95% CI = 0.56, 0.83), higher family support (OR = 0.80; 95% CI = 0.69, 0.92), better self-rated health (OR = 0.28; 95% CI = 0.16, 0.49), and fewer depressive symptoms (OR = 0.59; 95% CI = 0.43, 0.81). Conclusions. Depression trajectories after a major protest are comparable to those after major population events. Health care professionals should be aware of the mental health consequences during and after social movements, particularly among individuals lacking social support. PMID:28207329

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA

PubMed Central

2016-01-01

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results. PMID:27983843

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA.

PubMed

Hayatshahi, Hamed S; Roe, Daniel R; Galindo-Murillo, Rodrigo; Hall, Kathleen B; Cheatham, Thomas E

2017-01-26

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results.

Free energy barrier for melittin reorientation from a membrane-bound state to a transmembrane state.

PubMed

Irudayam, Sheeba J; Pobandt, Tobias; Berkowitz, Max L

2013-10-31

An important step in a phospholipid membrane pore formation by melittin antimicrobial peptide is a reorientation of the peptide from a surface into a transmembrane conformation. Experiments measure the fraction of peptides in the surface state and the transmembrane state, but no computational study exists that quantifies the free energy curve for the reorientation. In this work we perform umbrella sampling simulations to calculate the potential of mean force (PMF) for the reorientation of melittin from a surface-bound state to a transmembrane state and provide a molecular level insight in understanding the peptide-lipid properties that influence the existence of the free energy barrier. The PMFs were calculated for a peptide to lipid (P/L) ratio of 1/128 and 4/128. We observe that the free energy barrier is reduced when the P/L ratio increases. In addition, we study the cooperative effect; specifically we investigate if the reorientation barrier is smaller for a second melittin, given that another neighboring melittin was already in the transmembrane orientation. We observe that indeed the barrier of the PMF curve is reduced in this case, thus confirming the presence of a cooperative effect.

K + block is the mechanism of functional asymmetry in bacterial Na v channels

DOE PAGES

Ngo, Van; Wang, Yibo; Haas, Stephan; ...

2016-01-04

Crystal structures of several bacterial Na v channels have been recently published and molecular dynamics simulations of ion permeation through these channels are consistent with many electrophysiological properties of eukaryotic channels. Bacterial Na v channels have been characterized as functionally asymmetric, and the mechanism of this asymmetry has not been clearly understood. To address this question, we combined non-equilibrium simulation data with two-dimensional equilibrium unperturbed landscapes generated by umbrella sampling and Weighted Histogram Analysis Methods for multiple ions traversing the selectivity filter of bacterial Na vAb channel. This approach provided new insight into the mechanism of selective ion permeation inmore » bacterial Nav channels. The non-equilibrium simulations indicate that two or three extracellular K + ions can block the entrance to the selectivity filter of Na vAb in the presence of applied forces in the inward direction, but not in the outward direction. The block state occurs in an unstable local minimum of the equilibrium unperturbed free-energy landscape of two K+ ions that can be ‘locked’ in place bymodest applied forces. In contrast to K +, three Na + ions move favorably through the selectivity filter together as a unit in a loose “knock-on” mechanism of permeation in both inward and outward directions, and there is no similar local minimum in the two-dimensional free-energy landscape of two Na + ions for a block state. The useful work predicted by the non-equilibrium simulations that is required to break the K + block is equivalent to large applied potentials experimentally measured for two bacterial Na v channels to induce inward currents of K + ions. Here, these results illustrate how inclusion of non-equilibrium factors in the simulations can provide detailed information about mechanisms of ion selectivity that is missing from mechanisms derived from either crystal structures or equilibrium unperturbed free-energy landscapes.« less

K+ Block Is the Mechanism of Functional Asymmetry in Bacterial Nav Channels

PubMed Central

Ngo, Van; Wang, Yibo; Haas, Stephan; Noskov, Sergei Y.; Farley, Robert A.

2016-01-01

Crystal structures of several bacterial Nav channels have been recently published and molecular dynamics simulations of ion permeation through these channels are consistent with many electrophysiological properties of eukaryotic channels. Bacterial Nav channels have been characterized as functionally asymmetric, and the mechanism of this asymmetry has not been clearly understood. To address this question, we combined non-equilibrium simulation data with two-dimensional equilibrium unperturbed landscapes generated by umbrella sampling and Weighted Histogram Analysis Methods for multiple ions traversing the selectivity filter of bacterial NavAb channel. This approach provided new insight into the mechanism of selective ion permeation in bacterial Nav channels. The non-equilibrium simulations indicate that two or three extracellular K+ ions can block the entrance to the selectivity filter of NavAb in the presence of applied forces in the inward direction, but not in the outward direction. The block state occurs in an unstable local minimum of the equilibrium unperturbed free-energy landscape of two K+ ions that can be ‘locked’ in place by modest applied forces. In contrast to K+, three Na+ ions move favorably through the selectivity filter together as a unit in a loose “knock-on” mechanism of permeation in both inward and outward directions, and there is no similar local minimum in the two-dimensional free-energy landscape of two Na+ ions for a block state. The useful work predicted by the non-equilibrium simulations that is required to break the K+ block is equivalent to large applied potentials experimentally measured for two bacterial Nav channels to induce inward currents of K+ ions. These results illustrate how inclusion of non-equilibrium factors in the simulations can provide detailed information about mechanisms of ion selectivity that is missing from mechanisms derived from either crystal structures or equilibrium unperturbed free-energy landscapes. PMID:26727271

A cost analysis of family planning in Bangladesh.

PubMed

Fiedler, J L; Day, L M

1997-01-01

This article presents a step-down cost analysis using secondary data sources from 26 Bangladesh non-government organizations (NGOs) providing family planning services under a US Agency for International Development-funded umbrella organization. The unit costs of the NGOs' Maternal-Child Health (MCH) clinics and community-based distribution (CBD) systems were calculated and found to be minimally different. Several simulations were conducted to investigate the impact of alternative cost-reduction measures. The more general financial analysis proved more insightful than the unit cost analysis in terms of identifying means by which to improve the efficiency of the family planning operations of these NGOs. The analysis revealed that 56 per cent of total expenditures in the two-tiered umbrella's organizational structure are incurred in management operations and overheads. Of the remaining 44 per cent of project expenditures, 39 per cent is spent on the CBD program and 5 per cent on the MCH clinics. Within the CBD program, most resources are spent providing 4 million contacts (two-thirds of the annual total) which do not involve contraceptive re-supply. The clinics devote more resources to providing MCH services than to providing family planning services. The findings suggest that significant savings could be generated by containing administrative costs, improving operational efficiency, and reducing unnecessary or redundant fieldworker contacts. The magnitude of the potential savings raises a fundamental question about the continued viability and sustainability of this supply-driven CBD strategy.

Transitioning NWChem to the Next Generation of Manycore Machines

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

Bylaska, Eric J.; Apra, Edoardo; Kowalski, Karol

The NorthWest Chemistry (NWChem) modeling software is a popular molecular chemistry simulation software that was designed from the start to work on massively parallel processing supercomputers[6, 28, 49]. It contains an umbrella of modules that today includes Self Consistent Field (SCF), second order Mller-Plesset perturbation theory (MP2), Coupled Cluster, multi-conguration selfconsistent eld (MCSCF), selected conguration interaction (CI), tensor contraction engine (TCE) many body methods, density functional theory (DFT), time-dependent density functional theory (TDDFT), real time time-dependent density functional theory, pseudopotential plane-wave density functional theory (PSPW), band structure (BAND), ab initio molecular dynamics, Car-Parrinello molecular dynamics, classical molecular dynamics (MD), QM/MM,more » AIMD/MM, GIAO NMR, COSMO, COSMO-SMD, and RISM solvation models, free energy simulations, reaction path optimization, parallel in time, among other capabilities[ 22]. Moreover new capabilities continue to be added with each new release.« less

Intra- and intermolecular interaction inducing pyramidalization on both sides of a proline dipeptide during isomerization: an ab initio QM/MM molecular dynamics simulation study in explicit water.

PubMed

Yonezawa, Yasushige; Nakata, Kazuto; Sakakura, Kota; Takada, Toshikazu; Nakamura, Haruki

2009-04-01

The cis-trans isomerization of the peptide bond preceding a proline plays important roles in protein folding and biological function. Although many experimental and theoretical studies have been done, the mechanism has not yet been clearly elucidated. We studied the cis-trans isomerization of the proline dipeptide (Ace-Pro-NMe) in explicit water by molecular dynamics simulations using a combined potential derived from ab initio quantum mechanics and empirical molecular mechanics. We obtained the free energy landscape during the isomerization by using the umbrella sampling method. The free energy landscape is in good accordance with previous experimental and theoretical values. We observed that in the middle of the isomerization, the prolyl nitrogen transiently takes pyramidal conformations in two polarized directions and that, simultaneously, the prolyl C-N bond extends. We show that these geometrical changes cooperatively transform the prolyl nitrogen from a sp(2)-hybridized electronic state into a sp(3)-hybridized one, and thus realize a transition state that reduces the rotational barriers separating the cis- and trans-states. We also found that the hydration of the prolyl nitrogen stabilizes the negative pyramidal conformation, while an intramolecular interaction mainly stabilizes the positive one. Fluctuations in the polarity and magnitude of the pyramidal conformation during the isomerization are interpreted as a competition between the hydrogen-bonding partners for the prolyl nitrogen between different sides of the pyrrolidine ring.

Development of a tuned interfacial force field parameter set for the simulation of protein adsorption to silica glass.

PubMed

Snyder, James A; Abramyan, Tigran; Yancey, Jeremy A; Thyparambil, Aby A; Wei, Yang; Stuart, Steven J; Latour, Robert A

2012-12-01

Adsorption free energies for eight host-guest peptides (TGTG-X-GTGT, with X = N, D, G, K, F, T, W, and V) on two different silica surfaces [quartz (100) and silica glass] were calculated using umbrella sampling and replica exchange molecular dynamics and compared with experimental values determined by atomic force microscopy. Using the CHARMM force field, adsorption free energies were found to be overestimated (i.e., too strongly adsorbing) by about 5-9 kcal/mol compared to the experimental data for both types of silica surfaces. Peptide adsorption behavior for the silica glass surface was then adjusted using a modified version of the CHARMM program, which we call dual force-field CHARMM, which allows separate sets of nonbonded parameters (i.e., partial charge and Lennard-Jones parameters) to be used to represent intra-phase and inter-phase interactions within a given molecular system. Using this program, interfacial force field (IFF) parameters for the peptide-silica glass systems were corrected to obtain adsorption free energies within about 0.5 kcal/mol of their respective experimental values, while IFF tuning for the quartz (100) surface remains for future work. The tuned IFF parameter set for silica glass will subsequently be used for simulations of protein adsorption behavior on silica glass with greater confidence in the balance between relative adsorption affinities of amino acid residues and the aqueous solution for the silica glass surface.

Development of a Tuned Interfacial Force Field Parameter Set for the Simulation of Protein Adsorption to Silica Glass

PubMed Central

Snyder, James A.; Abramyan, Tigran; Yancey, Jeremy A.; Thyparambil, Aby A.; Wei, Yang; Stuart, Steven J.; Latour, Robert A.

2012-01-01

Adsorption free energies for eight host–guest peptides (TGTG-X-GTGT, with X = N, D, G, K, F, T, W, and V) on two different silica surfaces [quartz (100) and silica glass] were calculated using umbrella sampling and replica exchange molecular dynamics and compared with experimental values determined by atomic force microscopy. Using the CHARMM force field, adsorption free energies were found to be overestimated (i.e., too strongly adsorbing) by about 5–9 kcal/mol compared to the experimental data for both types of silica surfaces. Peptide adsorption behavior for the silica glass surface was then adjusted using a modified version of the CHARMM program, which we call dual force-field CHARMM, which allows separate sets of nonbonded parameters (i.e., partial charge and Lennard-Jones parameters) to be used to represent intra-phase and inter-phase interactions within a given molecular system. Using this program, interfacial force field (IFF) parameters for the peptide-silica glass systems were corrected to obtain adsorption free energies within about 0.5 kcal/mol of their respective experimental values, while IFF tuning for the quartz (100) surface remains for future work. The tuned IFF parameter set for silica glass will subsequently be used for simulations of protein adsorption behavior on silica glass with greater confidence in the balance between relative adsorption affinities of amino acid residues and the aqueous solution for the silica glass surface. PMID:22941539

Guest Controlled Nonmonotonic Deep Cavity Cavitand Assembly State Switching.

PubMed

Tang, Du; Barnett, J Wesley; Gibb, Bruce C; Ashbaugh, Henry S

2017-11-30

Octa-acid (OA) and tetra-endo-methyl octa-acid (TEMOA) are water-soluble, deep-cavity cavitands with nanometer-sized nonpolar pockets that readily bind complementary guests, such as n-alkanes. Experimentally, OA exhibits a progression of 1:1 to 2:2 to 2:1 host/guest complexes (X:Y where X is the number of hosts and Y is the number of guests) with increasing alkane chain length from methane to tetradecane. Differing from OA only by the addition of four methyl groups ringing the portal of the pocket, TEMOA exhibits a nonmonotonic progression of assembly states from 1:1 to 2:2 to 1:1 to 2:1 with increasing guest length. Here we present a systematic molecular simulation study to parse the molecular and thermodynamic determinants that distinguish the succession of assembly stoichiometries observed for these similar hosts. Potentials of mean force between hosts and guests, determined via umbrella sampling, are used to characterize association free energies. These free energies are subsequently used in a reaction network model to predict the equilibrium distributions of assemblies. Our models accurately reproduce the experimentally observed trends, showing that TEMOA's endo-methyl units constrict the opening of the binding pocket, limiting the conformations available to bound guests and disrupting the balance between monomeric complexes and dimeric capsules. The success of our simulations demonstrate their utility at interpreting the impact of even simple chemical modifications on supramolecular assembly and highlight their potential to aid bottom-up design.

Conformation-dependent DNA attraction

NASA Astrophysics Data System (ADS)

Li, Weifeng; Nordenskiöld, Lars; Zhou, Ruhong; Mu, Yuguang

2014-05-01

Understanding how DNA molecules interact with other biomolecules is related to how they utilize their functions and is therefore critical for understanding their structure-function relationships. For a long time, the existence of Z-form DNA (a left-handed double helical version of DNA, instead of the common right-handed B-form) has puzzled the scientists, and the definitive biological significance of Z-DNA has not yet been clarified. In this study, the effects of DNA conformation in DNA-DNA interactions are explored by molecular dynamics simulations. Using umbrella sampling, we find that for both B- and Z-form DNA, surrounding Mg2+ ions always exert themselves to screen the Coulomb repulsion between DNA phosphates, resulting in very weak attractive force. On the contrary, a tight and stable bound state is discovered for Z-DNA in the presence of Mg2+ or Na+, benefiting from their hydrophobic nature. Based on the contact surface and a dewetting process analysis, a two-stage binding process of Z-DNA is outlined: two Z-DNA first attract each other through charge screening and Mg2+ bridges to phosphate groups in the same way as that of B-DNA, after which hydrophobic contacts of the deoxyribose groups are formed via a dewetting effect, resulting in stable attraction between two Z-DNA molecules. The highlighted hydrophobic nature of Z-DNA interaction from the current study may help to understand the biological functions of Z-DNA in gene transcription.Understanding how DNA molecules interact with other biomolecules is related to how they utilize their functions and is therefore critical for understanding their structure-function relationships. For a long time, the existence of Z-form DNA (a left-handed double helical version of DNA, instead of the common right-handed B-form) has puzzled the scientists, and the definitive biological significance of Z-DNA has not yet been clarified. In this study, the effects of DNA conformation in DNA-DNA interactions are explored by molecular dynamics simulations. Using umbrella sampling, we find that for both B- and Z-form DNA, surrounding Mg2+ ions always exert themselves to screen the Coulomb repulsion between DNA phosphates, resulting in very weak attractive force. On the contrary, a tight and stable bound state is discovered for Z-DNA in the presence of Mg2+ or Na+, benefiting from their hydrophobic nature. Based on the contact surface and a dewetting process analysis, a two-stage binding process of Z-DNA is outlined: two Z-DNA first attract each other through charge screening and Mg2+ bridges to phosphate groups in the same way as that of B-DNA, after which hydrophobic contacts of the deoxyribose groups are formed via a dewetting effect, resulting in stable attraction between two Z-DNA molecules. The highlighted hydrophobic nature of Z-DNA interaction from the current study may help to understand the biological functions of Z-DNA in gene transcription. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr03235c

287(g): Cross-Delegating State and Local Law Enforcement Officers with Federal Immigration Authority - Homeland Security Remedy or Rue?

DTIC Science & Technology

2008-12-01

ICE Office of Investigations uses its legal authority to investigate issues such as immigration crime , human rights violations, and human smuggling...communities. Crimes committed by foreign nationals — many exploited by terrorists — pose ideological, legal and resource challenges to state and local...umbrella of the Special Agent In Charge (SAC) in Denver , Colorado . Utah ICE OI falls under the supervisory umbrella of the Assistant Special Agent In

Security Force Assistance Logistics: The Key to Self-Reliance?

DTIC Science & Technology

2011-05-19

internal defense – the umbrella term that SFA falls under – and directly linked to assisting the foreign security force (FSF) “with the procurement...ideology.6 To some extent or another logistics figures prominently under the umbrella of military advising, so there is understandably a certain degree...billion” under the Mutual Defense Assistance Program (MDAP), which “included more than 1,100 medium-gun M47 and M48 Patton tanks, 152 light-gun tanks

Coarse-Grain Simulations Reveal Movement of the Synaptobrevin C-Terminus in Response to Piconewton Forces

PubMed Central

Lindau, Manfred; Hall, Benjamin A.; Chetwynd, Alan; Beckstein, Oliver; Sansom, Mark S.P.

2012-01-01

Fusion of neurosecretory vesicles with the plasma membrane is mediated by SNARE proteins, which transfer a force to the membranes. However, the mechanism by which this force transfer induces fusion pore formation is still unknown. The neuronal vesicular SNARE protein synaptobrevin 2 (syb2) is anchored in the vesicle membrane by a single C-terminal transmembrane (TM) helix. In coarse-grain molecular-dynamics simulations, self-assembly of the membrane occurred with the syb2 TM domain inserted, as expected from experimental data. The free-energy profile for the position of the syb2 membrane anchor in the membrane was determined using umbrella sampling. To predict the free-energy landscapes for a reaction pathway pulling syb2 toward the extravesicular side of the membrane, which is the direction of the force transfer from the SNARE complex, harmonic potentials were applied to the peptide in its unbiased position, pulling it toward new biased equilibrium positions. Application of piconewton forces to the extravesicular end of the TM helix in the simulation detached the synaptobrevin C-terminus from the vesicle's inner-leaflet lipid headgroups and pulled it deeper into the membrane. This C-terminal movement was facilitated and hindered by specific mutations in parallel with experimentally observed facilitation and inhibition of fusion. Direct application of such forces to the intravesicular end of the TM domain resulted in tilting motion of the TM domain through the membrane with an activation energy of ∼70 kJ/mol. The results suggest a mechanism whereby fusion pore formation is induced by movement of the charged syb2 C-terminus within the membrane in response to pulling and tilting forces generated by C-terminal zippering of the SNARE complex. PMID:23009845

Dynamic Histogram Analysis To Determine Free Energies and Rates from Biased Simulations.

PubMed

Stelzl, Lukas S; Kells, Adam; Rosta, Edina; Hummer, Gerhard

2017-12-12

We present an algorithm to calculate free energies and rates from molecular simulations on biased potential energy surfaces. As input, it uses the accumulated times spent in each state or bin of a histogram and counts of transitions between them. Optimal unbiased equilibrium free energies for each of the states/bins are then obtained by maximizing the likelihood of a master equation (i.e., first-order kinetic rate model). The resulting free energies also determine the optimal rate coefficients for transitions between the states or bins on the biased potentials. Unbiased rates can be estimated, e.g., by imposing a linear free energy condition in the likelihood maximization. The resulting "dynamic histogram analysis method extended to detailed balance" (DHAMed) builds on the DHAM method. It is also closely related to the transition-based reweighting analysis method (TRAM) and the discrete TRAM (dTRAM). However, in the continuous-time formulation of DHAMed, the detailed balance constraints are more easily accounted for, resulting in compact expressions amenable to efficient numerical treatment. DHAMed produces accurate free energies in cases where the common weighted-histogram analysis method (WHAM) for umbrella sampling fails because of slow dynamics within the windows. Even in the limit of completely uncorrelated data, where WHAM is optimal in the maximum-likelihood sense, DHAMed results are nearly indistinguishable. We illustrate DHAMed with applications to ion channel conduction, RNA duplex formation, α-helix folding, and rate calculations from accelerated molecular dynamics. DHAMed can also be used to construct Markov state models from biased or replica-exchange molecular dynamics simulations. By using binless WHAM formulated as a numerical minimization problem, the bias factors for the individual states can be determined efficiently in a preprocessing step and, if needed, optimized globally afterward.

Coarse-grain simulations reveal movement of the synaptobrevin C-terminus in response to piconewton forces.

PubMed

Lindau, Manfred; Hall, Benjamin A; Chetwynd, Alan; Beckstein, Oliver; Sansom, Mark S P

2012-09-05

Fusion of neurosecretory vesicles with the plasma membrane is mediated by SNARE proteins, which transfer a force to the membranes. However, the mechanism by which this force transfer induces fusion pore formation is still unknown. The neuronal vesicular SNARE protein synaptobrevin 2 (syb2) is anchored in the vesicle membrane by a single C-terminal transmembrane (TM) helix. In coarse-grain molecular-dynamics simulations, self-assembly of the membrane occurred with the syb2 TM domain inserted, as expected from experimental data. The free-energy profile for the position of the syb2 membrane anchor in the membrane was determined using umbrella sampling. To predict the free-energy landscapes for a reaction pathway pulling syb2 toward the extravesicular side of the membrane, which is the direction of the force transfer from the SNARE complex, harmonic potentials were applied to the peptide in its unbiased position, pulling it toward new biased equilibrium positions. Application of piconewton forces to the extravesicular end of the TM helix in the simulation detached the synaptobrevin C-terminus from the vesicle's inner-leaflet lipid headgroups and pulled it deeper into the membrane. This C-terminal movement was facilitated and hindered by specific mutations in parallel with experimentally observed facilitation and inhibition of fusion. Direct application of such forces to the intravesicular end of the TM domain resulted in tilting motion of the TM domain through the membrane with an activation energy of ∼70 kJ/mol. The results suggest a mechanism whereby fusion pore formation is induced by movement of the charged syb2 C-terminus within the membrane in response to pulling and tilting forces generated by C-terminal zippering of the SNARE complex. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Orthogonal sampling in free-energy calculations of residue mutations in a tripeptide: TI versus λ-LEUS.

PubMed

Bieler, Noah S; Hünenberger, Philippe H

2015-08-15

In a recent article (Bieler et al., J. Chem. Theory Comput. 2014, 10, 3006), we introduced a combination of λ-dynamics and local-elevation umbrella-sampling termed λ-LEUS to calculate free-energy changes associated with alchemical processes using molecular dynamics simulations. This method was suggested to be more efficient than thermodynamic integration (TI), because the dynamical variation of the alchemical variable λ opens up pathways to circumvent barriers in the orthogonal space (defined by the N - 1 degrees of freedom that are not subjected to the sampling enhancement), a feature λ-LEUS shares with Hamiltonian replica-exchange (HR) approaches. However, the mutation considered, hydroquinone to benzene in water, was no real challenge in terms of orthogonal-space properties, which were restricted to solvent-relaxation processes. In the present article, we revisit the comparison between TI and λ-LEUS considering non-trivial mutations of the central residue X of a KXK tripeptide in water (with X = G, E, K, S, F, or Y). Side-chain interactions that may include salt bridges, hydrogen bonds or steric clashes lead to slow relaxation in the orthogonal space, mainly in the two-dimensional subspace spanned by the central φ and ψ dihedral angles of the peptide. The efficiency enhancement afforded by λ-LEUS is confirmed in this more complex test system and can be attributed explicitly to the improved sampling of the orthogonal space. The sensitivity of the results to the nontrivial choices of a mass parameter and of a thermostat coupling time for the alchemical variable is also investigated, resulting in recommended ranges of 50 to 100 u nm(2) and 0.2 to 0.5 ps, respectively. © 2015 Wiley Periodicals, Inc.

Threat to democracy: Physical and mental health impact of democracy movement in Hong Kong.

PubMed

Hou, Wai Kai; Hall, Brian J; Canetti, Daphna; Lau, Kam Man; Ng, Sin Man; Hobfoll, Stevan E

2015-11-01

This study examined the prevalence and critical predictors of anxiety and depressive symptoms and self-rated health, following the Umbrella Movement in Hong Kong. Random digit dialing recruited a population-representative sample of 1208 Chinese Hong Kong citizens (mean age=46.89 years; 63% female) in the first two weeks of February 2015. Respondents gave their informed consent and reported personal, social, and economic resource loss since the Umbrella Movement (Conservation of Resources-Evaluation), current anxiety symptoms (State-Trait Anxiety Inventory) and depressive symptoms (Patient Health Questionnaire-9), and self-rated health (1=very good, 4=very bad). A total of 47.35% (95% CI=44.55, 50.17) respondents reported moderate/severe anxiety symptoms and 14.4% (95% CI=12.54, 16.50) reported moderate/severe depressive symptoms; 9.11% (95% CI=7.61, 10.86) reported "poor" or "very poor" health. Multivariable regressions revealed that personal and social resource loss was associated with higher anxiety and depressive symptoms and greater odds of "very poor" health (adjusted odds ratios/incidence rate ratios=5-102%), independent of lower education level and income and being unmarried. This study was cross-sectional in nature and thus could not determine causality from the associations between resource loss and outcome variables. Second, the telephone survey relied on self-reports; response bias and social desirability could influence respondents' answers and discount data validity. Third, potential confounders such as preexisting mental and physical health issues and concurrent predictors like exposure to the Umbrella Movement were not assessed. This is one of the first studies following any recent political movement (e.g., The Arab Spring) to quantify distress and the associated correlates of distress among affected citizens. Perceived psychosocial resource losses were critical predictors of poor outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.

An intertebrate ecosystem engineer likely covered under the umbrella of sage-grouse conservation

USGS Publications Warehouse

Carlisle, Jason D.; Stewart, David R.; Chalfoun, Anna D.

2017-01-01

Conservation practitioners often rely on areas designed to protect species of greatest conservation priority to also conserve co-occurring species (i.e., the umbrella species concept). The extent to which vertebrate species may serve as suitable umbrellas for invertebrate species, however, has rarely been explored. Sage-grouse (Centrocercus spp.) have high conservation priority throughout much of the rangelands of western North America and are considered an umbrella species through which the conservation of entire rangeland ecosystems can be accomplished. Harvester ants are ecosystem engineers and play important roles in the maintenance and function of rangeland ecosystems. We compared indices of the abundance of western harvester ants (Pogonomyrmex occidentalis) and Greater Sage-Grouse (Centrocercus urophasianus) at 72 sites in central Wyoming, USA, in 2012. The abundance of harvester ant mounds was best predicted by a regression model that included a combination of local habitat characteristics and the abundance of sage-grouse. When controlling for habitat-related factors, areas with higher abundances of sage-grouse pellets (an index of sage-grouse abundance and/or habitat use) had higher abundances of ant mounds than areas with lower abundances of sage-grouse pellets. The causal mechanism underlying this positive relationship between sage-grouse and ant mound abundance at the fine scale could be indirect (e.g., both species prefer similar environmental conditions) or direct (e.g., sage-grouse prefer areas with a high abundance of ant mounds because ants are an important prey item during certain life stages). We observed no relationship between a broad-scale index of breeding sage-grouse density and the abundance of ant mounds. We suspect that consideration of the nonbreeding habitat of sage-grouse and finer-scale measures of sagegrouse abundance are critical to the utility of sage-grouse as an umbrella species for the conservation of harvester ants and their important role in rangeland ecosystems.

Nature and Intensity of the 22-23 April 2015 Eruptions of Volcán Calbuco, Chile, from Satellite, Lightning, and Field Observations

NASA Astrophysics Data System (ADS)

Van Eaton, A. R.; Amigo, A.; Bertin, D.; Mastin, L. G.; Giacosa, R.; Behnke, S. A.

2015-12-01

On 22 April 2015, Calbuco Volcano in southern Chile erupted for the first time in 43 years. The two primary phases of eruption, separated by a few hours, produced pyroclastic density currents, lahars, and spectacular vertical eruption columns that rose into the stratosphere. Clear weather conditions allowed the populated areas of Puerto Montt and Puerto Varas full view of the lightning-rich eruption, which was rapidly shared through social media. A wealth of remote-sensing data was also publically available in near real-time. We used this information to assess the eruption behavior by combining satellite-based umbrella growth rates, and the location and frequency of volcanic lightning. Umbrella expansion rates from GOES-13 satellite retrievals correspond to eruption rates of about 4x106 kg s-1 for the first eruptive phase and 6x106 kg s-1 for the second phase, following the approach of Pouget et al. (2013, JVGR, 258, 100-112). The location and timing of lightning flashes were obtained from the World Wide Lightning Location Network (WWLLN) Global Volcanic Lightning Monitor, which is updated approximately every minute (Ewert et al., 2010, Fall AGU Abstract AE31A-04). Interestingly, the onset of detected flashes was delayed by ~30 min after the start of each eruptive phase. Lighting provided a useful proxy for the waxing or waning intensity of the eruption, and helped identify the end of significant ash emissions. Using the 1-D volcanic plume model Plumeria, we have also simulated the vertical distribution of ash and ice in the plumes to examine potential causes of the extraordinary amount of volcanic lightning (1,094 flashes detected). Our analysis provides information on eruption timing, duration, and mass flow rate, which are necessary for ash dispersal modeling within hours of eruption. Results are also consistent with the field-based measurements of total erupted volume. We suggest that the combination of satellite-detected umbrella expansion rates with lightning data may provide a useful approach to constrain near real-time inputs for ash dispersal models and hazard warnings.

Intense pumping and time- and frequency-resolved CARS for driving and tracking structural deformation and recovery of liquid nitromethane molecules

NASA Astrophysics Data System (ADS)

Wang, Chang; Wu, Hong-lin; Song, Yun-fei; He, Xing; Yang, Yan-qiang; Tan, Duo-wang

2015-11-01

A modified CARS technique with an intense nonresonant femtosecond laser is presented to drive the structural deformation of liquid nitromethane molecules and track their structural relaxation process. The CARS spectra reveal that the internal rotation of the molecule can couple with the CN symmetric stretching vibration and the molecules undergo ultrafast structural deformation of the CH3 groups from 'opened umbrella' to 'closed umbrella' shape, and then experience a structural recovery process within 720 fs.

An umbrella review of meta-analyses of interventions to improve maternal outcomes for teen mothers.

PubMed

SmithBattle, Lee; Loman, Deborah G; Chantamit-O-Pas, Chutima; Schneider, Joanne Kraenzle

2017-08-01

The purpose of this study was to perform an umbrella review of meta-analyses of intervention studies designed to improve outcomes of pregnant or parenting teenagers. An extensive search retrieved nine reports which provided 21 meta-analyses analyses. Data were extracted by two reviewers. Methodological quality was assessed using the AMSTAR Instrument. Most effect sizes were small but high quality studies showed significant outcomes for reduced low birth weight (RR = 0.60), repeat pregnancies/births (OR = 0.47-0.62), maternal education (OR = 1.21-1.83), and maternal employment (OR = 1.26). Several parenting outcomes (parent-child teaching interaction post-intervention [SMD = -0.91] and at follow-up [SMD = -1.07], and parent-child relationship post-intervention [SMD = -0.71] and at follow-up [SMD = -0.90]) were significant, but sample sizes were very small. Many reports did not include moderator analyses. Behavioral interventions offer limited resources and occur too late to mitigate the educational and social disparities that precede teen pregnancy. Future intervention research and policies that redress the social determinants of early childbearing are recommended. Copyright © 2017 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Evaluating Force Fields for the Computational Prediction of Ionized Arginine and Lysine Side-Chains Partitioning into Lipid Bilayers and Octanol.

PubMed

Sun, Delin; Forsman, Jan; Woodward, Clifford E

2015-04-14

Abundant peptides and proteins containing arginine (Arg) and lysine (Lys) amino acids can apparently permeate cell membranes with ease. However, the mechanisms by which these peptides and proteins succeed in traversing the free energy barrier imposed by cell membranes remain largely unestablished. Precise thermodynamic studies (both theoretical and experimental) on the interactions of Arg and Lys residues with model lipid bilayers can provide valuable clues to the efficacy of these cationic peptides and proteins. We have carried out molecular dynamics simulations to calculate the interactions of ionized Arg and Lys side-chains with the zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer for 10 widely used lipid/protein force fields: CHARMM36/CHARMM36, SLIPID/AMBER99SB-ILDN, OPLS-AA/OPLS-AA, Berger/OPLS-AA, Berger/GROMOS87, Berger/GROMOS53A6, GROMOS53A6/GROMOS53A6, nonpolarizable MARTINI, polarizable MARTINI, and BMW MARTINI. We performed umbrella sampling simulations to obtain the potential of mean force for Arg and Lys side-chains partitioning from water to the bilayer interior. We found significant differences between the force fields, both for the interactions between side-chains and bilayer surface, as well as the free energy cost for placing the side-chain at the center of the bilayer. These simulation results were compared with the Wimley-White interfacial scale. We also calculated the free energy cost for transferring ionized Arg and Lys side-chains from water to both dry and wet octanol. Our simulations reveal rapid diffusion of water molecules into octanol whereby the equilibrium mole fraction of water in the wet octanol phase was ∼25%. Surprisingly, our free energy calculations found that the high water content in wet octanol lowered the water-to-octanol partitioning free energies for cationic residues by only 0.6 to 0.7 kcal/mol.

Theoretical studies on FGFR isoform selectivity of FGFR1/FGFR4 inhibitors by molecular dynamics simulations and free energy calculations.

PubMed

Fu, Weitao; Chen, Lingfeng; Wang, Zhe; Kang, Yanting; Wu, Chao; Xia, Qinqin; Liu, Zhiguo; Zhou, Jianmin; Liang, Guang; Cai, Yuepiao

2017-02-01

The activation and overexpression of fibroblast growth factor receptors (FGFRs) are highly correlated with a variety of cancers. Most small molecule inhibitors of FGFRs selectively target FGFR1-3, but not FGFR4. Hence, designing highly selective inhibitors towards FGFR4 remains a great challenge because FGFR4 and FGFR1 have a high sequence identity. Recently, two small molecule inhibitors of FGFRs, ponatinib and AZD4547, have attracted huge attention. Ponatinib, a type II inhibitor, has high affinity towards FGFR1/4 isoforms, but AZD4547, a type I inhibitor of FGFR1, displays much reduced inhibition toward FGFR4. In this study, conventional molecular dynamics (MD) simulations, molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculations and umbrella sampling (US) simulations were carried out to reveal the principle of the binding preference of ponatinib and AZD4547 towards FGFR4/FGFR1. The results provided by MM/GBSA illustrate that ponatinib has similar binding affinities to FGFR4 and FGFR1, while AZD4547 has much stronger binding affinity to FGFR1 than to FGFR4. A comparison of the individual energy terms suggests that the selectivity of AZD4547 towards FGFR1 versus FGFR4 is primarily controlled by the variation of the van der Waals interactions. The US simulations reveal that the PMF profile of FGFR1/AZD4547 has more peaks and valleys compared with that of FGFR4/AZD4547, suggesting that the dissociation process of AZD4547 from FGFR1 are easily trapped into local minima. Moreover, it is observed that FGFR1/AZD4547 has much higher PMF depth than FGFR4/AZD4547, implying that it is more difficult for AZD4547 to escape from FGFR1 than from FGFR4. The physical principles provided by this study extend our understanding of the binding mechanisms and provide valuable guidance for the rational design of FGFR isoform selective inhibitors.

Psychometric properties of the Brand Personality Scale: evidence from a business school.

PubMed

Caruana, Albert; Pitt, Leyland F; Berthon, Pierre; Berthon, J-P

2007-06-01

The Brand Personality Scale has received considerable attention and has been frequently used and cited in the branding literature. This paper describes an investigation of the psychometric characteristics of the Brand Personality Scale in a business school context where umbrella branding is used. A sample (N=262) of students attending the MBA program of a major business school in eastern USA completed the scale. Results indicate problems with the scale's dimensionality, poor reliability, convergent and nomological validity of the Ruggedness dimension, and lack of support for discriminant validity. Managerial and research implications and limitations are noted.

Product release mechanism and the complete enzyme catalysis cycle in yeast cytosine deaminase (yCD): A computational study.

PubMed

Zhao, Yuan; She, Nai; Zhang, Xin; Wang, Chaojie; Mo, Yirong

2017-08-01

Yeast cytosine deaminase (yCD) is critical in gene-directed enzyme prodrug therapy as it catalyzes the hydrolytic deamination of cytosine. The product (uracil) release process is considered as rate-limiting in the whole enzymatic catalysis and includes the cleavage of the uracil-metal bond and the delivery of free uracil out of the reactive site. Herein extensive combined random acceleration molecular dynamics (RAMD) and molecular dynamics (MD) simulations coupled with the umbrella sampling technique have been performed to study the product transport mechanism. Five channels have been identified, and the thermodynamic and dynamic characterizations for the two most favorable channels have been determined and analyzed. The free energy barrier for the most beneficial pathway is about 13kcal/mol and mainly results from the cleavage of hydrogen bonds between the ligand uracil and surrounding residues Asn51, Glu64, and Asp155. The conjugated rings of Phe114 and Trp152 play gating and guiding roles in the product delivery via π⋯π van der Waals interactions with the product. Finally, the full cycle of the enzymatic catalysis has been determined, making the whole process computationally more precise. Copyright © 2017 Elsevier B.V. All rights reserved.

Roles of urea and TMAO on the interaction between extended non-polar peptides

NASA Astrophysics Data System (ADS)

Su, Zhaoqian; Dias, Cristiano

Urea and trimethylamine n-oxide (TMAO) are small molecules known to destabilize and stabilize, respectively, the structure of proteins when added to aqueous solution. To unravel the molecular mechanisms of these cosolvents on protein structure we perform explicit all-atom molecular dynamics simulations of extended poly-alanine and polyleucine dimers. We use an umbrella sampling protocol to compute the potential of mean force (PMF) of dimers at different concentrations of urea and TMAO. We find that the large non-polar side chain of leucine is affected by urea whereas backbone atoms and alanine's side chain are not. Urea is found to occupy positions between leucine's side chains that are not accessible to water. This accounts for extra Lennard-Jones bonds between urea and side chains that favors the unfolded state. These bonds compete with urea-solvent interactions that favor the folded state. The sum of these two energetic terms provide the enthalpic driving force for unfolding. We show here that this enthalpy correlate with the potential of mean force of poly-leucine dimers. Moreover, the framework developed here is general and may be used to provide insights into effects of other small molecules on protein interactions. The effect of the TMAO will be in the presentation. Department of Physics, University Heights, Newark, New Jersey, 07102-1982.

Mapping intermolecular interactions and active site conformations: from human MMP-1 crystal structure to molecular dynamics free energy calculations.

PubMed

Nash, Anthony; Birch, Helen L; de Leeuw, Nora H

2017-02-01

The zinc-dependent Matrix Metalloproteinases (MMPs) found within the extracellular matrix (ECM) of vertebrates are linked to pathological processes such as arthritis, skin ulceration and cancer. Although a general backbone proteolytic mechanism is understood, crystallographic data continue to suggest an active site that is too narrow to encompass the respective substrate. We present a fully parameterised Molecular Dynamics (MD) study of the structural properties of an MMP-1-collagen crystallographic structure (Protein Data Bank - 4AUO), followed by an exploration of the free energy surface of a collagen polypeptide chain entering the active site, using a combined meta-dynamics and umbrella sampling (MDUS) approach. We conclude that the interactions between MMP-1 and the collagen substrate are in good agreement with a number of experimental studies. As such, our unrestrained MD simulations and our MDUS results, which indicate an energetic barrier for a local uncoiling and insertion event, can inform future investigations of the collagen-peptide non-bonded association steps with the active site prior to proteolytic mechanisms. The elucidation of such free energy barriers provides a better understanding of the role of the enzyme in the ECM and is important in the design of future MMP inhibitors.

Unraveling the differences of the hydrolytic activity of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase: a quantum mechanics-molecular mechanics modeling study.

PubMed

Bueren-Calabuig, Juan A; Pierdominici-Sottile, Gustavo; Roitberg, Adrian E

2014-06-05

Chagas' disease, also known as American trypanosomiasis, is a lethal, chronic disease that currently affects more than 10 million people in Central and South America. The trans-sialidase from Trypanosoma cruzi (T. cruzi, TcTS) is a crucial enzyme for the survival of this parasite: sialic acids from the host are transferred to the cell surface glycoproteins of the trypanosome, thereby evading the host's immune system. On the other hand, the sialidase of T. rangeli (TrSA), which shares 70% sequence identity with TcTS, is a strict hydrolase and shows no trans-sialidase activity. Therefore, TcTS and TrSA represent an excellent framework to understand how different catalytic activities can be achieved with extremely similar structures. By means of combined quantum mechanics-molecular mechanics (QM/MM, SCC-DFTB/Amberff99SB) calculations and umbrella sampling simulations, we investigated the hydrolysis mechanisms of TcTS and TrSA and computed the free energy profiles of these reactions. The results, together with our previous computational investigations, are able to explain the catalytic mechanism of sialidases and describe how subtle differences in the active site make TrSA a strict hydrolase and TcTS a more efficient trans-sialidase.

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

PubMed

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

2017-01-12

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

Energetics of subdomain movements and fluorescence probe solvation environment change in ATP-bound myosin.

PubMed

Harris, Michael J; Woo, Hyung-June

2008-11-01

Energetics of conformational changes experienced by an ATP-bound myosin head detached from actin was studied by all-atom explicit water umbrella sampling simulations. The statistics of coupling between large scale domain movements and smaller scale structural features were examined, including the closing of the ATP binding pocket, and a number of key hydrogen bond formations shown to play roles in structural and biochemical studies. The statistics for the ATP binding pocket open/close transition show an evolution of the relative stability from the open state in the early stages of the recovery stroke to the stable closed state after the stroke. The change in solvation environment of the fluorescence probe Trp507 (scallop numbering; 501 in Dictyostelium discoideum) indicates that the probe faithfully reflects the closing of the binding pocket as previously shown in experimental studies, while being directly coupled to roughly the early half of the overall large scale conformational change of the converter domain rotation. The free energy change of this solvation environment change, in particular, is -1.3 kcal/mol, in close agreement with experimental estimates. In addition, our results provide direct molecular level data allowing for interpretations of the fluorescence experiments of myosin conformational change in terms of the de-solvation of Trp side chain.

Effect of inter-species selective interactions on the thermodynamics and nucleation free-energy barriers of a tessellating polyhedral compound

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

Escobedo, Fernando A., E-mail: fe13@cornell.edu

The phase behavior and the homogeneous nucleation of an equimolar mixture of octahedra and cuboctahedra are studied using thermodynamic integration, Gibbs-Duhem integration, and umbrella sampling simulations. The components of this mixture are modeled as polybead objects of equal edge lengths so that they can assemble into a space-filling compound with the CsCl crystal structure. Taking as reference the hard-core system where the compound crystal does not spontaneously nucleate, we quantified the effect of inter-species selective interactions on facilitating the disorder-to-order transition. Facet selective and facet non-selective inter-species attractions were considered, and while the former was expectedly more favorable toward themore » target tessellating structure, the latter was found to be similarly effective in nucleating the crystal compound. Ranges for the strength of attractions and degree of supersaturation were identified where the nucleation free-energy barrier was small enough to foretell a fast process but large enough to prevent spinodal fluctuations that can trap the system in dense metastable states lacking long-range order. At those favorable conditions, the tendency toward the local orientational order favored by packing entropy is amplified and found to play a key role seeding nuclei with the CsCl structure.« less

Exploring the free energy landscape of a model β-hairpin peptide and its isoform.

PubMed

Narayanan, Chitra; Dias, Cristiano L

2014-10-01

Secondary structural transitions from α-helix to β-sheet conformations are observed in several misfolding diseases including Alzheimer's and Parkinson's. Determining factors contributing favorably to the formation of each of these secondary structures is therefore essential to better understand these disease states. β-hairpin peptides form basic components of anti-parallel β-sheets and are suitable model systems for characterizing the fundamental forces stabilizing β-sheets in fibrillar structures. In this study, we explore the free energy landscape of the model β-hairpin peptide GB1 and its E2 isoform that preferentially adopts α-helical conformations at ambient conditions. Umbrella sampling simulations using all-atom models and explicit solvent are performed over a large range of end-to-end distances. Our results show the strong preference of GB1 and the E2 isoform for β-hairpin and α-helical conformations, respectively, consistent with previous studies. We show that the unfolded states of GB1 are largely populated by misfolded β-hairpin structures which differ from each other in the position of the β-turn. We discuss the energetic factors contributing favorably to the formation of α-helix and β-hairpin conformations in these peptides and highlight the energetic role of hydrogen bonds and non-bonded interactions. © 2014 Wiley Periodicals, Inc.

Communication: Potentials of mean force study of ionic liquid ion pair aggregation in polar covalent molecule solvents

NASA Astrophysics Data System (ADS)

Bandlamudi, Santosh Rathan Paul; Benjamin, Kenneth M.

2018-05-01

Molecular dynamics (MD) simulations were conducted for 1-ethyl-3-methylimidazolium methylsulfate [EMIM][MeSO4] dissolved in six polar covalent molecules [acetic acid, acetone, chloroform, dimethyl sulfoxide (DMSO), isopropyl alcohol, and methanol] to understand the free energies of ionic liquid (IL) ion pairing/aggregation in the limit of infinite dilution. Free energy landscapes or potentials of mean force (PMF) were computed using umbrella sampling and the weighted histogram analysis method. The PMF studies showed the strongest IL ion pairing in chloroform, and the strength of IL ion pairing decreases in the order of chloroform, acetone, propanol, acetic acid, DMSO, and methanol. In the limit of infinite dilution, the free energy curves for IL ion aggregation in co-solvents were characterized by two distinct minima [global (˜3.6 Å) and local (˜5.7 Å)], while free energy values at these minima differed significantly for IL in each co-solvent. The PMF studies were extended for determining the free energy of IL ion aggregation as a function of concentration of methanol. Studies showed that as the concentration of methanol increased, the free energy of ion aggregation decreased, suggesting greater ion pair stability, in agreement with previously reported MD clustering and radial distribution function data.

Interaction of gabaergic ketones with model membranes: A molecular dynamics and experimental approach.

PubMed

Miguel, Virginia; Sánchez-Borzone, Mariela E; García, Daniel A

2018-08-01

γ-Aminobutyric-acid receptor (GABA A -R), a membrane intrinsic protein, is activated by GABA and modulated by a wide variety of recognized drugs. GABA A -R is also target for several insecticides which act by recognition of a non-competitive blocking site. Mentha oil is rich in several ketones with established activity against various insects/pests. Considering that mint ketones are highly lipophilic, their action mechanism could involve, at least in part, a non-specific receptor modulation by interacting with the surrounding lipids. In the present work, we studied in detail the effect on membranes of five cyclic ketones present in mint plants, with demonstrated insecticide and gabaergic activity. Particularly, we have explored their effect on the organization and dynamics of the membrane, by using Molecular Dynamics (MD) Simulation studies in a bilayer model of DPPC. We performed free diffusion MD and obtained spatially resolved free energy profiles of ketones partition into bilayers based on umbrella sampling. The most favored location of ketones in the membrane corresponded to the lower region of the carbonyl groups. Both hydrocarbon chains were slightly affected by the presence of ketones, presenting an ordering effect for the methylene groups closer to the carbonyl. MD simulations results were also contrasted with experimental data from fluorescence anisotropy studies which evaluate changes in membrane fluidity. In agreement, these assays indicated that the presence of ketones between lipid molecules induced an enhancement of the intermolecular interaction, increasing the molecular order throughout the bilayer thickness. Copyright © 2018 Elsevier B.V. All rights reserved.

Atomistic Detailed Mechanism and Weak Cation-Conducting Activity of HIV-1 Vpu Revealed by Free Energy Calculations

PubMed Central

Padhi, Siladitya; Burri, Raghunadha Reddy; Jameel, Shahid; Priyakumar, U. Deva

2014-01-01

The viral protein U (Vpu) encoded by HIV-1 has been shown to assist in the detachment of virion particles from infected cells. Vpu forms cation-specific ion channels in host cells, and has been proposed as a potential drug target. An understanding of the mechanism of ion transport through Vpu is desirable, but remains limited because of the unavailability of an experimental structure of the channel. Using a structure of the pentameric form of Vpu – modeled and validated based on available experimental data – umbrella sampling molecular dynamics simulations (cumulative simulation time of more than 0.4 µs) were employed to elucidate the energetics and the molecular mechanism of ion transport in Vpu. Free energy profiles corresponding to the permeation of Na+ and K+ were found to be similar to each other indicating lack of ion selection, consistent with previous experimental studies. The Ser23 residue is shown to enhance ion transport via two mechanisms: creating a weak binding site, and increasing the effective hydrophilic length of the channel, both of which have previously been hypothesized in experiments. A two-dimensional free energy landscape has been computed to model multiple ion permeation, based on which a mechanism for ion conduction is proposed. It is shown that only one ion can pass through the channel at a time. This, along with a stretch of hydrophobic residues in the transmembrane domain of Vpu, explains the slow kinetics of ion conduction. The results are consistent with previous conductance studies that showed Vpu to be a weakly conducting ion channel. PMID:25392993

Pliocene Model Intercomparison (PlioMIP) Phase 2: Scientific Objectives and Experimental Design

NASA Technical Reports Server (NTRS)

Haywood, A. M.; Dowsett, H. J.; Dolan, A. M.; Rowley, D.; Abe-Ouchi, A.; Otto-Bliesner, B.; Chandler, M. A.; Hunter, S. J.; Lunt, D. J.; Pound, M.;

Sparsity-weighted outlier FLOODing (OFLOOD) method: Efficient rare event sampling method using sparsity of distribution.

PubMed

Harada, Ryuhei; Nakamura, Tomotake; Shigeta, Yasuteru

2016-03-30

As an extension of the Outlier FLOODing (OFLOOD) method [Harada et al., J. Comput. Chem. 2015, 36, 763], the sparsity of the outliers defined by a hierarchical clustering algorithm, FlexDice, was considered to achieve an efficient conformational search as sparsity-weighted "OFLOOD." In OFLOOD, FlexDice detects areas of sparse distribution as outliers. The outliers are regarded as candidates that have high potential to promote conformational transitions and are employed as initial structures for conformational resampling by restarting molecular dynamics simulations. When detecting outliers, FlexDice defines a rank in the hierarchy for each outlier, which relates to sparsity in the distribution. In this study, we define a lower rank (first ranked), a medium rank (second ranked), and the highest rank (third ranked) outliers, respectively. For instance, the first-ranked outliers are located in a given conformational space away from the clusters (highly sparse distribution), whereas those with the third-ranked outliers are nearby the clusters (a moderately sparse distribution). To achieve the conformational search efficiently, resampling from the outliers with a given rank is performed. As demonstrations, this method was applied to several model systems: Alanine dipeptide, Met-enkephalin, Trp-cage, T4 lysozyme, and glutamine binding protein. In each demonstration, the present method successfully reproduced transitions among metastable states. In particular, the first-ranked OFLOOD highly accelerated the exploration of conformational space by expanding the edges. In contrast, the third-ranked OFLOOD reproduced local transitions among neighboring metastable states intensively. For quantitatively evaluations of sampled snapshots, free energy calculations were performed with a combination of umbrella samplings, providing rigorous landscapes of the biomolecules. © 2015 Wiley Periodicals, Inc.

Comparison of clinical outcomes of multi-point umbrella suturing and single purse suturing with two-point traction after procedure for prolapse and hemorrhoids (PPH) surgery.

PubMed

Jiang, Huiyong; Hao, Xiuyan; Xin, Ying; Pan, Youzhen

2017-11-01

To compare the clinical outcomes of multipoint umbrella suture and single-purse suture with two-point traction after procedure for prolapse and hemorrhoids surgery (PPH) for the treatment of mixed hemorrhoids. Ninety patients were randomly divided into a PPH plus single-purse suture group (Group A) and a PPH plus multipoint umbrella suture (Group B). All operations were performed by an experienced surgeon. Operation time, width of the specimen, hemorrhoids retraction extent, postoperative pain, postoperative bleeding, and length of hospitalization were recorded and compared. Statistical analysis was conducted by t-test and χ2 test. There were no significant differences in sex, age, course of disease, and degree of prolapse of hemorrhoids between the two groups. The operative time in Group A was significantly shorter than that in Group B (P < 0.05). However, the incidence rates of submucosal hematoma and incomplete hemorrhoid core retraction were significantly lower in Group B (P < 0.05), whereas the width of the specimens in Group B was greater than that in Group A (P < 0.05). There were fewer redundant skin tags in Group B at three months follow-up. No significant difference in postoperative pain, postoperative bleeding, and time of hospital stay (P > 0.05 for all comparisons) was observed. The multipoint umbrella suture showed better clinical outcomes because of its targeted suture according to the extent of hemorrhoid prolapse. Copyright © 2017. Published by Elsevier Ltd.

Thermodynamic free energy methods to investigate shape transitions in bilayer membranes.

PubMed

Ramakrishnan, N; Tourdot, Richard W; Radhakrishnan, Ravi

2016-06-01

The conformational free energy landscape of a system is a fundamental thermodynamic quantity of importance particularly in the study of soft matter and biological systems, in which the entropic contributions play a dominant role. While computational methods to delineate the free energy landscape are routinely used to analyze the relative stability of conformational states, to determine phase boundaries, and to compute ligand-receptor binding energies its use in problems involving the cell membrane is limited. Here, we present an overview of four different free energy methods to study morphological transitions in bilayer membranes, induced either by the action of curvature remodeling proteins or due to the application of external forces. Using a triangulated surface as a model for the cell membrane and using the framework of dynamical triangulation Monte Carlo, we have focused on the methods of Widom insertion, thermodynamic integration, Bennett acceptance scheme, and umbrella sampling and weighted histogram analysis. We have demonstrated how these methods can be employed in a variety of problems involving the cell membrane. Specifically, we have shown that the chemical potential, computed using Widom insertion, and the relative free energies, computed using thermodynamic integration and Bennett acceptance method, are excellent measures to study the transition from curvature sensing to curvature inducing behavior of membrane associated proteins. The umbrella sampling and WHAM analysis has been used to study the thermodynamics of tether formation in cell membranes and the quantitative predictions of the computational model are in excellent agreement with experimental measurements. Furthermore, we also present a method based on WHAM and thermodynamic integration to handle problems related to end-point-catastrophe that are common in most free energy methods.

QM/MM free-energy simulations of reaction in Serratia marcescens Chitinase B reveal the protonation state of Asp142 and the critical role of Tyr214.

PubMed

Jitonnom, Jitrayut; Limb, Michael A L; Mulholland, Adrian J

2014-05-08

Serratia marcescens Chitinase B (ChiB), belonging to the glycosidase family 18 (GH18), catalyzes the hydrolysis of β-1,4-glycosidic bond, with retention of configuration, via an unusual substrate-assisted mechanism, in which the substrate itself acts as an intramolecular nucleophile. Here, both elementary steps (glycosylation and deglycosylation) of the ChiB-catalyzed reaction are investigated by means of combined quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations at the SCC-DFTB/CHARMM22 level of theory. We examine the influence of the Asp142 protonation state on the reaction and the role that this residue performs in the reaction. Our simulations show that reaction with a neutral Asp142 is preferred and demonstrate that this residue provides electrostatic stabilization of the oxazolinium ion intermediate formed in the reaction. Insight into the conformational itinerary ((1,4)B↔(4)H5↔(4)C1) adopted by the substrate (bound in subsite -1) along the preferred reaction pathway is also provided by the simulations. The relative energies of the stationary points found along the reaction pathway calculated with SCC-DFTB and B3LYP were compared. The results suggest that SCC-DFTB is an accurate method for estimating the relative barriers for both steps of the reaction; however, it was found to overestimate the relative energy of an intermediate formed in the reaction when compared with the higher level of theory. Glycosylation is suggested to be a rate-determining step in the reaction with calculated overall reaction free-energy barrier of 20.5 kcal/mol, in a reasonable agreement with the 16.1 kcal/mol barrier derived from the experiment. The role of Tyr214 in catalysis was also investigated with the results, indicating that the residue plays a critical role in the deglycosylation step of the reaction. Simulations of the enzyme-product complex were also performed with an unbinding event suggested to have been observed, affording potential new mechanistic insight into the release of the product of ChiB.

Exercise for adults with fibromyalgia: an umbrella systematic review with synthesis of best evidence.

PubMed

Bidonde, Julia; Busch, Angela Jean; Bath, Brenna; Milosavljevic, Stephan

2014-01-01

The objective of this umbrella systematic review was to identify, evaluate, and synthesize systematic reviews of physical activity interventions for adults with fibromyalgia (FM) focussing on four outcomes: pain, multidimensional function (wellness or quality of life), physical function (self-reported physical function or measured physical fitness) and adverse effects. A further objective was to link these outcomes with details of the interventions so as to guide and shape future practice and research. Electronic databases including Medline, EMBASE, CINAHL, AMED, the Cochrane Library, and DARE, were searched for the January 1(st) 2007 to March 31(st) 2013 period. Nine systematic reviews (60 RCTs with 3816 participants) were included. Meta-analysis was not conducted due to the heterogeneity of the sample. We found positive results of diverse exercise interventions on pain, multidimensional function, and self-reported physical function, and no supporting evidence for new (to FM) interventions (i.e., qigong, tai chi). There were no serious adverse effects reported. The variability of the interventions in the reviews prevented us from answering important clinical questions to guide practical decisions about optimal modes or dosages (i.e., frequency, intensity, duration). Finally, the number of review articles is proliferating, leading researchers and reviewers to consider the rigor and quality of the information being reviewed. As well, consumers of these reviews (i.e., clinicians, individuals with FM) should not rely on them without careful consideration.

An ellipsoid-chain model for conjugated polymer solutions

NASA Astrophysics Data System (ADS)

Lee, Cheng K.; Hua, Chi C.; Chen, Show A.

2012-02-01

We propose an ellipsoid-chain model which may be routinely parameterized to capture large-scale properties of semiflexible, amphiphilic conjugated polymers in various solvent media. The model naturally utilizes the defect locations as pivotal centers connecting adjacent ellipsoids (each currently representing ten monomer units), and a variant umbrella-sampling scheme is employed to construct the potentials of mean force (PMF) for specific solvent media using atomistic dynamics data and simplex optimization. The performances, both efficacy and efficiency, of the model are thoroughly evaluated by comparing the simulation results on long, single-chain (i.e., 300-mer) structures with those from two existing, finer-grained models for a standard conjugated polymer (i.e., poly(2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene) or MEH-PPV) in two distinct solvents (i.e., chloroform or toluene) as well as a hybrid, binary-solvent medium (i.e., chloroform/toluene = 1:1 in number density). The coarse-grained Monte Carlo (CGMC) simulation of the ellipsoid-chain model is shown to be the most efficient—about 300 times faster than the coarse-grained molecular dynamics (CGMD) simulation of the finest CG model that employs explicit solvents—in capturing elementary single-chain structures for both single-solvent media, and is a few times faster than the coarse-grained Langevin dynamics (CGLD) simulation of another implicit-solvent polymer model with a slightly greater coarse-graining level than in the CGMD simulation. For the binary-solvent system considered, however, both of the two implicit-solvent schemes (i.e., CGMC and CGLD) fail to capture the effects of conspicuous concentration fluctuations near the polymer-solvent interface, arising from a pronounced coupling between the solvent molecules and different parts of the polymer. Essential physical implications are elaborated on the success as well as the failure of the two implicit-solvent CG schemes under varying solvent conditions. Within the ellipsoid-chain model, the impact of synthesized defects on local segmental ordering as well as bulk chain conformation is also scrutinized, and essential consequences in practical applications discussed. In future perspectives, we remark on strategy that takes advantage of the coordination among various CG models and simulation schemes to warrant computational efficiency and accuracy, with the anticipated capability of simulating larger-scale, many-chain aggregate systems.

Health education for patients with acute coronary syndrome and type 2 diabetes mellitus: an umbrella review of systematic reviews and meta-analyses.

PubMed

Liu, Xian-Liang; Shi, Yan; Willis, Karen; Wu, Chiung-Jung Jo; Johnson, Maree

2017-10-16

This umbrella review aimed to identify the current evidence on health education-related interventions for patients with acute coronary syndrome (ACS) or type two diabetes mellitus (T2DM); identify the educational content, delivery methods, intensity, duration and setting required. The purpose was to provide recommendations for educational interventions for high-risk patients with both ACS and T2DM. Umbrella review of systematic reviews and meta-analyses. Inpatient and postdischarge settings. Patients with ACS and T2DM. CINAHL, Cochrane Library, Joanna Briggs Institute, Journals@Ovid, EMBase, Medline, PubMed and Web of Science databases from January 2000 through May 2016. Clinical outcomes (such as glycated haemoglobin), behavioural outcomes (such as smoking), psychosocial outcomes (such as anxiety) and medical service use. Fifty-one eligible reviews (15 for ACS and 36 for T2DM) consisting of 1324 relevant studies involving 2 88 057 patients (15 papers did not provide the total sample); 30 (58.8%) reviews were rated as high quality. Nurses only and multidisciplinary teams were the most frequent professionals to provide education, and most educational interventions were delivered postdischarge. Face-to-face sessions were the most common delivery formats, and many education sessions were also delivered by telephone or via web contact. The frequency of educational sessions was weekly or monthly, and an average of 3.7 topics was covered per education session. Psychoeducational interventions were generally effective at reducing smoking and admissions for patients with ACS. Culturally appropriate health education, self-management educational interventions, group medical visits and psychoeducational interventions were generally effective for patients with T2DM. Results indicate that there is a body of current evidence about the efficacy of health education, its content and delivery methods for patients with ACS or T2DM. These results provide recommendations about the content for, and approach to, health education intervention for these high-risk patients. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Health education for patients with acute coronary syndrome and type 2 diabetes mellitus: an umbrella review of systematic reviews and meta-analyses

PubMed Central

Liu, Xian-liang; Shi, Yan; Willis, Karen; Wu, Chiung-Jung (Jo); Johnson, Maree

2017-01-01

Objectives This umbrella review aimed to identify the current evidence on health education-related interventions for patients with acute coronary syndrome (ACS) or type two diabetes mellitus (T2DM); identify the educational content, delivery methods, intensity, duration and setting required. The purpose was to provide recommendations for educational interventions for high-risk patients with both ACS and T2DM. Design Umbrella review of systematic reviews and meta-analyses. Setting Inpatient and postdischarge settings. Participants Patients with ACS and T2DM. Data sources CINAHL, Cochrane Library, Joanna Briggs Institute, Journals@Ovid, EMBase, Medline, PubMed and Web of Science databases from January 2000 through May 2016. Outcomes measures Clinical outcomes (such as glycated haemoglobin), behavioural outcomes (such as smoking), psychosocial outcomes (such as anxiety) and medical service use. Results Fifty-one eligible reviews (15 for ACS and 36 for T2DM) consisting of 1324 relevant studies involving 2 88 057 patients (15 papers did not provide the total sample); 30 (58.8%) reviews were rated as high quality. Nurses only and multidisciplinary teams were the most frequent professionals to provide education, and most educational interventions were delivered postdischarge. Face-to-face sessions were the most common delivery formats, and many education sessions were also delivered by telephone or via web contact. The frequency of educational sessions was weekly or monthly, and an average of 3.7 topics was covered per education session. Psychoeducational interventions were generally effective at reducing smoking and admissions for patients with ACS. Culturally appropriate health education, self-management educational interventions, group medical visits and psychoeducational interventions were generally effective for patients with T2DM. Conclusions Results indicate that there is a body of current evidence about the efficacy of health education, its content and delivery methods for patients with ACS or T2DM. These results provide recommendations about the content for, and approach to, health education intervention for these high-risk patients. PMID:29042383

Free energy study of H2O, N2O5, SO2, and O3 gas sorption by water droplets/slabs

NASA Astrophysics Data System (ADS)

Li, Wentao; Pak, Chi Yuen; Tse, Ying-Lung Steve

2018-04-01

Understanding gas sorption by water in the atmosphere is an active research area because the gases can significantly alter the radiation and chemical properties of the atmosphere. We attempt to elucidate the molecular details of the gas sorption of water and three common atmospheric gases (N2O5, SO2, and O3) by water droplets/slabs in molecular dynamics simulations. The system size effects are investigated, and we show that the calculated solvation free energy decreases linearly as a function of the reciprocal of the number of water molecules from 1/215 to 1/1000 in both the slab and the droplet systems. By analyzing the infinitely large system size limit by extrapolation, we find that all our droplet results are more accurate than the slab results when compared to the experimental values. We also show how the choice of restraints in umbrella sampling can affect the sampling efficiency for the droplet systems. The free energy changes were decomposed into the energetic ΔU and entropic -TΔS contributions to reveal the molecular details of the gas sorption processes. By further decomposing ΔU into Lennard-Jones and Coulombic interactions, we observe that the ΔU trends are primarily determined by local effects due to the size of the gas molecule, charge distribution, and solvation structure around the gas molecule. Moreover, we find that there is a strong correlation between the change in the entropic contribution and the mean residence time of water, which is spatially nonlocal and related to the mobility of water.

Neyman-Pearson classification algorithms and NP receiver operating characteristics

PubMed Central

Tong, Xin; Feng, Yang; Li, Jingyi Jessica

2018-01-01

In many binary classification applications, such as disease diagnosis and spam detection, practitioners commonly face the need to limit type I error (that is, the conditional probability of misclassifying a class 0 observation as class 1) so that it remains below a desired threshold. To address this need, the Neyman-Pearson (NP) classification paradigm is a natural choice; it minimizes type II error (that is, the conditional probability of misclassifying a class 1 observation as class 0) while enforcing an upper bound, α, on the type I error. Despite its century-long history in hypothesis testing, the NP paradigm has not been well recognized and implemented in classification schemes. Common practices that directly limit the empirical type I error to no more than α do not satisfy the type I error control objective because the resulting classifiers are likely to have type I errors much larger than α, and the NP paradigm has not been properly implemented in practice. We develop the first umbrella algorithm that implements the NP paradigm for all scoring-type classification methods, such as logistic regression, support vector machines, and random forests. Powered by this algorithm, we propose a novel graphical tool for NP classification methods: NP receiver operating characteristic (NP-ROC) bands motivated by the popular ROC curves. NP-ROC bands will help choose α in a data-adaptive way and compare different NP classifiers. We demonstrate the use and properties of the NP umbrella algorithm and NP-ROC bands, available in the R package nproc, through simulation and real data studies. PMID:29423442

Neyman-Pearson classification algorithms and NP receiver operating characteristics.

PubMed

Tong, Xin; Feng, Yang; Li, Jingyi Jessica

2018-02-01

In many binary classification applications, such as disease diagnosis and spam detection, practitioners commonly face the need to limit type I error (that is, the conditional probability of misclassifying a class 0 observation as class 1) so that it remains below a desired threshold. To address this need, the Neyman-Pearson (NP) classification paradigm is a natural choice; it minimizes type II error (that is, the conditional probability of misclassifying a class 1 observation as class 0) while enforcing an upper bound, α, on the type I error. Despite its century-long history in hypothesis testing, the NP paradigm has not been well recognized and implemented in classification schemes. Common practices that directly limit the empirical type I error to no more than α do not satisfy the type I error control objective because the resulting classifiers are likely to have type I errors much larger than α, and the NP paradigm has not been properly implemented in practice. We develop the first umbrella algorithm that implements the NP paradigm for all scoring-type classification methods, such as logistic regression, support vector machines, and random forests. Powered by this algorithm, we propose a novel graphical tool for NP classification methods: NP receiver operating characteristic (NP-ROC) bands motivated by the popular ROC curves. NP-ROC bands will help choose α in a data-adaptive way and compare different NP classifiers. We demonstrate the use and properties of the NP umbrella algorithm and NP-ROC bands, available in the R package nproc, through simulation and real data studies.

The Cholangiocyte Glycocalyx Stabilizes the 'Biliary HCO3 Umbrella': An Integrated Line of Defense against Toxic Bile Acids.

PubMed

Maillette de Buy Wenniger, Lucas J; Hohenester, Simon; Maroni, Luca; van Vliet, Sandra J; Oude Elferink, Ronald P; Beuers, Ulrich

2015-01-01

Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a 'biliary HCO3(-) umbrella', i.e. apical cholangiocellular HCO3(-) secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the 'biliary HCO3(-) umbrella' and thus preventing cholangiotoxicity of bile acids. The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (α1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pKa ≥4), but not taurochenodeoxycholate (pKa <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the 'biliary HCO3(-) umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity. 2015 S. Karger AG, Basel.

Imaging of oxygen gradients in giant umbrella cells: an ex vivo PLIM study.

PubMed

Zhdanov, A V; Golubeva, A V; Okkelman, I A; Cryan, J F; Papkovsky, D B

2015-10-01

O2 plays a pivotal role in aerobic metabolism and regulation of cell and tissue function. Local differences and fluctuations in tissue O2 levels are well documented; however, the physiological significance of O2 microgradients, particularly at the subcellular level, remains poorly understood. Using the cell-penetrating phosphorescent O2 probe Pt-Glc and confocal fluorescence microscopy, we visualized O2 distribution in individual giant (>100-μm) umbrella cells located superficially in the urinary bladder epithelium. We optimized conditions for in vivo phosphorescent staining of the inner surface of the mouse bladder and subsequent ex vivo analysis of excised live tissue. Imaging experiments revealed significant (≤85 μM) and heterogeneous deoxygenation within respiring umbrella cells, with radial O2 gradients of up to 40 μM across the cell, or ∼0.6 μM/μm. Deeply deoxygenated (5-15 μM O2) regions were seen to correspond to the areas enriched with polarized mitochondria. Pharmacological activation of mitochondrial respiration decreased oxygenation and O2 gradients in umbrella cells, while inhibition with antimycin A dissipated the gradients and caused gradual reoxygenation of the tissue to ambient levels. Detailed three-dimensional maps of O2 distribution potentially can be used for the modeling of intracellular O2-dependent enzymatic reactions and downstream processes, such as hypoxia-inducible factor signaling. Further ex vivo and in vivo studies on intracellular and tissue O2 gradients using confocal imaging can shed light on the molecular mechanisms regulating O2-dependent (patho)physiological processes in the bladder and other tissues. Copyright © 2015 the American Physiological Society.

An Umbrella Review of Nuts Intake and Risk of Cardiovascular Disease.

PubMed

Schwingshackl, Lukas; Hoffmann, Georg; Missbach, Benjamin; Stelmach-Mardas, Marta; Boeing, Heiner

2017-01-01

Nuts have been an indispensable component of the human diet for hundreds because of their unique nutrient composition and are thought to play a beneficial part in the prevention of cardiovascular diseases. To evaluate the extent, validity and presence of evidence for studies investigating the impact of nuts intake on biomarkers of cardiovascular disease and cardiovascular events, we performed an umbrella review of all published meta-analyses synthesizing data from both observational studies and randomized controlled trials. PubMed (between 1966 and April 2016) was searched for systematic reviews and meta-analyses. Methodological quality was assessed by applying the AMSTAR score (0-11 points), and the meta-evidence by applying NutriGrade, our recently developed scoring system (0-10 points). In total, 14 meta-analyses were included in the umbrella review. Only 4 out of 14 reported an AMSTAR score ≥8 (high methodological quality), whereas NutriGrade meta-evidence score varied between 2 (very low meta-evidence) and 7.9 (moderate meta-evidence). There is consistent evidence from intervention trials, reporting significant reductions for total cholesterol, and from observational studies that higher intakes of nuts were associated with reduced risk of cardiovascular disease and hypertension. On the other side no effect could be observed for stroke, HDL-cholesterol, and blood pressure in the normal range. In summary, the present umbrella review showed that nuts intake was associated with reduced risk of cardiovascular disease and hypertension, and lower levels of total cholesterol. The observed evidence is limited by the moderate methodological quality and very low to moderate quality of evidence. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

In situ characterization of glycans in the urothelium of donkey bladder: evidence of secretion of sialomucins.

PubMed

Desantis, Salvatore; Accogli, Gianluca; Zizza, Sara; Arrighi, Silvana

2013-09-01

The glycoprotein pattern was investigated by lectin histochemistry in the urothelium lining the urinary bladder of the donkey Equus asinus. Tissue sections were stained with a panel of twelve lectins, in combination with saponification and sialidase digestion (K-s). The urinary bladder urothelium has three distinct layers from the basal zone to the lumen consisting of basal, intermediate and superficial cells (umbrella cells). Cytoplasm of basal cells reacted with SNA, PNA, K-s-PNA, GSA I-B4 and Con A showing glycans ending with Neu5Acα2,6Gal/GalNAc, Neu5AcGalβ1,3GalNAc, αGal and with terminal/internal αMan. The cytoplasm of umbrella cells displayed an increase of Neu5AcGalβ1,3GalNAc and the appearance of Neu5AcGalβ1,3GalNAc, Neu5acα2,3Galβ1,4GlcNAc and Neu5AcGalNAc residues (MAL II, K-s-SBA and K-s-HPA staining). Scattered umbrella cells were characterized by glycans terminating with GalNAc binding DBA, SBA and HPA. The mucosa forms folds with a crypt-like appearance where the urothelium shows a different pattern of glycans. The bladder luminal surface stained with K-s-PNA, K-s-DBA, KOH-s-SBA, and K-s-HPA displaying a coating of sialoglycoproteins belonging to O-linked glycans (typical secretory moieties). These findings show that different glycosylation patterns exist along the donkey bladder urothelium, and different sub-populations of umbrella cells are present secreting the sialoglycans which constitute the protective gel layer lining the bladder. Copyright © 2013 Elsevier GmbH. All rights reserved.

Policy determinants of physical activity across the life course: a 'DEDIPAC' umbrella systematic literature review.

PubMed

Puggina, Anna; Aleksovska, Katina; Buck, Christoph; Burns, Con; Cardon, Greet; Carlin, Angela; Chantal, Simon; Ciarapica, Donatella; Condello, Giancarlo; Coppinger, Tara; Cortis, Cristina; D'Haese, Sara; De Craemer, Marieke; Di Blasio, Andrea; Hansen, Sylvia; Iacoviello, Licia; Issartel, Johann; Izzicupo, Pascal; Jaeschke, Lina; Kanning, Martina; Kennedy, Aileen; Chun Man Ling, Fiona; Luzak, Agnes; Napolitano, Giorgio; Nazare, Julie-Anne; Perchoux, Camille; Pischon, Tobias; Polito, Angela; Sannella, Alessandra; Schulz, Holger; Sohun, Rhoda; Steinbrecher, Astrid; Schlicht, Wolfgang; Ricciardi, Walter; MacDonncha, Ciaran; Capranica, Laura; Boccia, Stefania

2018-02-01

Despite the large number of studies and reviews available, the evidence regarding the policy determinants of physical activity (PA) is inconclusive. This umbrella systematic literature review (SLR) summarizes the current evidence on the policy determinants of PA across the life course, by pooling the results of the available SLRs and meta-analyses (MAs). A systematic online search was conducted on MEDLINE, ISI Web of Science, Scopus and SPORTDiscus databases up to April 2016. SLRs and MAs of observational studies investigating the association between policy determinants of PA and having PA as outcome were considered eligible. The extracted data were assessed based on the importance of the determinants, the strength of evidence and the methodological quality. Fourteen reviews on 27 policy determinants of PA were eligible for this umbrella SLR. The majority of the reviews were of moderate quality. Among children, a clear association between time spent outdoors and PA emerged. Among adults, working hours were negatively associated with PA, though evidence was limited. At the population level, community- and street-scale urban design and land use policies were found to positively support PA levels, but levels of evidences were low. With this umbrella SLR the policy determinants of PA at individual-level and population-level have been summarized and assessed. None of the investigated policy determinants had a convincing level of evidence, and very few had a probable level of evidence. Further research is needed, preferably by using prospective study designs, standardized definitions of PA and objective measurement of PA. © The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association.

Architectural Aspects of Grid Computing and its Global Prospects for E-Science Community

NASA Astrophysics Data System (ADS)

Ahmad, Mushtaq

2008-05-01

The paper reviews the imminent Architectural Aspects of Grid Computing for e-Science community for scientific research and business/commercial collaboration beyond physical boundaries. Grid Computing provides all the needed facilities; hardware, software, communication interfaces, high speed internet, safe authentication and secure environment for collaboration of research projects around the globe. It provides highly fast compute engine for those scientific and engineering research projects and business/commercial applications which are heavily compute intensive and/or require humongous amounts of data. It also makes possible the use of very advanced methodologies, simulation models, expert systems and treasure of knowledge available around the globe under the umbrella of knowledge sharing. Thus it makes possible one of the dreams of global village for the benefit of e-Science community across the globe.

Free energy calculations of short peptide chains using Adaptively Biased Molecular Dynamics

NASA Astrophysics Data System (ADS)

Karpusenka, Vadzim; Babin, Volodymyr; Roland, Christopher; Sagui, Celeste

2008-10-01

We performed a computational study of monomer peptides composed of methionine, alanine, leucine, glutamate, lysine (all amino acids with a helix-forming propensities); and proline, glycine tyrosine, serine, arginine (which all have poor helix-forming propensities). The free energy landscapes as a function of the handedness and radius of gyration have been calculated using the recently introduced Adaptively Biased Molecular Dynamics (ABMD) method, combined with replica exchange, multiple walkers, and post-processing Umbrella Correction (UC). Minima that correspond to some of the left- and right-handed 310-, α- and π-helixes were identified by secondary structure assignment methods (DSSP, Stride). The resulting free energy surface (FES) and the subsequent steered molecular dynamics (SMD) simulation results are in agreement with the empirical evidence of preferred secondary structures for the peptide chains considered.

Evidence for curricular and instructional design approaches in undergraduate medical education: An umbrella review.

PubMed

Onyura, Betty; Baker, Lindsay; Cameron, Blair; Friesen, Farah; Leslie, Karen

2016-01-01

An umbrella review compiles evidence from multiple reviews into a single accessible document. This umbrella review synthesizes evidence from systematic reviews on curricular and instructional design approaches in undergraduate medical education, focusing on learning outcomes. We conducted bibliographic database searches in Medline, EMBASE and ERIC from database inception to May 2013 inclusive, and digital keyword searches of leading medical education journals. We identified 18,470 abstracts; 467 underwent duplicate full-text scrutiny. Thirty-six articles met all eligibility criteria. Articles were abstracted independently by three authors, using a modified Kirkpatrick model for evaluating learning outcomes. Evidence for the effectiveness of diverse educational approaches is reported. This review maps out empirical knowledge on the efficacy of a broad range of educational approaches in medical education. Critical knowledge gaps, and lapses in methodological rigour, are discussed, providing valuable insight for future research. The findings call attention to the need for adopting evaluative strategies that explore how contextual variabilities and individual (teacher/learner) differences influence efficacy of educational interventions. Additionally, the results underscore that extant empirical evidence does not always provide unequivocal answers about what approaches are most effective. Educators should incorporate best available empirical knowledge with experiential and contextual knowledge.

Structural Characterization of Amyloid β17-42 Dimer by Potential of Mean Force Analysis: Insights from Molecular Dynamics Simulations.

PubMed

Dutta, Mary; Chutia, Rajkalyan; Mattaparthi, Venkata Satish Kumar

2017-01-01

Recent experiments with Amyloid β1-42 peptide have indicated that the initial dimerization of Aβ1-42 monomers to form amyloid dimers stand out as a key event in the generation of toxic oligomers. However, the structural characterization of Aβ1-42 dimer at the atomistic level and the dimerization mechanism by which Aβ1-42 peptides co-aggregate still remains not clear. In the present study, the process of Aβ17-42 peptide dimerization which is known to play an important role in the plaque formation in Alzheimer's disease was evaluated in terms of potential of mean force. The Aβ17-42 dimer was constructed using PatchDock server. We have used molecular dynamics (MD) simulation with the umbrella sampling methodology to compute the Potential of Mean Force for the dimerization of Aβ17-42. The global minima structure at the minimum distance of separation was isolated from the calculated free energy profile and the interactions involved in the formation of the dimer structure were examined. Protein-protein interfaces and the residueresidue interactions vital for generation of the dimer complexes were also evaluated. The simulation results elucidated the interaction between the monomeric units to be governed primarily by the hydrophobic and hydrogen bonds. The resultant Aβ17-42 dimer was found to have an increased β-strands propensity at the hydrophobic regions encompassing the CHC region. Furthermore, specific hydrophobic residues were found to play a vital role in the formation of the dimer complex. From the results we may therefore conclude hydrophobic region encompassing the CHC region to be crucial in dimerization process. The findings from this study provide detailed information for the complex process of early events of Aβ aggregation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

ATP transport through VDAC and the VDAC-tubulin complex probed by equilibrium and nonequilibrium MD simulations.

PubMed

Noskov, Sergei Yu; Rostovtseva, Tatiana K; Bezrukov, Sergey M

2013-12-23

Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane, serves as a principal pathway for ATP, ADP, and other respiratory substrates across this membrane. Using umbrella-sampling simulations, we established the thermodynamic and kinetic components governing ATP transport across the VDAC1 channel. We found that there are several low-affinity binding sites for ATP along the translocation pathway and that the main barrier for ATP transport is located around the center of the channel and is formed predominantly by residues in the N-terminus. The binding affinity of ATP to an open channel was found to be in the millimolar to micromolar range. However, we show that this weak binding increases the ATP translocation probability by about 10-fold compared with the VDAC pore in which attractive interactions were artificially removed. Recently, it was found that free dimeric tubulin induces a highly efficient, reversible blockage of VDAC reconstituted into planar lipid membranes. It was proposed that by blocking VDAC permeability for ATP/ADP and other mitochondrial respiratory substrates tubulin controls mitochondrial respiration. Using the Rosetta protein-protein docking algorithm, we established a tentative structure of the VDAC-tubulin complex. An extensive set of equilibrium and nonequilibrium (under applied electric field) molecular dynamics (MD) simulations was used to establish the conductance of the open and blocked channel. It was found that the presence of the unstructured C-terminal tail of tubulin in the VDAC pore decreases its conductance by more than 40% and switches its selectivity from anionic to cationic. The subsequent 1D potential of mean force (PMF) computations for the VDAC-tubulin complex show that the state renders ATP transport virtually impossible. A number of residues pivotal for tubulin binding to the channel were identified that help to clarify the molecular details of VDAC-tubulin interaction and to provide new insight into the mechanism of the control of mitochondria respiration by VDAC.

Modeling Conformational Transitions and Energetics of Ligand Binding with the Glutamate Receptor Ligand Binding Domain

NASA Astrophysics Data System (ADS)

Kurnikova, Maria

2009-03-01

Understanding of protein motion and energetics of conformational transitions is crucial to understanding protein function. The glutamate receptor ligand binding domain (GluR2 S1S2) is a two lobe protein, which binds ligand at the interface of two lobes and undergoes conformational transition. The cleft closure conformational transition of S1S2 has been implicated in gating of the ion channel formed by the transmembrane domain of the receptor. In this study we present a composite multi-faceted theoretical analysis of the detailed mechanism of this conformational transition based on rigid cluster decomposition of the protein structure [1] and identifying hydrogen bonds that are responsible for stabilizing the closed conformation [2]. Free energy of the protein reorganization upon ligand binding was calculated using combined Thermodynamic Integration (TI) and Umbrella Sampling (US) simulations [3]. Ligand -- protein interactions in the binding cleft were analyzed using Molecular Dynamics, continuum electrostatics and QM/MM models [4]. All model calculations compare well with corresponding experimental measurements. [4pt] [1] Protein Flexibility using Constraints from Molecular Dynamics Simulations T. Mamonova, B. Hespenheide, R. Straub, M. F. Thorpe, M. G. Kurnikova , Phys. Biol., 2, S137 (2005)[0pt] [2] Theoretical Study of the Glutamate Receptor Ligand Binding Domain Flexibility and Conformational Reorganization T. Mamonova, K. Speranskiy, and M. Kurnikova , Prot.: Struct., Func., Bioinf., 73,656 (2008)[0pt] [3] Energetics of the cleft closing transition and glutamate binding in the Glutamate Receptor ligand Binding Domain T. Mamonova, M. Yonkunas, and M. Kurnikova Biochemistry 47, 11077 (2008)[0pt] [4] On the Binding Determinants of the Glutamate Agonist with the Glutamate Receptor Ligand Binding Domain K. Speranskiy and M. Kurnikova Biochemistry 44, 11208 (2005)

Simple physics-based analytical formulas for the potentials of mean force of the interaction of amino-acid side chains in water. V. Like-charged side chains.

PubMed

Makowski, Mariusz; Liwo, Adam; Sobolewski, Emil; Scheraga, Harold A

2011-05-19

A new model of side-chain-side-chain interactions for charged side-chains of amino acids, to be used in the UNRES force-field, has been developed, in which a side chain consists of a nonpolar and a charged site. The interaction energy between the nonpolar sites is composed of a Gay-Berne and a cavity term; the interaction energy between the charged sites consists of a Lennard-Jones term, a Coulombic term, a generalized-Born term, and a cavity term, while the interaction energy between the nonpolar and charged sites is composed of a Gay-Berne and a polarization term. We parametrized the energy function for the models of all six pairs of natural like-charged amino-acid side chains, namely propionate-propionate (for the aspartic acid-aspartic acid pair), butyrate-butyrate (for the glutamic acid-glutamic acid pair), propionate-butyrate (for the aspartic acid-glutamic acid pair), pentylamine cation-pentylamine cation (for the lysine-lysine pair), 1-butylguanidine cation-1-butylguanidine cation (for the arginine-arginine pair), and pentylamine cation-1-butylguanidine cation (for the lysine-arginine pair). By using umbrella-sampling molecular dynamics simulations in explicit TIP3P water, we determined the potentials of mean force of the above-mentioned pairs as functions of distance and orientation and fitted analytical expressions to them. The positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the orientation of the molecules were well represented by analytical expressions for all systems. The values of the parameters of all the energy components are physically reasonable, which justifies use of such potentials in coarse-grain protein-folding simulations. © 2011 American Chemical Society

Reaction Rate Theory in Coordination Number Space: An Application to Ion Solvation

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

Roy, Santanu; Baer, Marcel D.; Mundy, Christopher J.

2016-04-14

Understanding reaction mechanisms in many chemical and biological processes require application of rare event theories. In these theories, an effective choice of a reaction coordinate to describe a reaction pathway is essential. To this end, we study ion solvation in water using molecular dynamics simulations and explore the utility of coordination number (n = number of water molecules in the first solvation shell) as the reaction coordinate. Here we compute the potential of mean force (W(n)) using umbrella sampling, predicting multiple metastable n-states for both cations and anions. We find with increasing ionic size, these states become more stable andmore » structured for cations when compared to anions. We have extended transition state theory (TST) to calculate transition rates between n-states. TST overestimates the rate constant due to solvent-induced barrier recrossings that are not accounted for. We correct the TST rates by calculating transmission coefficients using the reactive flux method. This approach enables a new way of understanding rare events involving coordination complexes. We gratefully acknowledge Liem Dang and Panos Stinis for useful discussion. This research used resources of the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. SR, CJM, and GKS were supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences. MDB was supported by MS3 (Materials Synthesis and Simulation Across Scales) Initiative, a Laboratory Directed Research and Development Program at Pacific Northwest National Laboratory (PNNL). PNNL is a multiprogram national laboratory operated by Battelle for the U.S. Department of Energy.« less

Phase diagram of heteronuclear Janus dumbbells

NASA Astrophysics Data System (ADS)

O'Toole, Patrick; Giacometti, Achille; Hudson, Toby

Using Aggregation-Volume-Bias Monte Carlo simulations along with Successive Umbrella Sampling and Histogram Re-weighting, we study the phase diagram of a system of dumbbells formed by two touching spheres having variable sizes, as well as different interaction properties. The first sphere ($h$) interacts with all other spheres belonging to different dumbbells with a hard-sphere potential. The second sphere ($s$) interacts via a square-well interaction with other $s$ spheres belonging to different dumbbells and with a hard-sphere potential with all remaining $h$ spheres. We focus on the region where the $s$ sphere is larger than the $h$ sphere, as measured by a parameter $1\\le \\alpha\\le 2 $ controlling the relative size of the two spheres. As $\\alpha \\to 2$ a simple fluid of square-well spheres is recovered, whereas $\\alpha \\to 1$ corresponds to the Janus dumbbell limit, where the $h$ and $s$ spheres have equal sizes. Many phase diagrams falling into three classes are observed, depending on the value of $\\alpha$. The $1.8 \\le \\alpha \\le 2$ is dominated by a gas-liquid phase separation very similar to that of a pure square-well fluid with varied critical temperature and density. When $1.3 \\le \\alpha \\le 1.8$ we find a progressive destabilization of the gas-liquid phase diagram by the onset of self-assembled structures, that eventually lead to a metastability of the gas-liquid transition below $\\alpha=1.2$.

Theoretical Studies of Interactions between O-Phosphorylated and Standard Amino-Acid Side-Chain Models in Water

PubMed Central

Wiśniewska, Marta; Sobolewski, Emil; Ołdziej, Stanisław; Liwo, Adam; Scheraga, Harold A.; Makowski, Mariusz

2015-01-01

Phosphorylation is a common post-translational modification of the amino-acid side chains (serine, tyrosine, and threonine) that contain hydroxyl groups. The transfer of the negatively charged phosphate group from an ATP molecule to such amino-acid side chains leads to changes in the local conformations of proteins and the pattern of interactions with other amino-acid side-chains. A convenient characteristic of the side chain–side chain interactions in the context of an aqueous environment is the potential of mean force (PMF) in water. A series of umbrella-sampling molecular dynamic (MD) simulations with the AMBER force field were carried out for pairs of O-phosphorylated serine (pSer), threonine (pThr), and tyrosine, (pTyr) with natural amino acids in a TIP3P water model as a solvent at 298 K. The weighted-histogram analysis method was used to calculate the four-dimensional potentials of mean force. The results demonstrate that the positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the relative orientation depend on the character of the interacting pairs. More distinct minima are observed for oppositely charged pairs such as, e.g., O-phosphorylated side-chains and positively charged ones, such as the side-chains of lysine and arginine. PMID:26100791

Ion-Specific Induced Fluctuations and Free Energetics of Aqueous Protein Hydrophobic Interfaces: Toward Connecting to Specific-Ion Behaviors at Aqueous Liquid–Vapor Interfaces

PubMed Central

2015-01-01

We explore anion-induced interface fluctuations near protein–water interfaces using coarse-grained representations of interfaces as proposed by Willard and Chandler (J. Phys. Chem. B2010, 114, 1954−195820055377). We use umbrella sampling molecular dynamics to compute potentials of mean force along a reaction coordinate bridging the state where the anion is fully solvated and one where it is biased via harmonic restraints to remain at the protein–water interface. Specifically, we focus on fluctuations of an interface between water and a hydrophobic region of hydrophobin-II (HFBII), a 71 amino acid residue protein expressed by filamentous fungi and known for its ability to form hydrophobically mediated self-assemblies at interfaces such as a water/air interface. We consider the anions chloride and iodide that have been shown previously by simulations as displaying specific-ion behaviors at aqueous liquid–vapor interfaces. We find that as in the case of a pure liquid–vapor interface, at the hydrophobic protein–water interface, the larger, less charge-dense iodide anion displays a marginal interfacial stability compared with that of the smaller, more charge-dense chloride anion. Furthermore, consistent with the results at aqueous liquid–vapor interfaces, we find that iodide induces larger fluctuations of the protein–water interface than chloride. PMID:24701961

Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease

NASA Astrophysics Data System (ADS)

Dahan, Arik; Markovic, Milica; Keinan, Shahar; Kurnikov, Igor; Aponick, Aaron; Zimmermann, Ellen M.; Ben-Shabat, Shimon

2017-11-01

Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA2, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA2 to release the free drug. The linker length dictates the affinity of the PL-drug conjugate to PLA2, and the optimal linker will enable maximal PLA2-mediated activation. Thermodynamic integration and Weighted Histogram Analysis Method (WHAM)/Umbrella Sampling method were used to compute the changes in PLA2 transition state binding free energy of the prodrug molecule (ΔΔGtr) associated with decreasing/increasing linker length. The simulations revealed that 6-carbons linker is the optimal one, whereas shorter or longer linkers resulted in decreased PLA2-mediated activation. These in-silico results were shown to be in excellent correlation with experimental in-vitro data. Overall, this modern computational approach enables optimization of the molecular design of novel prodrugs, which may allow targeting the free drug specifically to the diseased intestinal tissue of IBD patients.

Simple Physics-Based Analytical Formulas for the Potentials of Mean Force of the Interaction of Amino Acid Side Chains in Water. VII. Charged-Hydrophobic/Polar and Polar-Hydrophobic/Polar Side Chains.

PubMed

Makowski, Mariusz; Liwo, Adam; Scheraga, Harold A

2017-01-19

The physics-based potentials of side-chain-side-chain interactions corresponding to pairs composed of charged and polar, polar and polar, charged and hydrophobic, and hydrophobic and hydrophobic side chains have been determined. A total of 144 four-dimensional potentials of mean force (PMFs) of all possible pairs of molecules modeling these pairs were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation, and the analytical expressions were then fitted to the PMFs. Depending on the type of interacting sites, the analytical approximation to the PMF is a sum of terms corresponding to van der Waals interactions and cavity-creation involving the nonpolar sections of the side chains and van der Waals, cavity-creation, and electrostatic (charge-dipole or dipole-dipole) interaction energies and polarization energies involving the charged or polar sections of the side chains. The model used in this work reproduces all features of the interacting pairs. The UNited RESidue force field with the new side-chain-side-chain interaction potentials was preliminarily tested with the N-terminal part of the B-domain of staphylococcal protein A (PDBL 1BDD ; a three-α-helix bundle) and UPF0291 protein YnzC from Bacillus subtilis (PDB: 2HEP ; an α-helical hairpin).

Conformation-dependent DNA attraction.

PubMed

Li, Weifeng; Nordenskiöld, Lars; Zhou, Ruhong; Mu, Yuguang

2014-06-21

Understanding how DNA molecules interact with other biomolecules is related to how they utilize their functions and is therefore critical for understanding their structure-function relationships. For a long time, the existence of Z-form DNA (a left-handed double helical version of DNA, instead of the common right-handed B-form) has puzzled the scientists, and the definitive biological significance of Z-DNA has not yet been clarified. In this study, the effects of DNA conformation in DNA-DNA interactions are explored by molecular dynamics simulations. Using umbrella sampling, we find that for both B- and Z-form DNA, surrounding Mg(2+) ions always exert themselves to screen the Coulomb repulsion between DNA phosphates, resulting in very weak attractive force. On the contrary, a tight and stable bound state is discovered for Z-DNA in the presence of Mg(2+) or Na(+), benefiting from their hydrophobic nature. Based on the contact surface and a dewetting process analysis, a two-stage binding process of Z-DNA is outlined: two Z-DNA first attract each other through charge screening and Mg(2+) bridges to phosphate groups in the same way as that of B-DNA, after which hydrophobic contacts of the deoxyribose groups are formed via a dewetting effect, resulting in stable attraction between two Z-DNA molecules. The highlighted hydrophobic nature of Z-DNA interaction from the current study may help to understand the biological functions of Z-DNA in gene transcription.

Free energy landscape and transition pathways from Watson–Crick to Hoogsteen base pairing in free duplex DNA

PubMed Central

Yang, Changwon; Kim, Eunae; Pak, Youngshang

2015-01-01

Houghton (HG) base pairing plays a central role in the DNA binding of proteins and small ligands. Probing detailed transition mechanism from Watson–Crick (WC) to HG base pair (bp) formation in duplex DNAs is of fundamental importance in terms of revealing intrinsic functions of double helical DNAs beyond their sequence determined functions. We investigated a free energy landscape of a free B-DNA with an adenosine–thymine (A–T) rich sequence to probe its conformational transition pathways from WC to HG base pairing. The free energy landscape was computed with a state-of-art two-dimensional umbrella molecular dynamics simulation at the all-atom level. The present simulation showed that in an isolated duplex DNA, the spontaneous transition from WC to HG bp takes place via multiple pathways. Notably, base flipping into the major and minor grooves was found to play an important role in forming these multiple transition pathways. This finding suggests that naked B-DNA under normal conditions has an inherent ability to form HG bps via spontaneous base opening events. PMID:26250116

Transitioning NWChem to the Next Generation of Manycore Machines

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

Bylaska, Eric J.; Apra, E; Kowalski, Karol

The NorthWest chemistry (NWChem) modeling software is a popular molecular chemistry simulation software that was designed from the start to work on massively parallel processing supercomputers [1-3]. It contains an umbrella of modules that today includes self-consistent eld (SCF), second order Møller-Plesset perturbation theory (MP2), coupled cluster (CC), multiconguration self-consistent eld (MCSCF), selected conguration interaction (CI), tensor contraction engine (TCE) many body methods, density functional theory (DFT), time-dependent density functional theory (TDDFT), real-time time-dependent density functional theory, pseudopotential plane-wave density functional theory (PSPW), band structure (BAND), ab initio molecular dynamics (AIMD), Car-Parrinello molecular dynamics (MD), classical MD, hybrid quantum mechanicsmore » molecular mechanics (QM/MM), hybrid ab initio molecular dynamics molecular mechanics (AIMD/MM), gauge independent atomic orbital nuclear magnetic resonance (GIAO NMR), conductor like screening solvation model (COSMO), conductor-like screening solvation model based on density (COSMO-SMD), and reference interaction site model (RISM) solvation models, free energy simulations, reaction path optimization, parallel in time, among other capabilities [4]. Moreover, new capabilities continue to be added with each new release.« less

Vection is modulated by the semantic meaning of stimuli and experimental instructions.

PubMed

Ogawa, Masaki; Seno, Takeharu

2014-01-01

Vection strength is modulated by the semantic meanings of stimuli. In experiment 1--even though vection stimuli were of uniform size, color, and luminance--when they also had semantic meaning as falling objects, vection was inhibited. Specifically, stimuli perceived as feathers, petals, and leaves did not effectively induce vection. In experiment 2 we used the downward motion of identical dots to induce vection. Participants observed stimuli while holding either an umbrella or a wooden sword. Results showed that vection was inhibited when participants held the umbrella and the stimuli was perceived as rain or snow falling. The two experiments suggest that vection is modulated by the semantic meaning of stimuli.

Encephalitis, proventricular and ventricular myositis, and myenteric ganglioneuritis in an umbrella cockatoo.

PubMed

Joyner, K L; Kock, N; Styles, D

1989-01-01

Myenteric ganglioneuritis and encephalomyelitis were diagnosed in an umbrella cockatoo. The cockatoo exhibited clinical signs that were milder than those associated with this syndrome, such as anorexia, muscle wasting, regurgitation, depression, and changes in fecal consistency. The gross lesions also differed from earlier reports in that only the duodenum and proximal jejunum were grossly dilated. Normally the proventriculus and ventriculus are dilated without visible intestinal changes. The histopathological lesions, however, such as perivascular cuffs in the brain stem and muscular mass of the ventriculus and proventriculus, were similar to earlier reports. A virus was suspected, although transmission and isolation of a virus has not occurred in other reports and was not attempted in this case.

Dissociative electron attachment and vibrational excitation of CF{sub 3}Cl: Effect of two vibrational modes revisited

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

Tarana, Michal; JILA, University of Colorado and NIST, Boulder, Colorado 80309-0440; Houfek, Karel

We present a study of dissociative electron attachment and vibrational excitation processes in electron collisions with the CF{sub 3}Cl molecule. The calculations are based on the two-dimensional nuclear dynamics including the C-Cl symmetric stretch coordinate and the CF{sub 3} symmetric deformation (umbrella) coordinate. The complex potential energy surfaces are calculated using the ab initio R-matrix method. The results for dissociative attachment and vibrational excitation of the umbrella mode agree quite well with experiment whereas the cross section for excitation of the C-Cl symmetric stretch vibrations is about a factor-of-three too low in comparison with experimental data.

On the use of transition matrix methods with extended ensembles.

PubMed

Escobedo, Fernando A; Abreu, Charlles R A

2006-03-14

Different extended ensemble schemes for non-Boltzmann sampling (NBS) of a selected reaction coordinate lambda were formulated so that they employ (i) "variable" sampling window schemes (that include the "successive umbrella sampling" method) to comprehensibly explore the lambda domain and (ii) transition matrix methods to iteratively obtain the underlying free-energy eta landscape (or "importance" weights) associated with lambda. The connection between "acceptance ratio" and transition matrix methods was first established to form the basis of the approach for estimating eta(lambda). The validity and performance of the different NBS schemes were then assessed using as lambda coordinate the configurational energy of the Lennard-Jones fluid. For the cases studied, it was found that the convergence rate in the estimation of eta is little affected by the use of data from high-order transitions, while it is noticeably improved by the use of a broader window of sampling in the variable window methods. Finally, it is shown how an "elastic" window of sampling can be used to effectively enact (nonuniform) preferential sampling over the lambda domain, and how to stitch the weights from separate one-dimensional NBS runs to produce a eta surface over a two-dimensional domain.

ADVANCING SITE CHARACTERIZATION AND MONITORING ...

EPA Pesticide Factsheets

There is no astract available for htis product. If further information is requested, please refer to the bibliogaphic citation and contact the person listed under Contract field. The overall objective of this task is to provide the Agency with improved state-of-the-science guidance, strategies, and techniques to more accurately and effectively collect environmental samples. Under this umbrella objective, research is being conducted to: (a) reduce/minimize the loss of VOCs during sample collection, handling, and preservation, (b) collect undisturbed surface sediments so that the effects of recent depositional events (e.g., flooding or dredging) can clearly be delineated as to their influence on the contamination concentrations present downstream (or where the sediments are deposited), and (c) to determine an effective method to effectively and efficiently separate asbestos in soils from the rest of the soil matrix while maintaining the integrity (i.e, no fiber size reduction) of the asbestos fibers.

Well-tempered metadynamics converges asymptotically.

PubMed

Dama, James F; Parrinello, Michele; Voth, Gregory A

2014-06-20

Metadynamics is a versatile and capable enhanced sampling method for the computational study of soft matter materials and biomolecular systems. However, over a decade of application and several attempts to give this adaptive umbrella sampling method a firm theoretical grounding prove that a rigorous convergence analysis is elusive. This Letter describes such an analysis, demonstrating that well-tempered metadynamics converges to the final state it was designed to reach and, therefore, that the simple formulas currently used to interpret the final converged state of tempered metadynamics are correct and exact. The results do not rely on any assumption that the collective variable dynamics are effectively Brownian or any idealizations of the hill deposition function; instead, they suggest new, more permissive criteria for the method to be well behaved. The results apply to tempered metadynamics with or without adaptive Gaussians or boundary corrections and whether the bias is stored approximately on a grid or exactly.

Well-Tempered Metadynamics Converges Asymptotically

NASA Astrophysics Data System (ADS)

Dama, James F.; Parrinello, Michele; Voth, Gregory A.

2014-06-01

Metadynamics is a versatile and capable enhanced sampling method for the computational study of soft matter materials and biomolecular systems. However, over a decade of application and several attempts to give this adaptive umbrella sampling method a firm theoretical grounding prove that a rigorous convergence analysis is elusive. This Letter describes such an analysis, demonstrating that well-tempered metadynamics converges to the final state it was designed to reach and, therefore, that the simple formulas currently used to interpret the final converged state of tempered metadynamics are correct and exact. The results do not rely on any assumption that the collective variable dynamics are effectively Brownian or any idealizations of the hill deposition function; instead, they suggest new, more permissive criteria for the method to be well behaved. The results apply to tempered metadynamics with or without adaptive Gaussians or boundary corrections and whether the bias is stored approximately on a grid or exactly.

Free energy profile of RNA hairpins: a molecular dynamics simulation study.

PubMed

Deng, Nan-Jie; Cieplak, Piotr

2010-02-17

RNA hairpin loops are one of the most abundant secondary structure elements and participate in RNA folding and protein-RNA recognition. To characterize the free energy surface of RNA hairpin folding at an atomic level, we calculated the potential of mean force (PMF) as a function of the end-to-end distance, by using umbrella sampling simulations in explicit solvent. Two RNA hairpins containing tetraloop cUUCGg and cUUUUg are studied with AMBER ff99 and CHARMM27 force fields. Experimentally, the UUCG hairpin is known to be significantly more stable than UUUU. In this study, the calculations using AMBER force field give a qualitatively correct description for the folding of two RNA hairpins, as the calculated PMF confirms the global stability of the folded structures and the resulting relative folding free energy is in quantitative agreement with the experimental result. The hairpin stabilities are also correctly differentiated by the more rapid molecular mechanics-Poisson Boltzmann-surface area approach, but the relative free energy estimated from this method is overestimated. The free energy profile shows that the native state basin and the unfolded state plateau are separated by a wide shoulder region, which samples a variety of native-like structures with frayed terminal basepair. The calculated PMF lacks major barriers that are expected near the transition regions, and this is attributed to the limitation of the 1-D reaction coordinate. The PMF results are compared with other studies of small RNA hairpins using kinetics method and coarse grained models. The two RNA hairpins described by CHARMM27 are significantly more deformable than those represented by AMBER. Compared with the AMBER results, the CHARMM27 calculated DeltaG(fold) for the UUUU tetraloop is in better agreement with the experimental results. However, the CHARMM27 calculation does not confirm the global stability of the experimental UUCG structure; instead, the extended conformations are predicted to be thermodynamically stable in solution. This finding is further supported by separate unrestrained CHARMM27 simulations, in which the UUCG hairpin unfolds spontaneously within 10 ns. The instability of the UUCG hairpin originates from the loop region, and propagates to the stem. The results of this study provide a molecular picture of RNA hairpin unfolding and reveal problems in the force field descriptions for the conformational energy of certain RNA hairpin. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The changing face of Hanford security 1990--1994

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

Thielman, J.

The meltdown of the Cold War was a shock to the systems built to cope with it. At the DOE`s Hanford Site in Washington State, a world-class safeguards and security system was suddenly out of step with the times. The level of protection for nuclear and classified materials was exceptional. But the cost was high and the defense facilities that funded security were closing down. The defense mission had created an umbrella of security over the sprawling Hanford Site. Helicopters designed to ferry special response teams to any trouble spot on the 1,456 square-kilometer site made the umbrella analogy almostmore » literally true. Facilities were grouped into areas, fenced off like a military base, and entrance required a badge check for everyone. Within the fence, additional rings of protection were set up around security interests or targets. The security was effective, but costly to operate and inconvenient for employees and visitors alike. Moreover, the umbrella meant that virtually all employees needed a security clearance just to get to work, whether they worked on classified or unclassified projects. Clearly, some fundamental rethinking of safeguards and security was needed. The effort to meet that challenge is the story of transition at Hanford and documented here.« less

The most popular terms for medically unexplained symptoms: the views of CFS patients.

PubMed

Picariello, Federica; Ali, Sheila; Moss-Morris, Rona; Chalder, Trudie

2015-05-01

Medically unexplained symptoms/syndromes are common, highly distressing and are often associated with profound disability. One of the controversies surrounding this area relates to which umbrella term should be used to group such symptoms. The purpose of this research was to establish the preferences of patients with chronic fatigue syndrome (CFS) for an umbrella term for medically unexplained symptoms. A cross-sectional mixed methods survey design was used. Participants were asked to indicate their three most preferred terms out of a list of commonly used terms and to provide any extra comments. Frequency analysis was employed to look at the preferences of terms for each rank. Comments were analysed using principles of inductive thematic analysis. Eighty-seven patients with CFS completed a self-report survey. The term "Persistent Physical Symptoms" was the most popular first choice term chosen by 20.7% of patients. Terms containing the word "physical" were consistently more likely to be chosen. Three main themes emerged from the thematic analysis: 1) Physical nature of the illness, 2) Stigma, and 3) Evaluation of the terms, giving a more in-depth understanding of the findings. According to CFS patients, an umbrella term has to reflect the physical experience of MUS. Copyright © 2015 Elsevier Inc. All rights reserved.

Behavioral determinants of physical activity across the life course: a "DEterminants of DIet and Physical ACtivity" (DEDIPAC) umbrella systematic literature review.

PubMed

Condello, Giancarlo; Puggina, Anna; Aleksovska, Katina; Buck, Christoph; Burns, Con; Cardon, Greet; Carlin, Angela; Simon, Chantal; Ciarapica, Donatella; Coppinger, Tara; Cortis, Cristina; D'Haese, Sara; De Craemer, Marieke; Di Blasio, Andrea; Hansen, Sylvia; Iacoviello, Licia; Issartel, Johann; Izzicupo, Pascal; Jaeschke, Lina; Kanning, Martina; Kennedy, Aileen; Ling, Fiona Chun Man; Luzak, Agnes; Napolitano, Giorgio; Nazare, Julie-Anne; Perchoux, Camille; Pesce, Caterina; Pischon, Tobias; Polito, Angela; Sannella, Alessandra; Schulz, Holger; Sohun, Rhoda; Steinbrecher, Astrid; Schlicht, Wolfgang; Ricciardi, Walter; MacDonncha, Ciaran; Capranica, Laura; Boccia, Stefania

2017-05-02

Low levels of physical activity (PA) are a global concern and increasing PA engagement is becoming a priority in current public health policies. Despite the large number of studies and reviews available, the evidence regarding the behavioral determinants of PA is still inconclusive. Thus, the aim of this umbrella systematic literature review (SLR) was to summarize the evidence on the behavioral determinants of PA across the life course. A systematic online search was conducted on MEDLINE, ISI Web of Science, Scopus, and SPORTDiscus databases. The search was limited to studies published in English from January, 2004 to April, 2016. SLRs and meta-analyses (MAs) of observational studies that investigated the behavioral determinants of PA were considered eligible. The extracted data were assessed based on the importance of the determinants, the strength of evidence, and the methodological quality. The full protocol is available from PROSPERO (PROSPERO 2014:CRD42015010616). Seventeen reviews on 35 behavioral determinants of PA were eligible for this umbrella SLR. Regardless of age, the most investigated determinants were those related with 'screen use' and 'smoking'. For youth, probable positive evidence emerged for 'previous PA' and 'independent mobility and active transport' among children and adolescents. For the adult population, 'transition to university' and 'pregnancy/having a child' showed probable negative associations. Although the majority of the evidence was limited and most of the determinants were not associated with PA, this umbrella SLR provided a comprehensive overview of the associations between behavioral determinants and PA. Youth should be physically active in the early years and increase active transportation to/from school, independent mobility, and 'free-range activities' without adult supervision, whilst adult PA behaviors are mostly influenced by the life events. Finally, more research is needed that incorporates prospective study designs, standardized definitions of PA, objective measurement methods of PA assessment, and the use of interactionist and mediational approaches for the evaluation of different behavioral determinants influencing PA behaviors.

The macro-economic determinants of health and health inequalities-umbrella review protocol.

PubMed

Naik, Yannish; Baker, Peter; Walker, Ian; Tillmann, Taavi; Bash, Kristin; Quantz, Darryl; Hillier-Brown, Frances; Bambra, Clare

2017-11-03

The economic determinants of health have been widely recognised as crucial factors affecting health; however, to date, no comprehensive review has been undertaken to summarise these factors and the ways in which they can influence health. We conceptualise the economy as a complex system made up of underlying approaches, regulation from institutions, markets, finance, labour, the public-private balance as well as production and distributional effects, which collectively impact on health through the effect of moderators. This protocol details the methods for an umbrella review to explore the macro-economic factors, strategies, policies and interventions that affect health outcomes and health inequalities. We will identify relevant systematic reviews using search terms derived from the Journal of Economic Literature classification. Reviews will be included if they meet the Database of Abstracts and Reviews of Effects criteria for systematic reviews. Reviews of studies with and without controls will be included; both association and intervention studies will be included. Primary outcomes will include but are not limited to morbidity, mortality, prevalence and incidence of conditions and life expectancy. Secondary outcomes will include health inequalities by gender, ethnicity or socio-economic status. Six databases will be searched using tailored versions of our piloted search strategy to locate relevant reviews. Data will be extracted using a standardized pro forma, and the findings will be synthesized into a conceptual framework to address our review aim. Our umbrella review protocol provides a robust method to systematically appraise the evidence in this field, using new conceptual models derived specifically to address the study question. This will yield important information for policymakers, practitioners and researchers at the local, national and international level. It will also help set the future research agenda in this field and guide the development of interventions. This umbrella review protocol has been registered with PROSPERO CRD42017068357 .

Selecting a Conservation Surrogate Species for Small Fragmented Habitats Using Ecological Niche Modelling

PubMed Central

Nekaris, K. Anne-Isola; Arnell, Andrew P.; Svensson, Magdalena S.

2015-01-01

Simple Summary Large “charismatic” animals (with widespread popular appeal) are often used as flagship species to raise awareness for conservation. Deforestation and forest fragmentation are among the main threats to biodiversity, and in many places such species are disappearing. In this paper we aim to find a suitable species among the less charismatic animal species left in the fragmented forests of South-western Sri Lanka. We selected ten candidates, using a questionnaire survey along with computer modelling of their distributions. The red slender loris and the fishing cat came out as finalists as they were both appealing to local people, and fulfilled selected ecological criteria. Abstract Flagship species are traditionally large, charismatic animals used to rally conservation efforts. Accepted flagship definitions suggest they need only fulfil a strategic role, unlike umbrella species that are used to shelter cohabitant taxa. The criteria used to select both flagship and umbrella species may not stand up in the face of dramatic forest loss, where remaining fragments may only contain species that do not suit either set of criteria. The Cinderella species concept covers aesthetically pleasing and overlooked species that fulfil the criteria of flagships or umbrellas. Such species are also more likely to occur in fragmented habitats. We tested Cinderella criteria on mammals in the fragmented forests of the Sri Lankan Wet Zone. We selected taxa that fulfilled both strategic and ecological roles. We created a shortlist of ten species, and from a survey of local perceptions highlighted two finalists. We tested these for umbrella characteristics against the original shortlist, utilizing Maximum Entropy (MaxEnt) modelling, and analysed distribution overlap using ArcGIS. The criteria highlighted Loris tardigradus tardigradus and Prionailurus viverrinus as finalists, with the former having highest flagship potential. We suggest Cinderella species can be effective conservation surrogates especially in habitats where traditional flagship species have been extirpated. PMID:26479135

The Dynamics of Volcanic Umbrella Clouds

NASA Astrophysics Data System (ADS)

Tait, S.; Kaminski, E. C.; Carazzo, G.; Limare, A.

2017-12-01

Atmospheric injection of volcanic ash during explosive eruptions is controlled by the dynamics of a volcanic column and associated umbrella cloud, which are subject to a wind field, and are connected by a turbulent fountain which initiates horizontal spreading at the neutral buoyancy level. We present a new theoretical and experimental study of an axisymmetric turbulent umbrella cloud intruding horizontally at its neutral buoyancy level into a static environment linearly stratified in density. The intrusion is fed by a constant horizontal volume flux (Q0) at a finite radius (R0), where it has a constant thickness (2H0). The characteristics of the fountain (R0, H0, Q0) derive from a vertical forced plume (source momentum and buoyancy fluxes Mi , Fi) and environmental stratification N. Buoyancy drives horizontal flow but, despite high Reynolds number, impedes entrainment of ambient fluid into the umbrella cloud. Turbulent stresses are nevertheless crucial in the momentum balance. Our theory highlights the vertical profiles of density and velocity within the current of which we present experimental measurements. Initially, current buoyancy is opposed by the inertia of the ambient fluid, and current radius (RN(t)) grows linearly in time. Subsequently, turbulent drag opposes buoyancy, and the current breaks down into two parts: i) between the source and a transition radius (R0T(t)), a steady region where current thickness (2H) and mean velocity (U) are time-independent and decreasing functions of r ; ii), a contiguous unsteady « frontal » region, between the transition radius and the front (RTN), in which the current thickens. The theory predicts current shape and an asymptotic spreading behaviour (RN t^5/9) which agree well with experimental data. Our analysis of satellite observations of several sustained plinian events including the Pinatubo 1991 climactic eruption shows that both the initial and asymptotic spreading regimes predicted by the model are present.

Students' Development of Representational Competence Through the Sense of Touch

NASA Astrophysics Data System (ADS)

Magana, Alejandra J.; Balachandran, Sadhana

2017-06-01

Electromagnetism is an umbrella encapsulating several different concepts like electric current, electric fields and forces, and magnetic fields and forces, among other topics. However, a number of studies in the past have highlighted the poor conceptual understanding of electromagnetism concepts by students even after instruction. This study aims to identify novel forms of "hands-on" instruction that can result in representational competence and conceptual gain. Specifically, this study aimed to identify if the use of visuohaptic simulations can have an effect on student representations of electromagnetic-related concepts. The guiding questions is How do visuohaptic simulations influence undergraduate students' representations of electric forces? Participants included nine undergraduate students from science, technology, or engineering backgrounds who participated in a think-aloud procedure while interacting with a visuohaptic simulation. The think-aloud procedure was divided in three stages, a prediction stage, a minimally visual haptic stage, and a visually enhanced haptic stage. The results of this study suggest that students' accurately characterized and represented the forces felt around a particle, line, and ring charges either in the prediction stage, a minimally visual haptic stage or the visually enhanced haptic stage. Also, some students accurately depicted the three-dimensional nature of the field for each configuration in the two stages that included a tactile mode, where the point charge was the most challenging one.

The 1815 Tambora ash fall: implications for transport and deposition of distal ash on land and in the deep sea

NASA Astrophysics Data System (ADS)

Kandlbauer, Jessica; Carey, Steven N.; Sparks, R. Stephen J.

2013-04-01

Tambora volcano lies on the Sanggar Peninsula of Sumbawa Island in the Indonesian archipelago. During the great 1815 explosive eruption, the majority of the erupted pyroclastic material was dispersed and subsequently deposited into the Indian Ocean and Java Sea. This study focuses on the grain size distribution of distal 1815 Tambora ash deposited in the deep sea compared to ash fallen on land. Grain size distribution is an important factor in assessing potential risks to aviation and human health, and provides additional information about the ash transport mechanisms within volcanic umbrella clouds. Grain size analysis was performed using high precision laser diffraction for a particle range of 0.2 μm-2 mm diameter. The results indicate that the deep-sea samples provide a smooth transition to the land samples in terms of grain size distributions despite the different depositional environments. Even the very fine ash fraction (<10 μm) is deposited in the deep sea, suggesting vertical density currents as a fast and effective means of transport to the seafloor. The measured grain size distribution is consistent with an improved atmospheric gravity current sedimentation model that takes into account the finite duration of an eruption. In this model, the eruption time and particle fall velocity are the critical parameters for assessing the ash component depositing while the cloud advances versus the ash component depositing once the eruption terminates. With the historical data on eruption duration (maximum 24 h) and volumetric flow rate of the umbrella cloud (˜1.5-2.5 × 1011 m3/s) as input to the improved model, and assuming a combination of 3 h Plinian phase and 21 h co-ignimbrite phase, it reduces the mean deviation of the predicted versus observed grain size distribution by more than half (˜9.4 % to ˜3.7 %) if both ash components are considered.

Effects of Rolling and Cooling Conditions on Microstructure of Umbrella-Bone Steel

NASA Astrophysics Data System (ADS)

Wu, Yan-Xin; Fu, Jian-Xun; Zhang, Hua; Xu, Jie; Zhai, Qi-Jie

2017-10-01

The effects of deformation temperature and cooling rate on the micro-structure evolution of umbrella-bone steel was investigated using a Gleeble thermal-mechanical testing machine and dynamic continuous cooling transformation (CCT) curves. The results show that fast cooling which lowers the starting temperature of ferrite transformation leads to finer ferrite grains and more pearlite. Low temperature deformation enhances the hardening effect of austenite and reduces hardenability, allowing a wider range of cooling rates and thus avoiding martensite transformation after deformation. According to the phase transformation rules, the ultimate tensile strength and reduction in area of the wire rod formed in the optimized industrial trial are 636 MPa and 73.6 %, respectively, showing excellent strength and plasticity.

Investigations of belukha whales in coastal waters of western and northern Alaska, 1982-1983: marking and tracking of whales in Bristol Bay

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

Frost, K.J.; Lowry, L.F.; Nelson, R.R.

1983-12-01

A 2-year study was conducted in Bristol Bay, Alaska, to develop and test techniques for marking belukha whales with visual and radio tags. Information was also gathered on belukha distribution and abundance, foods and feeding, and rates and causes of mortality. Two types of radio packages were developed: an OAR backpack designed to be bolted through the dorsal ridge, and a Telonics barnacle tag with an umbrella-stake attachment. Testing of tags and attachments revealed that the more-powerful OAR radio could be received at longer distances and lower antenna heights, and the the umbrella-stake attachment penetrated too deeply for reliable usemore » on belukhas.« less

Replica Exchange Molecular Dynamics in the Age of Heterogeneous Architectures

NASA Astrophysics Data System (ADS)

Roitberg, Adrian

2014-03-01

The rise of GPU-based codes has allowed MD to reach timescales only dreamed of only 5 years ago. Even within this new paradigm there is still need for advanced sampling techniques. Modern supercomputers (e.g. Blue Waters, Titan, Keeneland) have made available to users a significant number of GPUS and CPUS, which in turn translate into amazing opportunities for dream calculations. Replica-exchange based methods can optimally use tis combination of codes and architectures to explore conformational variabilities in large systems. I will show our recent work in porting the program Amber to GPUS, and the support for replica exchange methods, where the replicated dimension could be Temperature, pH, Hamiltonian, Umbrella windows and combinations of those schemes.

Nonpharmacologic, nonherbal management of menopause-associated vasomotor symptoms: an umbrella systematic review (protocol).

PubMed

Goldstein, Karen M; McDuffie, Jennifer R; Shepherd-Banigan, Megan; Befus, Deanna; Coeytaux, Remy R; Van Noord, Megan G; Goode, Adam P; Masilamani, Varsha; Adam, Soheir; Nagi, Avishek; Williams, John W

2016-04-07

Vasomotor symptoms such as hot flashes and night sweats are a common concern of perimenopausal and postmenopausal women and are associated with a decreased quality of life. These symptoms can be effectively managed with hormone therapy, but safety concerns limit its use. Thus, understanding the effectiveness of nonpharmacologic therapies such as acupuncture or yoga is critical to managing these common symptoms in older women. Our review seeks to address the following question: In women with menopause-associated vasomotor symptoms, what are the effects on health-related quality of life, vasomotor symptoms, and adverse events of the following nonpharmacologic, nonherbal interventions as compared with any inactive control or active comparator: (a) acupuncture, (b) yoga, tai chi, and qigong, (c) structured exercise, and (d) meditation, mindfulness-based practices, and relaxation? We describe a protocol for an umbrella review approach, supplemented by evaluating randomized controlled trials (RCTs) published after the most recent good-quality systematic review for each of the eligible interventions. Specific interventions were chosen based on current literature and with input from a technical expert panel and organizational stakeholders. We will conduct a thorough literature search and perform a quality assessment of potentially included systematic reviews and RCTs. Our umbrella review, supplemented by an additional search for eligible RCTs, aims to synthesize existing evidence on the use of nonpharmacologic, nonherbal interventions to manage bothersome vasomotor symptoms in perimenopausal and postmenopausal women. PROSPERO CRD42016029335.

Uroplakins, specific membrane proteins of urothelial umbrella cells, as histological markers of metastatic transitional cell carcinomas.

PubMed Central

Moll, R.; Wu, X. R.; Lin, J. H.; Sun, T. T.

1995-01-01

Uroplakins (UPs) Ia, Ib, II, and III, transmembrane proteins constituting the asymmetrical unit membrane of urothelial umbrella cells, are the first specific urothelial differentiation markers described. We investigated the presence and localization patterns of UPs in various human carcinomas by applying immunohistochemistry (avidin-biotin-peroxidase complex method), using rabbit antibodies against UPs II and III, to paraffin sections. Positive reactions for UP III (sometimes very focal) were noted in 14 of the 16 papillary noninvasive transitional cell carcinomas (TCCs) (88%), 29 of the 55 invasive TCCs (53%), and 23 of the 35 TCC metastases (66%). Different localization patterns of UPs could be distinguished, including superficial membrane staining like that found in normal umbrella cells (in papillary carcinoma), luminal (microluminal) membrane staining (in papillary and invasive carcinoma), and, against expectations, peripheral membrane staining (in invasive carcinoma). Non-TCC carcinomas of various origins (n = 177) were consistently negative for UPs. The presence of UPs in metastatic TCCs represents a prime example of even advanced tumor progression being compatible with the (focal) expression of highly specialized differentiation repertoires. Although of only medium-grade sensitivity, UPs do seem to be highly specific urothelial lineage markers, thus operating up interesting histodiagnostic possibilities in cases of carcinoma metastases of uncertain origin. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:7485401

Theoretical study of the vibrational relaxation of the methyl radical in collisions with helium

NASA Astrophysics Data System (ADS)

Ma, Qianli; Dagdigian, Paul J.; Alexander, Millard H.

2013-03-01

We report a theoretical investigation of the relaxation of the umbrella vibrational mode (the ν2 mode) of the CH3 molecule in its ground tilde{X}^2A_2^' ' } electronic state in collisions with helium. We have calculated a four-dimensional potential energy surface (PES) for the interaction between CH3 with different umbrella displacements and a helium atom, using a restricted open-shell coupled-cluster method with inclusion of all single, double, and (perturbatively) triple excitations [RCCSD(T)]. With this PES we carried out full close-coupling scattering calculations including all CH3 umbrella-rotational levels with v2 ⩽ 3. To our knowledge, this work represents the first fully quantum calculations of ro-vibrational relaxation of a polyatomic. In more detail, we investigate propensities in the calculated ro-vibrational cross sections and the dependence on initial rotational excitation, as well as determining thermal rate constants. Overall, ro-vibrational relaxation is nearly two orders of magnitude less efficient than pure-rotational relaxation, with a noticeable dependence on the initial rotational level. We predict the room temperature v2 = 1 vibrational relaxation rate constant to be 5.4 × 10-12 cm3 molecule-1 s-1, compared to the rate constants for pure-rotational relaxation of the lower rotational levels (˜2.0 × 10-10 cm3 molecule-1 s-1).

A new minimally invasive heart surgery instrument for atrial fibrillation treatment: first in vitro and animal tests.

PubMed

Abadie, J; Faure, A; Chaillet, N; Rougeot, P; Beaufort, D; Goldstein, J P; Finlay, P A; Bogaerts, G

2006-06-01

The paper presents a new robotic system for beating heart surgery. The final goal of this project is to develop a tele-operated system for the thoracoscopic treatment of patients with atrial fibrillation. The system consists of a robot that moves an innovative end-effector used to perform lines as in the Cox-Maze technique. The device is an electrode mesh that is introduced in the thorax through a trocar and is deployed inside the left atrium, where it can create selective ablation lines at any atrial region, using radio frequency. The current version of the umbrella has 22 electrodes. Using visual feedback from an ultrasound based navigation system, the surgeon can choose which electrodes on the mesh to activate. Once the umbrella is in contact with the endocardium of the left atrium, at the expected position, the surgeon activates the chosen electrodes sequentially. The umbrella can then be moved to another position. In vitro and in vivo animal tests have been carried out in order to test and improve the instrument, the robotic system and the operative procedure. The performed trials proved the ability of the system to treat atrial fibrillation. More in vivo tests are currently being performed to make the robot and its device ready for clinical use. Copyright 2006 John Wiley & Sons, Ltd.

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

PubMed Central

Zheng, Weihua; Tsai, Min-Yeh; Chen, Mingchen; Wolynes, Peter G.

2016-01-01

A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1–40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer’s disease. PMID:27698130

Thiol Versus Hydroxamate as Zinc Binding Group In HDAC Inhibition: An Ab Initio QM/MM Molecular Dynamics Study

PubMed Central

Gong, Wenjing; Wu, Ruibo; Zhang, Yingkai

2015-01-01

Zinc-dependent histone deacetylases (HDACs) play a critical role in transcriptional repression and gene silencing, and are among the most attractive targets for the development of new therapeutics against cancer and various other diseases. Two HDAC inhibitors have been approved by FDA as anti-cancer drugs: one is SAHA whose hydroxamate is directly bound to zinc, the other is FK228 whose active form may use thiol as the zinc binding group. In spite of extensive studies, it remains to be ambiguous regarding how thiol and hydroxamate are bound to the zinc active site of HDACs. In this work, our computational approaches center on Born-Oppenheimer ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics with umbrella sampling, which allow for modeling of the zinc active site with reasonable accuracy while properly including dynamics and effects of protein environment. Meanwhile, an improved short-long effective function (SLEF2) to describe non-bonded interactions between zinc and other atoms has been employed in initial MM equilibrations. Our ab initio QM/MM MD simulations have confirmed that hydroxamate is neutral when it is bound to HDAC8, and found that thiol is deprotonated when directly bound to zinc in the HDAC active site. By comparing thiol and hydroxamate, our results elucidated the differences in their binding environment in the HDAC active sites, and emphasized the importance of the linker design to achieve more specific binding towards class IIa HDACs. PMID:26452222

Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.

PubMed

Gong, Wenjing; Wu, Ruibo; Zhang, Yingkai

2015-11-15

Zinc-dependent histone deacetylases (HDACs) play a critical role in transcriptional repression and gene silencing, and are among the most attractive targets for the development of new therapeutics against cancer and various other diseases. Two HDAC inhibitors have been approved by FDA as anti-cancer drugs: one is SAHA whose hydroxamate is directly bound to zinc, the other is FK228 whose active form may use thiol as the zinc binding group. In spite of extensive studies, it remains to be ambiguous regarding how thiol and hydroxamate are bound to the zinc active site of HDACs. In this work, our computational approaches center on Born-Oppenheimer ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics with umbrella sampling, which allow for modeling of the zinc active site with reasonable accuracy while properly including dynamics and effects of protein environment. Meanwhile, an improved short-long effective function (SLEF2) to describe non-bonded interactions between zinc and other atoms has been employed in initial MM equilibrations. Our ab initio QM/MM MD simulations have confirmed that hydroxamate is neutral when it is bound to HDAC8, and found that thiol is deprotonated when directly bound to zinc in the HDAC active site. By comparing thiol and hydroxamate, our results elucidated the differences in their binding environment in the HDAC active sites, and emphasized the importance of the linker design to achieve more specific binding toward class IIa HDACs. © 2015 Wiley Periodicals, Inc.

Modified Amber Force Field Correctly Models the Conformational Preference for Tandem GA pairs in RNA

PubMed Central

2015-01-01

Molecular mechanics with all-atom models was used to understand the conformational preference of tandem guanine-adenine (GA) noncanonical pairs in RNA. These tandem GA pairs play important roles in determining stability, flexibility, and structural dynamics of RNA tertiary structures. Previous solution structures showed that these tandem GA pairs adopt either imino (cis Watson–Crick/Watson–Crick A-G) or sheared (trans Hoogsteen/sugar edge A-G) conformations depending on the sequence and orientation of the adjacent closing base pairs. The solution structures (GCGGACGC)2 [Biochemistry, 1996, 35, 9677–9689] and (GCGGAUGC)2 [Biochemistry, 2007, 46, 1511–1522] demonstrate imino and sheared conformations for the two central GA pairs, respectively. These systems were studied using molecular dynamics and free energy change calculations for conformational changes, using umbrella sampling. For the structures to maintain their native conformations during molecular dynamics simulations, a modification to the standard Amber ff10 force field was required, which allowed the amino group of guanine to leave the plane of the base [J. Chem. Theory Comput., 2009, 5, 2088–2100] and form out-of-plane hydrogen bonds with a cross-strand cytosine or uracil. The requirement for this modification suggests the importance of out-of-plane hydrogen bonds in stabilizing the native structures. Free energy change calculations for each sequence demonstrated the correct conformational preference when the force field modification was used, but the extent of the preference is underestimated. PMID:24803859

Umbrella project for Bangladesh: strengthening NGO capacity and linkages to improve reproductive health service and information. RAS/98/P55.

PubMed

1999-06-01

In Bangladesh, the UN Population Fund is working to strengthen nongovernmental organization (NGO) capacity and linkages to improve reproductive health services and information. Specifically, the aim is to strengthen the technical and human resource capacity of participating NGOs and the functional linkages between national NGOs and relevant government agencies to help harmonize and standardize the delivery of reproductive health information and services. This umbrella project collaborates with RHI-participating NGOs in a policy paper on adolescent reproductive health, and will maintain contact with the regional dimension project to collaborate its activities. Programs implemented by partner NGOs are being reviewed and monitored, and linkages among national NGOs and government agencies are being developed. The main activities of the project are enumerated.

Biotechnology Process Engineering Center at MIT Home

Science.gov Websites

BPEC Definition 77 Massachusetts Avenue, Building 16 Room 429, Cambridge, MA 02139 Telephone (617 Leadership Council Facilities | Umbrella Programs | Events | News | Links | MIT | National Science Foundation

Free energy landscape and transition pathways from Watson-Crick to Hoogsteen base pairing in free duplex DNA.

PubMed

Yang, Changwon; Kim, Eunae; Pak, Youngshang

2015-09-18

Houghton (HG) base pairing plays a central role in the DNA binding of proteins and small ligands. Probing detailed transition mechanism from Watson-Crick (WC) to HG base pair (bp) formation in duplex DNAs is of fundamental importance in terms of revealing intrinsic functions of double helical DNAs beyond their sequence determined functions. We investigated a free energy landscape of a free B-DNA with an adenosine-thymine (A-T) rich sequence to probe its conformational transition pathways from WC to HG base pairing. The free energy landscape was computed with a state-of-art two-dimensional umbrella molecular dynamics simulation at the all-atom level. The present simulation showed that in an isolated duplex DNA, the spontaneous transition from WC to HG bp takes place via multiple pathways. Notably, base flipping into the major and minor grooves was found to play an important role in forming these multiple transition pathways. This finding suggests that naked B-DNA under normal conditions has an inherent ability to form HG bps via spontaneous base opening events. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Decision and cost-utility analyses of surgical versus transcatheter closure of patent ductus arteriosus: should you let a smile be your umbrella?

PubMed

Gray, D T; Weinstein, M C

1998-01-01

Decision and cost-utility analyses considered the tradeoffs of treating patent ductus arteriosus (PDA) using conventional surgery versus transcatheter implantation of the Rashkind occluder. Physicians and informed lay parents assigned utility scores to procedure success/complications combinations seen in prognostically similar pediatric patients with isolated PDA treated from 1982 to 1987. Utility scores multiplied by outcome frequencies from a comparative study generated expected utility values for the two approaches. Cost-utility analyses combined these results with simulated provider cost estimates from 1989. On a 0-100 scale (worst to best observed outcome), the median expected utility for surgery was 99.96, versus 98.88 for the occluder. Results of most sensitivity analyses also slightly favored surgery. Expected utility differences based on 1987 data were minimal. With a mean overall simulated cost of $8,838 vs $12,466 for the occluder, surgery was favored in most cost-utility analyses. Use of the inherently less invasive but less successful, more risky, and more costly occluder approach conferred no apparent net advantage in this study. Analyses of comparable current data would be informative.

Dose-response relationship between cigarette smoking and site-specific cancer risk: protocol for a systematic review with an original design combining umbrella and traditional reviews.

PubMed

Lugo, Alessandra; Bosetti, Cristina; Peveri, Giulia; Rota, Matteo; Bagnardi, Vincenzo; Gallus, Silvano

2017-11-01

Only a limited number of meta-analyses providing risk curve functions of dose-response relationships between various smoking-related variables and cancer-specific risk are available. To identify all relevant original publications on the issue, we will conduct a series of comprehensive systematic reviews based on three subsequent literature searches: (1) an umbrella review, to identify meta-analyses, pooled analyses and systematic reviews published before 28 April 2017 on the association between cigarette smoking and the risk of 28 (namely all) malignant neoplasms; (2) for each cancer site, an updated review of original publications on the association between cigarette smoking and cancer risk, starting from the last available comprehensive review identified through the umbrella review; and (3) a review of all original articles on the association between cigarette smoking and site-specific cancer risk included in the publications identified through the umbrella review and the updated reviews. The primary outcomes of interest will be (1) the excess incidence/mortality of various cancers for smokers compared with never smokers; and (2) the dose-response curves describing the association between smoking intensity, duration and time since stopping and incidence/mortality for various cancers. For each cancer site, we will perform a meta-analysis by pooling study-specific estimates for smoking status. We will also estimate the dose-response curves for other smoking-related variables through random-effects meta-regression models based on a non-linear dose-response relationship framework. Ethics approval is not required for this study. Main results will be published in peer-reviewed journals and will also be included in a publicly available website. We will provide therefore the most complete and updated estimates on the association between various measures of cigarette smoking and site-specific cancer risk. This will allow us to obtain precise estimates on the cancer burden attributable to cigarette smoking. This protocol was registered in the International Prospective Register of Systematic Reviews (CRD42017063991). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The solar ultraviolet B radiation protection provided by shading devices with regard to its diffuse component.

PubMed

Kudish, Avraham I; Harari, Marco; Evseev, Efim G

2011-10-01

The composition of the incident solar global ultraviolet B (UVB) radiation with regard to its beam and diffuse radiation fractions is highly relevant with regard to outdoor sun protection. This is especially true with respect to sun protection during leisure-time outdoor sun exposure at the shore and pools, where people tend to escape the sun under shade trees or different types of shading devices, e.g., umbrellas, overhangs, etc., believing they offer protection from the erythemal solar radiation. The degree of sun protection offered by such devices is directly related to the composition of the solar global UVB radiation, i.e., its beam and diffuse fractions. The composition of the incident solar global UVB radiation can be determined by measuring the global UVB (using Solar Light Co. Inc., Model 501A UV-Biometer) and either of its components. The beam component of the UVB radiation was determined by measuring the normal incidence beam radiation using a prototype, tracking instrument consisting of a Solar Light Co. Inc. Model 501A UV-Biometer mounted on an Eppley Solar Tracker Model St-1. The horizontal beam component of the global UVB radiation was calculated from the measured normal incidence using a simple geometric correlation and the diffuse component is determined as the difference between global and horizontal beam radiations. Horizontal and vertical surfaces positioned under a horizontal overhang/sunshade or an umbrella are not fully protected from exposure to solar global UVB radiation. They can receive a significant fraction of the UVB radiation, depending on their location beneath the shading device, the umbrella radius and the albedo (reflectance) of the surrounding ground surface in the case of a vertical surface. Shading devices such as an umbrella or horizontal overhang/shade provide relief from the solar global radiation and do block the solar global UVB radiation to some extent; nevertheless, a significant fraction of the solar global UVB radiation does penetrate this supposedly 'protective or comfort zone'. As a result, it is imperative to either apply sunscreen or cover up the exposed body surfaces even when under such shading devices. © 2011 John Wiley & Sons A/S.

Effect of acetone accumulation on structure and dynamics of lipid membranes studied by molecular dynamics simulations.

PubMed

Posokhov, Yevgen O; Kyrychenko, Alexander

2013-10-01

The modulation of the properties and function of cell membranes by small volatile substances is important for many biomedical applications. Despite available experimental results, molecular mechanisms of action of inhalants and organic solvents, such as acetone, on lipid membranes remain not well understood. To gain a better understanding of how acetone interacts with membranes, we have performed a series of molecular dynamics (MD) simulations of a POPC bilayer in aqueous solution in the presence of acetone, whose concentration was varied from 2.8 to 11.2 mol%. The MD simulations of passive distribution of acetone between a bulk water phase and a lipid bilayer show that acetone favors partitioning into the water-free region of the bilayer, located near the carbonyl groups of the phospholipids and at the beginning of the hydrocarbon core of the lipid membrane. Using MD umbrella sampling, we found that the permeability barrier of ~0.5 kcal/mol exists for acetone partitioning into the membrane. In addition, a Gibbs free energy profile of the acetone penetration across a bilayer demonstrates a favorable potential energy well of -3.6 kcal/mol, located at 15-16Å from the bilayer center. The analysis of the structural and dynamics properties of the model membrane revealed that the POPC bilayer can tolerate the presence of acetone in the concentration range of 2.8-5.6 mol%. The accumulation of the higher acetone concentration of 11.2 mol% results, however, in drastic disordering of phospholipid packing and the increase in the membrane fluidity. The acetone molecules push the lipid heads apart and, hence, act as spacers in the headgroup region. This effect leads to the increase in the average headgroup area per molecule. In addition, the acyl tail region of the membrane also becomes less dense. We suggest, therefore, that the molecular mechanism of acetone action on the phospholipid bilayer has many common features with the effects of short chain alcohols, DMSO, and chloroform. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparing solvophobic and multivalent induced collapse in polyelectrolyte brushes

DOE PAGES

Jackson, Nicholas E.; Brettmann, Blair K.; Vishwanath, Venkatram; ...

2017-02-03

Here, coarse-grained molecular dynamics enhanced by free-energy sampling methods is used to examine the roles of solvophobicity and multivalent salts on polyelectrolyte brush collapse. Specifically, we demonstrate that while ostensibly similar, solvophobic collapsed brushes and multivalent-ion collapsed brushes exhibit distinct mechanistic and structural features. Notably, multivalent-induced heterogeneous brush collapse is observed under good solvent polymer backbone conditions, demonstrating that the mechanism of multivalent collapse is not contingent upon a solvophobic backbone. Umbrella sampling of the potential of mean-force (PMF) between two individual brush strands confirms this analysis, revealing starkly different PMFs under solvophobic and multivalent conditions, suggesting the role ofmore » multivalent “bridging” as the discriminating feature in trivalent collapse. Structurally, multivalent ions show a propensity for nucleating order within collapsed brushes, whereas poor-solvent collapsed brushes are more disordered; this difference is traced to the existence of a metastable PMF minimum for poor solvent conditions, and a global PMF minimum for trivalent systems, under experimentally relevant conditions.« less

Comparing solvophobic and multivalent induced collapse in polyelectrolyte brushes

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

Jackson, Nicholas E.; Brettmann, Blair K.; Vishwanath, Venkatram

Here, coarse-grained molecular dynamics enhanced by free-energy sampling methods is used to examine the roles of solvophobicity and multivalent salts on polyelectrolyte brush collapse. Specifically, we demonstrate that while ostensibly similar, solvophobic collapsed brushes and multivalent-ion collapsed brushes exhibit distinct mechanistic and structural features. Notably, multivalent-induced heterogeneous brush collapse is observed under good solvent polymer backbone conditions, demonstrating that the mechanism of multivalent collapse is not contingent upon a solvophobic backbone. Umbrella sampling of the potential of mean-force (PMF) between two individual brush strands confirms this analysis, revealing starkly different PMFs under solvophobic and multivalent conditions, suggesting the role ofmore » multivalent “bridging” as the discriminating feature in trivalent collapse. Structurally, multivalent ions show a propensity for nucleating order within collapsed brushes, whereas poor-solvent collapsed brushes are more disordered; this difference is traced to the existence of a metastable PMF minimum for poor solvent conditions, and a global PMF minimum for trivalent systems, under experimentally relevant conditions.« less

Clinical Laboratory Science: Applied Biology with Great Potential.

ERIC Educational Resources Information Center

Stanley, Melissa

1990-01-01

Described are a variety of careers under the umbrella of medical technology. The status of medical technology and medical technology education are discussed. Different curricula for medical technology are compared. (CW)

Biotechnology Process Engineering Center at MIT Home

Science.gov Websites

is speaking at the 2004 Congressional Biomedical Research Caucus Briefings on July 14th. Her briefing | Education & Outreach | Research | Industrial Programs | Student Leadership Council Facilities | Umbrella

Harmonic Fourier beads method for studying rare events on rugged energy surfaces.

PubMed

Khavrutskii, Ilja V; Arora, Karunesh; Brooks, Charles L

2006-11-07

We present a robust, distributable method for computing minimum free energy paths of large molecular systems with rugged energy landscapes. The method, which we call harmonic Fourier beads (HFB), exploits the Fourier representation of a path in an appropriate coordinate space and proceeds iteratively by evolving a discrete set of harmonically restrained path points-beads-to generate positions for the next path. The HFB method does not require explicit knowledge of the free energy to locate the path. To compute the free energy profile along the final path we employ an umbrella sampling method in two generalized dimensions. The proposed HFB method is anticipated to aid the study of rare events in biomolecular systems. Its utility is demonstrated with an application to conformational isomerization of the alanine dipeptide in gas phase.

Effects of collagen and collagen hydrolysate from jellyfish umbrella on histological and immunity changes of mice photoaging.

PubMed

Fan, Jian; Zhuang, Yongliang; Li, Bafang

2013-01-17

Jellyfish collagen (JC) was extracted from jellyfish umbrella and hydrolyzed to prepare jellyfish collagen hydrolysate (JCH). The effects of JC and JCH on UV-induced skin damage of mice were evaluated by the skin moisture, microscopic analyses of skin and immunity indexes. The skin moisture analyses showed that moisture retention ability of UV-induced mice skin was increased by JC and JCH. Further histological analysis showed that JC and JCH could repair the endogenous collagen and elastin protein fibers, and could maintain the natural ratio of type I to type III collagen. The immunity indexes showed that JC and JCH play a role in enhancing immunity of photoaging mice in vivo. JCH showed much higher protective ability than JC. These results suggest that JCH as a potential novel antiphotoaging agent from natural resources.

Health Benefits of Dietary Whole Grains: An Umbrella Review of Meta-analyses.

PubMed

McRae, Marc P

2017-03-01

The purpose of this study is to review the effectiveness of the role of whole grain as a therapeutic agent in type 2 diabetes, cardiovascular disease, cancer, and obesity. An umbrella review of all published meta-analyses was performed. A PubMed search from January 1, 1980, to May 31, 2016, was conducted using the following search strategy: (whole grain OR whole grains) AND (meta-analysis OR systematic review). Only English language publications that provided quantitative statistical analysis on type 2 diabetes, cardiovascular disease, cancer, and weight loss were retrieved. Twenty-one meta-analyses were retrieved for inclusion in this umbrella review, and all the meta-analyses reported statistically significant positive benefits for reducing the incidence of type 2 diabetes (relative risk [RR] = 0.68-0.80), cardiovascular disease (RR = 0.63-0.79), and colorectal, pancreatic, and gastric cancers (RR = 0.57-0.94) and a modest effect on body weight, waist circumference, and body fat mass. Significant reductions in cardiovascular and cancer mortality were also observed (RR = 0.82 and 0.89, respectively). Some problems of heterogeneity, publication bias, and quality assessment were found among the studies. This review suggests that there is some evidence for dietary whole grain intake to be beneficial in the prevention of type 2 diabetes, cardiovascular disease, and colorectal, pancreatic, and gastric cancers. The potential benefits of these findings suggest that the consumption of 2 to 3 servings per day (~45 g) of whole grains may be a justifiable public health goal.

[Comparative experiments of stripping sheep maxillary sinus mucosal with new-type stripper and umbrella detacher].

PubMed

Jiadong, Fan; Yanfeng, Li; Le, Liu; Yishi, Han; Pin, Hu; Yue, Zhang; Wenya, Bao

2016-10-01

To compare the stripping length obtained through the model of 0.012 and 0.014 of the nickel-titanium dual-stage maxillary sinus mucosa stripper, and the umbrella detacher. Twenty-four goats (1.5-2 years old) were chosen, randomly divided into A, B, C groups, each group of eight. Group A was 0.012 model group, group B was 0.014 model group, group C was umbrella detacher group. Animal model was established, and maxillary sinus mucosa was stripped to the left and right sides of the bottom of the sinus in three groups. The data was measured when stripping to the limit or being perforated. The average length of group A was 12.41 mm±4.35 mm, two cases perforated. The average length of group B was 23.38 mm±4.84 mm, one case perforated. The average length of group C was 2.61 mm±0.30 mm. The population mean of stripping length in three groups was not all the same calculated by analysis of variance (P<0.01). There were significant differences in the stripping length of the three groups by the SNK test (P<0.05). The nickel-titanium dual-stage maxillary sinus mucosa stripper can achieve a larger mucosal stripping range. The stripper with a model of 0.014 has a moderate flexibility and safety, and it can strip a large area of sinus mucosa.
.

Molecular dynamics simulations of glyphosate in a DPPC lipid bilayer.

PubMed

Frigini, Ezequiel N; López Cascales, J J; Porasso, Rodolfo D

2018-07-01

Extensive molecular dynamics simulations have been performed to study the effect of glyphosate (in their neutral and charged forms, GLYP and GLYP 2- , respectively) on fully hydrated DiPalmitoylPhosphatidylCholine (DPPC) lipid bilayer. First, we calculated the free energy profile (using the Umbrella Sampling technique) for both states of charge of glyphosate. The minimum value for the free energy for GLYP is ∼-60 kJ mol -1 located at z = ±1.7 nm (from the lipid bilayer center), and there is almost no maximum at the center of the lipid bilayer. By contrast, the minimum for GLYP 2- is ∼-35 kJ mol -1 located at z = ± 1.4 nm (from the lipid bilayer center), and the maximum reaches ∼35 kJ mol -1 at the center of the lipid bilayer. Then, different lipid bilayer properties were analyzed for different glyphosate:lipid (G:L) ratios. The mean area per lipid was slightly affected, increasing only 5% (in the presence of glyphosate at high concentrations), which is in agreement with the slight decrease in deuterium order parameters. As for the thickness of the bilayer, it is observed that the state of charge produces opposite effects. On one hand, the neutral state produces an increase in the thickness of the lipid bilayer; on the other, the charged form produces a decrease in the thickness, which not depend linearly on the G:L ratios, either. The orientation of the DPPC head groups is practically unaffected throughout the range of the G:L ratios studied. Finally, the mobility of the lipids of the bilayer is strongly affected by the presence of glyphosate, considerably increasing its lateral diffusion coefficient noteworthy (one order of magnitude), with increasing G:L ratio. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular mechanics of Staphylococcus aureus adhesin, CNA, and the inhibition of bacterial adhesion by stretching collagen

PubMed Central

Madani, Ali; Garakani, Kiavash

2017-01-01

Bacterial adhesion to collagen, the most abundant protein in humans, is a critical step in the initiation and persistence of numerous bacterial infections. In this study, we explore the collagen binding mechanism of the multi-modular cell wall anchored collagen adhesin (CNA) in Staphylococcus aureus and examine how applied mechanical forces can modulate adhesion ability. The common structural-functional elements and domain organization of CNA are present across over 50 genera of bacteria. Through the use of molecular dynamics models and normal mode analysis, we shed light on the CNA’s structural and conformational dynamics and its interactions with collagen that lead to collagen binding. Our results suggest that the linker region, CNA165-173, acts as a hinge exhibiting bending, extensional, and torsional modes of structural flexibility and its residues are key in the interaction of the CNA-collagen complex. Steered molecular dynamics simulations were conducted with umbrella sampling. During the course of these simulations, the ‘locking’ latch from the CNA N2 domain was dissociated from its groove in the CNA N1 domain, implying the importance of the latch for effective ligand binding. Finally, we observed that the binding efficiency of the CNA N1-N2 domains to collagen decreases greatly with increasing tensile force application to the collagen peptides. Thus, CNA and similar adhesins might preferentially bind to sites in which collagen fibers are cleaved, such as in wounded, injured, or inflamed tissues, or in which the collagenous tissue is less mature. As alternative techniques for control of bacterial infection are in-demand due to the rise of bacterial antibiotic resistance, results from our computational studies with respect to the mechanoregulation of the collagen binding site may inspire new therapeutics and engineering solutions by mechanically preventing colonization and/or further pathogenesis. PMID:28665944

Modular reweighting software for statistical mechanical analysis of biased equilibrium data

NASA Astrophysics Data System (ADS)

Sindhikara, Daniel J.

2012-07-01

Here a simple, useful, modular approach and software suite designed for statistical reweighting and analysis of equilibrium ensembles is presented. Statistical reweighting is useful and sometimes necessary for analysis of equilibrium enhanced sampling methods, such as umbrella sampling or replica exchange, and also in experimental cases where biasing factors are explicitly known. Essentially, statistical reweighting allows extrapolation of data from one or more equilibrium ensembles to another. Here, the fundamental separable steps of statistical reweighting are broken up into modules - allowing for application to the general case and avoiding the black-box nature of some “all-inclusive” reweighting programs. Additionally, the programs included are, by-design, written with little dependencies. The compilers required are either pre-installed on most systems, or freely available for download with minimal trouble. Examples of the use of this suite applied to umbrella sampling and replica exchange molecular dynamics simulations will be shown along with advice on how to apply it in the general case. New version program summaryProgram title: Modular reweighting version 2 Catalogue identifier: AEJH_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEJH_v2_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License, version 3 No. of lines in distributed program, including test data, etc.: 179 118 No. of bytes in distributed program, including test data, etc.: 8 518 178 Distribution format: tar.gz Programming language: C++, Python 2.6+, Perl 5+ Computer: Any Operating system: Any RAM: 50-500 MB Supplementary material: An updated version of the original manuscript (Comput. Phys. Commun. 182 (2011) 2227) is available Classification: 4.13 Catalogue identifier of previous version: AEJH_v1_0 Journal reference of previous version: Comput. Phys. Commun. 182 (2011) 2227 Does the new version supersede the previous version?: Yes Nature of problem: While equilibrium reweighting is ubiquitous, there are no public programs available to perform the reweighting in the general case. Further, specific programs often suffer from many library dependencies and numerical instability. Solution method: This package is written in a modular format that allows for easy applicability of reweighting in the general case. Modules are small, numerically stable, and require minimal libraries. Reasons for new version: Some minor bugs, some upgrades needed, error analysis added. analyzeweight.py/analyzeweight.py2 has been replaced by “multihist.py”. This new program performs all the functions of its predecessor while being versatile enough to handle other types of histograms and probability analysis. “bootstrap.py” was added. This script performs basic bootstrap resampling allowing for error analysis of data. “avg_dev_distribution.py” was added. This program computes the averages and standard deviations of multiple distributions, making error analysis (e.g. from bootstrap resampling) easier to visualize. WRE.cpp was slightly modified purely for cosmetic reasons. The manual was updated for clarity and to reflect version updates. Examples were removed from the manual in favor of online tutorials (packaged examples remain). Examples were updated to reflect the new format. An additional example is included to demonstrate error analysis. Running time: Preprocessing scripts 1-5 minutes, WHAM engine <1 minute, postprocess script ∼1-5 minutes.

Promoting physical activity for children and adolescents in low- and middle-income countries: An umbrella systematic review: A review on promoting physical activity in LMIC.

PubMed

Barbosa Filho, Valter Cordeiro; Minatto, Giseli; Mota, Jorge; Silva, Kelly Samara; de Campos, Wagner; Lopes, Adair da Silva

2016-07-01

It is unknown how much previous reviews on promoting physical activity (PA) for children and adolescents (aged 6-18years) take into account studies from low- and middle-income countries (LMIC, based on the World Bank definition) and the level of evidence of the effect of PA interventions in this population. This study aims to answer such questions using an umbrella systematic review approach. We searched for peer-reviewed systematic reviews and original studies in eight electronic databases, screening of reference lists and expert contacts. Information in systematic reviews on PA interventions for children and adolescents from LMIC was discussed. Original studies on PA interventions (randomized-controlled trials [RCT], cluster-RCT and non-RCT) with children and adolescents from LMIC were eligible. We assessed the methodological quality in all studies, and the evidence level of effect on PA in intervention studies. Fifty systematic reviews (nine meta-analyses) and 25 original studies (20 different interventions) met eligibility criteria. Only 3.1% of mentioned studies in previous reviews were from LMIC. Strong and LMIC-specific evidence was found that school-based, multicomponent, and short-term (up to six months) interventions, focused on adolescents primarily (aged 13-18years), can promote PA in children and adolescents from LMIC. Other intervention characteristics had inconclusive evidence due to the low number of studies, low methodological quality, and/or small sample size. A minimal part of PA interventions mentioned in previous reviews are from LMIC. Our LMIC-specific analyses showed priorities of implementation and practical implication that can be used in public policies for PA promotion in LMIC. Copyright © 2016 Elsevier Inc. All rights reserved.

ENCOURAGING INNOVATION THROUGH UMBRELLA PERMITTING

EPA Science Inventory

The purpose of this project is to assess the behavioral, technical, economic, and environmental effects of removing disincentives to innovation in production and pollution management through more flexible environmental permitting. The study will examine the characteristics of tra...

Fermilab | LBNF | Home

Science.gov Websites

million to LBNF/DUNE in first-ever umbrella science agreement with U.S. Jo Johnson (UK Minister of State Minister of State for Universities, Science, Research and Innovation Jo Johnson signed the U.S.-UK Science

Comprehensive vacuum ultraviolet photoionization study of the CF3• trifluoromethyl radical using synchrotron radiation

NASA Astrophysics Data System (ADS)

Dossmann (Soldi-Lose), Héloïse; Garcia, Gustavo A.; Nahon, Laurent; de Miranda, Barbara K. C.; Alcaraz, Christian

2012-05-01

The trifluoromethyl radical, CF3•, is studied for the first time by means of threshold photoelectron spectroscopy (TPES). The radical is produced in the gas phase using the flash-pyrolysis technique from hexafluoroethane as a precursor. CF3+ total ion yield and mass-selected TPES of the radical are recorded using a spectrometer based upon velocity map imaging and Wiley-McLaren time-of-flight coupled to the synchrotron radiation. The high resolution of the instrument and of the photons allows the observation of rich vibrational progressions in the TPES of CF3•. By using Franck-Condon factors computed by Bowman and coworkers, we have been able to simulate the TPES. The initial vibrational temperature of the radical beam has been evaluated at 350 ± 70 K. The structures have been identified as transitions between (n1,n2) and (n1+,n2+) vibrational levels of CF3 and CF3+ with small excitation of the breathing mode, ν1+, and large excitation (n2+ = 10-26) of the umbrella mode, ν2+, in the cation. From the energy separation between the two resolved peaks of each band, a value of 994 ± 16 cm-1 has been derived for the ν1+ breathing frequency of CF3+. For the high-lying n2+ levels, the apparent ν2+ umbrella spacing, 820 ± 14 cm-1, is fairly constant. Taking into account the ν2+ anharmonicity calculated by Bowman and coworkers, we have deduced ν2+ = 809 ± 14 cm-1, and semi-empirical estimations of the adiabatic ionization energy IEad.(CF3•) are proposed in good agreement with most of previous works. A value of the vertical ionization potential, IEvert.(CF3•) = 11.02 eV, has been derived from the observation of a photoelectron spectrum recorded at a fixed photon energy of 12 eV.

Morphological keys in the differential diagnosis of bladder inverted papilloma. Study of two types, trabecular and glandular.

PubMed

Sabater Marco, Vicente; Navalón Verdejo, Pedro; Morera Faet, Arturo

2012-09-01

Inverted papilloma of the urinary bladder is an uncommon urothelial neoplasm that may be specially difficult to distinguish from urothelial carcinoma. Two patients with obstructive symptoms and hematuria have been studied. In the transurethral resection, accidentally, one showed a papillary lesion in the context of nodular hyperplasia of the prostate, where as the other showed a polypoid tumor of the urinary bladder Histologically, in both cases, a bladder inverted papilloma was demonstrated, originating from the surface transitional epithelium. Basal cells exhibited peripheral palisading pattern in the trabecular form. In the glandular type, Dogiel or umbrella cells into the gland-like structures, were recognized. Immunohistochemical stains for p53 and Ki-67 were negative. Umbrella cells were positive for cytokeratin 20. Two cases of bladder inverted papilloma with relevant morphological aspects are presented, which we consider useful for the differential diagnosis with urothelial carcinoma.

Communication: Reactivity borrowing in the mode selective chemistry of H + CHD3 → H2 + CD3

NASA Astrophysics Data System (ADS)

Ellerbrock, Roman; Manthe, Uwe

2017-12-01

Quantum state-resolved reaction probabilities for the H + CHD3 → H2 + CD3 reaction are calculated by accurate full-dimensional quantum dynamics calculations using the multi-layer multi-configurational time-dependent Hartree approach and the quantum transition state concept. Reaction probabilities of various ro-vibrational states of the CHD3 reactant are investigated for vanishing total angular momentum. While the reactivity of the different vibrational states of CHD3 mostly follows intuitive patterns, an unusually large reaction probability is found for CHD3 molecules triply excited in the CD3 umbrella-bending vibration. This surprising reactivity can be explained by a Fermi resonance-type mixing of the single CH-stretch excited and the triple CD3 umbrella-bend excited vibrational states of CHD3. These findings show that resonant energy transfer can significantly affect the mode-selective chemistry of CHD3 and result in counter-intuitive reactivity patterns.

Effects of Collagen and Collagen Hydrolysate from Jellyfish Umbrella on Histological and Immunity Changes of Mice Photoaging

PubMed Central

Fan, Jian; Zhuang, Yongliang; Li, Bafang

2013-01-01

Jellyfish collagen (JC) was extracted from jellyfish umbrella and hydrolyzed to prepare jellyfish collagen hydrolysate (JCH). The effects of JC and JCH on UV-induced skin damage of mice were evaluated by the skin moisture, microscopic analyses of skin and immunity indexes. The skin moisture analyses showed that moisture retention ability of UV-induced mice skin was increased by JC and JCH. Further histological analysis showed that JC and JCH could repair the endogenous collagen and elastin protein fibers, and could maintain the natural ratio of type I to type III collagen. The immunity indexes showed that JC and JCH play a role in enhancing immunity of photoaging mice in vivo. JCH showed much higher protective ability than JC. These results suggest that JCH as a potential novel antiphotoaging agent from natural resources. PMID:23344251

Oral healthcare challenges for older Punjabi-speaking immigrants.

PubMed

MacEntee, Michael I; Wong, Sabrina T; Smith, André; Beattie, B Lynn; Brondani, Mario; Bryant, S Ross; Graf, Peter; Soheilipour, Shimae

2014-06-01

This study explored how older Punjabi-speaking South-Asian immigrants (four focus groups; 33 participants) in Surrey, British Columbia, perceive oral health and related problems. Content analysis revealed two umbrella themes: (a) interpretations of mouth conditions and (b) challenges to oral health. The umbrella themes had four sub-themes: damage caused by heat (wai), disturbances caused by caries, coping with dentures, and quality of life. Three challenges were considered: home remedies, Western dentistry, and difficulties accessing dentists. Participants explained oral diseases in terms of a systemic infection (resha), and preferred to decrease imbalances of wai in the mouth with home remedies from India. We conclude that older Punjabi-speaking immigrants interpret oral health and disease in the context of both Western and Ayurvedic traditions, and that they manage dental problems with a mix of traditional remedies supplemented, if possible, by elective oral health care in India, and by emergency dental care in Canada.

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

PubMed

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

2013-10-24

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

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

PubMed Central

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

2013-01-01

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

The urothelium of a hibernator: the American black bear

PubMed Central

Spector, David A; Deng, Jie; Coleman, Richard; Wade, James B

2015-01-01

The American black bear undergoes a 3–5 month winter hibernation during which time bears do not eat, drink, defecate, or urinate. During hibernation renal function (GFR) is 16–50% of normal but urine is reabsorbed across the urinary bladder (UB) urothelium thus enabling metabolic recycling of all urinary constituents. To elucidate the mechanism(s) whereby urine is reabsorbed, we examined the UBs of five nonhibernating wild bears using light, electron (EM), and confocal immunofluorescent (IF) microscopy–concentrating on two components of the urothelial permeability barrier – the umbrella cell apical membranes and tight junctions (TJ). Bear UB has the same tissue layers (serosa, muscularis, lamina propria, urothelia) and its urothelia has the same cell layers (basal, intermediate, umbrella cells) as other mammalians. By EM, the bear apical membrane demonstrated a typical mammalian scalloped appearance with hinge and plaque regions – the latter containing an asymmetric trilaminar membrane and, on IF, uroplakins Ia, IIIa, and IIIb. The umbrella cell TJs appeared similar to those in other mammals and also contained TJ proteins occludin and claudin - 4, and not claudin –2. Thus, we were unable to demonstrate urothelial apical membrane or TJ differences between active black bears and other mammals. Expression and localization of UT-B, AQP-1 and -3, and Na+, K+-ATPase on bear urothelial membranes was similar to that of other mammals. Similar studies of urothelia of hibernating bears, including evaluation of the apical membrane lipid bilayer and GAGs layer are warranted to elucidate the mechanism(s) whereby hibernating bears reabsorb their daily urine output and thus ensure successful hibernation. PMID:26109187

Greater sage-grouse as an umbrella species for sagebrush-associated vertebrates

USGS Publications Warehouse

Rowland, M.M.; Wisdom, M.J.; Suring, L.H.; Meinke, C.W.

2006-01-01

Widespread degradation of the sagebrush ecosystem in the western United States, including the invasion of cheatgrass, has prompted resource managers to consider a variety of approaches to restore and conserve habitats for sagebrush-associated species. One such approach involves the use of greater sage-grouse, a species of prominent conservation interest, as an umbrella species. This shortcut approach assumes that managing habitats to conserve sage-grouse will simultaneously benefit other species of conservation concern. The efficacy of using sage-grouse as an umbrella species for conservation management, however, has not been fully evaluated. We tested that concept by comparing: (1) commonality in land-cover associations, and (2) spatial overlap in habitats between sage-grouse and 39 other sagebrush-associated vertebrate species of conservation concern in the Great Basin ecoregion. Overlap in species' land-cover associations with those of sage-grouse, based on the ?? (phi) correlation coefficient, was substantially greater for sagebrush obligates (x??=0.40) than non-obligates (x??=0.21). Spatial overlap between habitats of target species and those associated with sage-grouse was low (mean ?? = 0.23), but somewhat greater for habitats at high risk of displacement by cheatgrass (mean ?? = 0.33). Based on our criteria, management of sage-grouse habitats likely would offer relatively high conservation coverage for sagebrush obligates such as pygmy rabbit (mean ?? = 0.84), but far less for other species we addressed, such as lark sparrow (mean ?? = 0.09), largely due to lack of commonality in land-cover affinity and geographic ranges of these species and sage-grouse.

Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

PubMed

Campbell, Jared M; Bateman, Emma; Stephenson, Matthew D; Bowen, Joanne M; Keefe, Dorothy M; Peters, Micah D J

2016-07-01

Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine. Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.

New silicate-germanate Cs2Pb2[(Si0.6Ge0.4)2O7] from the series A2Pb2[B2O7], A = K, Cs, B = Si, Ge with the umbrella-like [PbO3]4- group

NASA Astrophysics Data System (ADS)

Belokoneva, Elena L.; Morozov, Ivan A.; Volkov, Anatoly S.; Dimitrova, Olga V.; Stefanovich, Sergey Yu.

2018-04-01

New silicate-germanate Cs2Pb2[(Si0.6Ge0.4)2O7] was synthesized in multi-components hydrothermal solution with 20 w.% concentration of Cs2CO3 mineralizer, pH = 10. Novel mixed compound belongs to the structure type A2Pb2[B2O7] previously indicated for powders with A = K, B=Si or Ge. Singe crystal structure determination of Cs2Pb2[(Si0.6Ge0.4)2O7] revealed the need for the correction of the space group of the earlier suggested structural model from P-3 to P-3m1, as well as for the splitting of the Pb-atom position. Umbrella-like groups [PbO3]4- are located between [(Si,Ge)O4]4- tetrahedra in mica-like honeycomb layers and play the role of tetrahedra with the Pb-lone-pair as the forth apex. Crystal chemical comparison revealed similarities and differences with the classical structure type of α-celsian Ba[Al2Si2O8] with the tetrahedral double layer. Recently investigated nonlinear optical acentric borates Pb2(BO3)(NO3) and Pb2(BO3)Cl are both related to this structural type, possessing umbrella-like groups [PbO3]4- and honeycomb layers [Pb2(BO3)]+ with the BO3-triangles on the tetrahedral positions.

Interactions of aqueous amino acids and proteins with the (110) surface of ZnS in molecular dynamics simulations

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

Nawrocki, Grzegorz; Cieplak, Marek

2014-03-07

The growing usage of nanoparticles of zinc sulfide as quantum dots and biosensors calls for a theoretical assessment of interactions of ZnS with biomolecules. We employ the molecular-dynamics-based umbrella sampling method to determine potentials of mean force for 20 single amino acids near the ZnS (110) surface in aqueous solutions. We find that five amino acids do not bind at all and the binding energy of the remaining amino acids does not exceed 4.3 kJ/mol. Such energies are comparable to those found for ZnO (and to hydrogen bonds in proteins) but the nature of the specificity is different. Cysteine canmore » bind with ZnS in a covalent way, e.g., by forming the disulfide bond with S in the solid. If this effect is included within a model incorporating the Morse potential, then the potential well becomes much deeper—the binding energy is close to 98 kJ/mol. We then consider tryptophan cage, a protein of 20 residues, and characterize its events of adsorption to ZnS. We demonstrate the relevance of interactions between the amino acids in the selection of optimal adsorbed conformations and recognize the key role of cysteine in generation of lasting adsorption. We show that ZnS is more hydrophobic than ZnO and that the density profile of water is quite different than that forming near ZnO—it has only a minor articulation into layers. Furthermore, the first layer of water is disordered and mobile.« less

Free energy barriers for escape of water molecules from protein hydration layer.

PubMed

Roy, Susmita; Bagchi, Biman

2012-03-08

Free energy barriers separating interfacial water molecules from the hydration layer at the surface of a protein to the bulk are obtained by using the umbrella sampling method of free energy calculation. We consider hydration layer of chicken villin head piece (HP-36) which has been studied extensively by molecular dynamics simulations. The free energy calculations reveal a strong sensitivity to the secondary structure. In particular, we find a region near the junction of first and second helix that contains a cluster of water molecules which are slow in motion, characterized by long residence times (of the order of 100 ps or more) and separated by a large free energy barrier from the bulk water. However, these "slow" water molecules constitute only about 5-10% of the total number of hydration layer water molecules. Nevertheless, they play an important role in stabilizing the protein conformation. Water molecules near the third helix (which is the important helix for biological function) are enthalpically least stable and exhibit the fastest dynamics. Interestingly, barrier height distributions of interfacial water are quite broad for water surrounding all the three helices (and the three coils), with the smallest barriers found for those near the helix-3. For the quasi-bound water molecules near the first and second helices, we use well-known Kramers' theory to estimate the residence time from the free energy surface, by estimating the friction along the reaction coordinate from the diffusion coefficient by using Einstein relation. The agreement found is satisfactory. We discuss the possible biological function of these slow, quasi-bound (but transient) water molecules on the surface.

STORMWATER BEST MANAGEMENT PRACTICE MONITORING

EPA Science Inventory

Implementation of an effective BMP monitoring program is not a straight-forward task. BMPs by definition are devices, practices, or methods used to manage stormwater runoff. This umbrella term lumps widely varying techniques into a single category. Also, with the existence of ...

New York hospital group striving for brand recognition. HealthStar Network.

PubMed

Herreria, J

1998-01-01

HealthStar Network established a new concept in its eastern market--a group of hospitals forming one association. Marketers of HealthStar are conducting a branding campaign to distinguish individual expertise under one umbrella company.

78 FR 25260 - Combined Notice of Filings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-30

...: Boardwalk Storage Company, LLC. Description: Revise Hub Services and Umbrella Pro Forma Agmts to be... Pipeline Company of America. Description: Negotiated Rate--EDF Trading to be effective 5/1/2013. Filed Date...: Kern River Gas Transmission Company. [[Page 25261

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

Sehgal, Ray M.; Maroudas, Dimitrios, E-mail: maroudas@ecs.umass.edu, E-mail: ford@ecs.umass.edu; Ford, David M., E-mail: maroudas@ecs.umass.edu, E-mail: ford@ecs.umass.edu

We have developed a coarse-grained description of the phase behavior of the isolated 38-atom Lennard-Jones cluster (LJ{sub 38}). The model captures both the solid-solid polymorphic transitions at low temperatures and the complex cluster breakup and melting transitions at higher temperatures. For this coarse model development, we employ the manifold learning technique of diffusion mapping. The outcome of the diffusion mapping analysis over a broad temperature range indicates that two order parameters are sufficient to describe the cluster's phase behavior; we have chosen two such appropriate order parameters that are metrics of condensation and overall crystallinity. In this well-justified coarse-variable space,more » we calculate the cluster's free energy landscape (FEL) as a function of temperature, employing Monte Carlo umbrella sampling. These FELs are used to quantify the phase behavior and onsets of phase transitions of the LJ{sub 38} cluster.« less

What causes psychosis? An umbrella review of risk and protective factors

PubMed Central

Radua, Joaquim; Ramella‐Cravaro, Valentina; Ioannidis, John P.A.; Reichenberg, Abraham; Phiphopthatsanee, Nacharin; Amir, Taha; Yenn Thoo, Hyi; Oliver, Dominic; Davies, Cathy; Morgan, Craig; McGuire, Philip; Murray, Robin M.; Fusar‐Poli, Paolo

2018-01-01

Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta‐analyses of observational studies which examined associations between socio‐demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non‐organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non‐significant according to a standardized classification based on: number of psychotic cases, random‐effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty‐five meta‐analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra‐high‐risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91‐17.72) and Black‐Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96‐6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North‐African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non‐right handedness). When only prospective studies were considered, the evidence was convincing for ultra‐high‐risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis. PMID:29352556

From early days of elitism to earning a wider respect.

PubMed

Stammer, T

1979-07-20

Gone are those early elitist days in the life of the Association of NHS Supplies Officers. It has widened its umbrella and its ambitions. Author traces the association's origins and ruminates on what lies in store for it.

Identifying the local and regional travel effects of activity centers in the Austin, Texas area.

DOT National Transportation Integrated Search

2015-02-01

Metropolitan planning organizations (MPOs) have become increasingly interested in : incorporating innovated land use planning and design into transportation plan-making. Many : design ideas are recommended under the umbrella of the New Urbanism; yet ...

Study shows women fail to land top grants

NASA Astrophysics Data System (ADS)

Jenner, Nicola

2014-05-01

Women in the UK are less successful than men at securing research council funding at almost every stage of their careers, according to an analysis published by Research Councils UK (RCUK) - the umbrella organization for the country's seven research councils.

Evaluation of the cooperative multi-carrier delivery initiatives.

DOT National Transportation Integrated Search

2013-12-01

In the last several years there has been a surge of interest in fostering more sustainable logistical operations in : urban areas. Under the umbrella of the generic term City Logistics, these initiatives try to take advantage of : the coordinating po...

Acid Rain: Resource Materials for Schools.

ERIC Educational Resources Information Center

American Biology Teacher, 1983

1983-01-01

Provides listings of acid rain resource material groups under: (1) printed materials (pamphlets, books, articles); (2) audiovisuals (slide/tape presentations, tape, video-cassette); (3) miscellaneous (buttons, pocket lab, umbrella); (4) transparencies; (5) bibliographies; and (6) curriculum materials. Sources and prices (when applicable) are…

Offshore energy boom providing opportunities outside Medicare's umbrella.

PubMed

Robb, N

1998-09-08

Physicians upset by limits imposed by the medicare system are getting a chance to spread their entrepreneurial wings on the East Coast. A boom in offshore exploration, led by Newfoundland's massive Hibernia project, has led to numerous business opportunities for physicians.

36 CFR 504.12 - Items to be checked.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Section 504.12 Parks, Forests, and Public Property SMITHSONIAN INSTITUTION RULES AND REGULATIONS GOVERNING SMITHSONIAN INSTITUTION BUILDINGS AND GROUNDS § 504.12 Items to be checked. Umbrellas, canes (not needed to... to be checked in buildings where checking facilities are provided. ...

Can Whole-Grain Foods Lower Blood Pressure?

MedlinePlus

... Flint AJ, et al. Whole grains and incident hypertension in men. American Journal of Clinical Nutrition. 2009;90:493. Dietary guidelines ... whole grains: An umbrella review of meta-analyses. Journal of Chiropractic Medicine. 2017;16:10. Feb. 22, 2018 Original ... . Mayo ...

Voluntary Organisation

ERIC Educational Resources Information Center

Williams, Shirley; Spiret, Claire; Dimitriadi, Yota; McCrindle, Rachel

2013-01-01

The World Association of Girl Guides and Girl Scouts (WAGGGS) is the umbrella organisation for Member Organisations from 145 countries, with a total membership of 10 million. While Member Organisations offer training and development within their own countries, WAGGGS offers international opportunities, such as leadership development at…

Self-expansion and flow in couples' momentary experiences: an experience sampling study.

PubMed

Graham, James M

2008-09-01

The self-expansion model of close relationships posits that when couples engage in exciting and activating conjoint activities, they feel connected with their partners and more satisfied with their relationships. In the present study, the experience sampling method was used to examine the predictions of the self-expansion model in couples' momentary experiences. In addition, the author generated several new hypotheses by integrating the self-expansion model with existing research on flow. Over the course of 1 week, 20 couples were signaled at quasi-random intervals to provide data on 1,265 unique experiences. The results suggest that the level of activation experienced during an activity was positively related to experience-level relationship quality. This relationship was consistent across free-time and nonfree-time contexts and was mediated by positive affect. Activation was not found to predict later affect unless the level of activation exceeded what was typical for the individual. Also examined was the influence of interpersonal context and activity type on self-expansion. The results support the self-expansion model and suggest that it could be considered under the broader umbrella of flow.

Development of a Decision Model for Selection of Appropriate Timely Delivery Techniques for Highway Projects

DOT National Transportation Integrated Search

2009-04-01

"The primary umbrella method used by the Oregon Department of Transportation (ODOT) to ensure on-time performance in standard construction contracting is liquidated damages. The assessment value is usually a matter of some judgment. In practice...

Virtual Beach Manager Toolset

EPA Science Inventory

The Virtual Beach Manager Toolset (VB) is a set of decision support software tools developed to help local beach managers make decisions as to when beaches should be closed due to predicted high levels of water borne pathogens. The tools are being developed under the umbrella of...

Lovelace simplifies, saves big with single-source imaging equipment service contract.

PubMed

1997-11-01

Lovelace Health System traded in its disorganized mess of service contracts for imaging and cardiology equipment for one umbrella contract--and is now saving more than $200,000 a year as a result. Find out how to achieve similar savings.

Offshore energy boom providing opportunities outside medicare's umbrella

PubMed Central

Robb, N

1998-01-01

Physicians upset by limits imposed by the medicare system are getting a chance to spread their entrepreneurial wings on the East Coast. A boom in offshore exploration, led by Newfoundland's massive Hibernia project, has led to numerous business opportunities for physicians. PMID:9757185

A Quantitative Evaluation of the Conservation Umbrella of Spotted Owl Management Areas in the Sierra Nevada

PubMed Central

Burnett, Ryan D.; Roberts, L. Jay

2015-01-01

Whether by design or default, single species management often serves as an umbrella for species with similar habitat requirements. In recent decades the focus of National Forest management in the Sierra Nevada of California has shifted towards increasing closed canopy mature forest conditions through the protection of areas occupied by the California Spotted Owl (Strix occidentalis occidentalis). To evaluate the implications of these habitat changes and the potential umbrella resulting from a system of owl reserves on the broader avian community, we estimated occupancy of birds inside and outside of Spotted Owl Home Range Core Areas in northeastern California. We used point count data in a multi-species hierarchical Bayesian model incorporating the detection history of 81 species over a two-year time period (2005-2006). A small set of vegetation cover and topography covariates were included in the model to account for broad differences in habitat conditions, as well as a term identifying whether or not a site was within a Core Area. Seventeen species had a negative Core Area effect, seven had a positive effect, and the rest were not significant. Estimated species richness was significantly different with 23.1 species per 100 m radius circle outside Core Areas and 21.7 inside Core Areas. The majority of the species negatively associated with Core Areas are tied to early successional and other disturbance-dependent habitats. Conservation and climate vulnerability rankings were mixed. On average we found higher scores (greater risk) for the species positively associated with Core Areas, but a larger number of species with the highest scores were negatively associated with Core Areas. We discuss the implications for managing the Sierra Nevada ecosystem and illustrate the role of monitoring broader suites of species in guiding management of large complex ecosystems. PMID:25905920

Cultural Proficiency. Research Brief

ERIC Educational Resources Information Center

Walker, Karen

2007-01-01

Cultural proficiency and diversity are often used interchangeably, yet there are some distinct differences between them. Cultural proficiency is the umbrella under which diversity falls. According to one source, "Cultural proficiency is a way of being that allows individuals and organizations to interact effectively with people who differ from…

Status Report on Speech Research, 1 January-31 March 1982.

DTIC Science & Technology

1982-03-01

PUMPKIN RHYTHM Nonwords SUBMARINE CONKZMER SURGERY ENGKSTERN THIRD FTERNAPS TOMATO HSPERACH UMBRELLA PGANTERLH VEHICLE PIOTLANING VIDEO PUANT VINEGAR ...and productionI (TABLE 6) data for Catalan subjects with special reference to ferment transions.Ordlnate: F2 ranges (in Hz)abaolsea: PS ranges (in

Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples

PubMed Central

Renfro, L. A.; Sargent, D. J.

2017-01-01

Abstract In recent years, cancers once viewed as relatively homogeneous in terms of organ location and treatment strategy are now better understood to be increasingly heterogeneous across biomarker and genetically defined patient subgroups. This has produced a shift toward development of biomarker-targeted agents during a time when funding for cancer research has been limited; as a result, the need for improved operational efficiency in studying many agent-and-target combinations in parallel has emerged. Platform trials, basket trials, and umbrella trials are new approaches to clinical research driven by this need for enhanced efficiency in the modern era of increasingly specific cancer subpopulations and decreased resources to study treatments for individual cancer subtypes in a traditional way. In this review, we provide an overview of these new types of clinical trial designs, including discussions of motivation for their use, recommended terminology, examples, and challenges encountered in their application. PMID:28177494

The Continuing Umbrella of Research Experiences (CURE): a model for training underserved scientists in cancer research.

PubMed

Franco, Idalid; Bailey, LeeAnn O; Bakos, Alexis D; Springfield, Sanya A

2011-03-01

Mentoring is a critical aspect of research and training; and the adoption of a successful mentoring model for guiding researchers through the educational pipeline is lacking. The Continuing Umbrella of Research Experiences (CURE) program was established in the Comprehensive Minority Biomedical Branch; which is part of the National Cancer Institute. This program offers unique training and career development opportunities to enhance diversity in cancer research. The CURE initiative focuses on broadening the cadre of underserved investigators engaging in cancer research. CURE begins with high school students and fosters scientific, academic and research excellence throughout the trainee's educational progression. The program supports students throughout the entirety of their training career. During this period, the trainee matures into a competitive early stage investigator; capable of securing advanced research project funding in academic and industry workforces. Thus, the CURE program provides a comprehensive vehicle for training and reinforces the critical mass of underserved investigators conducting cancer research.

Standardized methods for Grand Canyon fisheries research 2015

USGS Publications Warehouse

Persons, William R.; Ward, David L.; Avery, Luke A.

2013-01-01

This document presents protocols and guidelines to persons sampling fishes in the Grand Canyon, to help ensure consistency in fish handling, fish tagging, and data collection among different projects and organizations. Most such research and monitoring projects are conducted under the general umbrella of the Glen Canyon Dam Adaptive Management Program and include studies by the U.S. Geological Survey (USGS), U.S. Fish and Wildlife Service (FWS), National Park Service (NPS), the Arizona Game and Fish Department (AGFD), various universities, and private contractors. This document is intended to provide guidance to fieldworkers regarding protocols that may vary from year to year depending on specific projects and objectives. We also provide herein documentation of standard methods used in the Grand Canyon that can be cited in scientific publications, as well as a summary of changes in protocols since the document was first created in 2002.

Accurate rates of the complex mechanisms for growth and dissolu-tion of minerals using a combination of rare event theories

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

Stack, Andrew G; Raiten, Paolo; Gale, Julian D.

2012-01-01

Mineral growth and dissolution are often treated as occurring via a single, reversible process that governs the rate of reaction. We show that multiple, distinct intermediate states can occur during both growth and dissolution. Specifically, we have used metadynamics, a method to efficiently explore the free energy landscape of a system, coupled to umbrella sampling and reactive flux calculations, to examine the mechanism and rates of attachment and detachment of a barium ion onto a stepped, barite (BaSO4) surface. The activation energies calculated for the rate limiting reactions, which are different for attachment and detachment, precisely match those measured experimentallymore » during both growth and dissolution. These results can potentially explain anomalous, non-steady state mineral reaction rates observed experimentally, and will enable the design of more efficient growth inhibitors and facilitate an understanding of the effect of impurities.« less

CAST: a new program package for the accurate characterization of large and flexible molecular systems.

PubMed

Grebner, Christoph; Becker, Johannes; Weber, Daniel; Bellinger, Daniel; Tafipolski, Maxim; Brückner, Charlotte; Engels, Bernd

2014-09-15

The presented program package, Conformational Analysis and Search Tool (CAST) allows the accurate treatment of large and flexible (macro) molecular systems. For the determination of thermally accessible minima CAST offers the newly developed TabuSearch algorithm, but algorithms such as Monte Carlo (MC), MC with minimization, and molecular dynamics are implemented as well. For the determination of reaction paths, CAST provides the PathOpt, the Nudge Elastic band, and the umbrella sampling approach. Access to free energies is possible through the free energy perturbation approach. Along with a number of standard force fields, a newly developed symmetry-adapted perturbation theory-based force field is included. Semiempirical computations are possible through DFTB+ and MOPAC interfaces. For calculations based on density functional theory, a Message Passing Interface (MPI) interface to the Graphics Processing Unit (GPU)-accelerated TeraChem program is available. The program is available on request. Copyright © 2014 Wiley Periodicals, Inc.

Partitioning of 2,6-Bis(1H-Benzimidazol-2-yl)pyridine Fluorophore into a Phospholipid Bilayer: Complementary Use of Fluorescence Quenching Studies and Molecular Dynamics Simulations

PubMed Central

Kyrychenko, Alexander; Sevriukov, Igor Yu.; Syzova, Zoya A.; Ladokhin, Alexey S.; Doroshenko, Andrey O.

2014-01-01

Successful use of fluorescence sensing in elucidating the biophysical properties of lipid membranes requires knowledge of the distribution and location of an emitting molecule in the bilayer. We report here that 2,6-bis(1H-benzimidazol-2-yl)pyridine (BBP), which is almost non-fluorescent in aqueous solutions, reveals a strong emission enhancement in a hydrophobic environment of a phospholipid bilayer, making it interesting for fluorescence probing of water content in a lipid membrane. Comparing the fluorescence behavior of BBP in a wide variety of solvents with those in phospholipid vesicles, we suggest that the hydrogen bonding interactions between a BBP fluorophore and water molecules play a crucial role in the observed “light switch effect”. Therefore, the loss of water-induced fluorescence quenching inside a membrane are thought to be due to deep penetration of BBP into the hydrophobic, water-free region of a bilayer. Characterized by strong quenching by transition metal ions in solution, BBP also demonstrated significant shielding from the action of the quencher in the presence of phospholipid vesicles. We used the increase in fluorescence intensity, measured upon titration of probe molecules with lipid vesicles, to estimate the partition constant and the Gibbs free energy (ΔG) of transfer of BBP from aqueous buffer into a membrane. Partitioning BBP revealed strongly favorable ΔG, which depends only slightly on the lipid composition of a bilayer, varying in a range from -6.5 to -7.0 kcal/mol. To elucidate the binding interactions of the probe with a membrane on the molecular level, a distribution and favorable location of BBP in a POPC bilayer were modeled via atomistic molecular dynamics (MD) simulations using two different approaches: (i) free, diffusion-driven partitioning of the probe molecules into a bilayer and (ii) constrained umbrella sampling of a penetration profile of the dye molecule across a bilayer. Both of these MD approaches agreed with regard to the preferred location of a BBP fluorophore within the interfacial region of a bilayer, located between the hydrocarbon acyl tails and the initial portion of the lipid headgroups. MD simulations also revealed restricted permeability of water molecules into this region of a POPC bilayer, determining the strong fluorescence enhancement observed experimentally for the membrane-partitioned form of BBP. PMID:21211898

Mission of PROCINORTE'S Tropical and Subtropical Fruit Task Force

USDA-ARS?s Scientific Manuscript database

Canada, Mexico and United States are countries that share many interests in agricultural affairs. The three countries have been commercial partners for many years, and most recently they have been working under the North American Free Trade Agreement (NAFTA) umbrella. The three countries are natura...

Critiquing Whole Language and Classroom Inquiry. WLU Series.

ERIC Educational Resources Information Center

Boran, Sibel, Ed.; Comber, Barbara, Ed.

This book, part of the Whole Language Umbrella Series, offers a critical reexamination of "inquiry" and "whole language" as tools for rethinking literacy, schooling, and humanistic citizenship in the complexities of today's multicultural world. The essays in the book explore the political implications of literacy theories and…

Development of a decision model for selection of appropriate timely delivery techniques for highway projects : final report, April 2009.

DOT National Transportation Integrated Search

2009-04-01

The primary umbrella method used by the Oregon Department of Transportation (ODOT) to ensure on-time performance in standard construction contracting is liquidated damages. The assessment value is usually a matter of some judgment. In practice,...

[The interview as a research data collection method].

PubMed

Debout, Christophe

2016-04-01

The interview is a widely-used method for collecting research data, notably in qualitative and mixed protocols. However, it is an umbrella term which groups together numerous types of interviews adapted to the methodological diversity which characterises nursing science. Copyright © 2016. Published by Elsevier Masson SAS.

Under the Nuclear Umbrella.

ERIC Educational Resources Information Center

Williams, Leon F.

1987-01-01

Entertains the thesis that social work has a stake in the technological-humanistic debate and should greet the recent and spectacular technological failures with protest and alarm. Discusses relationship of nuclear issue and social work, effects of nuclear issue on children, and Chernobyl. Advocates pacifism, activism, and a coherent conception of…

"Supra-Institutional Research": A Cost-Effective Contribution towards Enhancement

ERIC Educational Resources Information Center

Yorke, Mantz

2010-01-01

Relatively inexpensive studies that go beyond the boundaries of individual institutions have considerable attraction, particularly at a time when resources are under significant constraint. These studies can be viewed as existing under the rather larger umbrella of "supra-institutional research". Three examples illustrate the argument…

A 10-year ecosystem restoration community of practice tracks large-scale restoration trends

EPA Science Inventory

In 2004, a group of large-scale ecosystem restoration practitioners across the United States convened to start the process of sharing restoration science, management, and best practices under the auspices of a traditional conference umbrella. This forum allowed scientists and dec...

Try This: Umbrella--Materials Testing

ERIC Educational Resources Information Center

Preston, Christine

2016-01-01

This article is the second in "Teaching Science's" "Try This" series. These hands-on activities are designed especially for early childhood students to encourage their natural curiosity and promote development of scientific thinking. In this activity, the problem-based learning approach means that the children are engaged in a…

Mission of PROCINORTE’s Tropical and Subtropical Fruit Taskforce

USDA-ARS?s Scientific Manuscript database

Canada, Mexico and United States are countries that share many interests in agricultural affairs. The three countries have been commercial partners for many years, and most recently they have been working under the North American Free Trade Agreement (NAFTA) umbrella. The three countries are natural...

Counseling in Brazil: Past, Present, and Future

ERIC Educational Resources Information Center

Hutz-Midgett, Aida; Hutz, Claudio Simon

2012-01-01

This article describes counseling in Brazil, which is rooted in career and vocational guidance. Although considered a distinct discipline, counseling falls under the umbrella of psychology. The multicultural movement is gaining momentum in Brazil, and counselors are pioneers working with socioracial minority college students. This is an emerging…

78 FR 14554 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-06

... Project Formative Research for the Development of CDC's Act Against AIDS Social Marketing Campaigns... period to develop various social marketing campaigns aimed at increasing HIV testing rates, increasing... social marketing campaigns under the umbrella of the larger Act Against AIDS campaign. The campaigns will...

Structure, Agency, Complexity Theory and Interdisciplinary Research in Education Studies

ERIC Educational Resources Information Center

Smith, John A.

2013-01-01

This article argues that Education Studies needs to develop its existing interdisciplinarity understanding of structures and agencies by giving greater attention to the modern process theories of self-organisation in the physical, biological, psychological and social sciences, sometimes given the umbrella term "complexity theory". The…

An Umbrella for Acid Rain.

ERIC Educational Resources Information Center

Randal, Judith

1979-01-01

The Environmental Protection Agency has awarded several grants to study effects of and possible solutions to the problem of "acid rain"; pollution from atmospheric nitric and sulfuric acids. The research program is administered through North Carolina State University at Raleigh and will focus on biological effects of acid rain. (JMF)

Transgender Youth

ERIC Educational Resources Information Center

Ludeke, Micah

2009-01-01

"Transgender" is an umbrella term for people who self-identify as other than their birth sex (male or female). The exploration of gender nonconformance occurs among people across all ethnic, racial, and socioeconomic groups. Transgender or questioning students may have unique challenges and stressors in their daily lives, including school. Often,…

Virtual Beach: Decision Support Tools for Beach Pathogen Prediction

EPA Science Inventory

The Virtual Beach Managers Tool (VB) is decision-making software developed to help local beach managers make decisions as to when beaches should be closed due to predicted high levels of water borne pathogens. The tool is being developed under the umbrella of EPA's Advanced Monit...

Connect Computer Education to Policies.

ERIC Educational Resources Information Center

Kimmelman, Paul

1985-01-01

The computer phenomenon has made rapid inroads into school curricula, often without proper board guidance or approval. Accordingly, this pamphlet discusses why and how computer education should be provided in schools and sets forth guidelines for school board policy regarding computers. An umbrella policy is proposed, defining "computer literacy"…

Program Spotlight: CRCHD Mock Grant Review

Cancer.gov

The NCI Center to Reduce Cancer Health Disparities (CRCHD) held a Professional Development Workshop for its Continuing Umbrella of Research Experience (CURE) scholars on June 23-24, 2014, in Rockville, Maryland. As part of the workshop, attendees had an opportunity to observe and participate in a Mock Grant Review.

BVDV: Detection, Risk Management and Control

USDA-ARS?s Scientific Manuscript database

The terms bovine viral diarrhea (BVD) and bovine viral diarrhea viruses (BVDV) are difficult to define in simple straightforward statements because both are umbrella terms covering a wide range of observations and entities. While diarrhea is in the name, BVD, it is used in reference to a number of ...

Conserved electrostatic fields at the Ras-effector interface measured through vibrational Stark effect spectroscopy explain the difference in tilt angle in the Ras binding domains of Raf and RalGDS.

PubMed

Walker, David M; Wang, Ruifei; Webb, Lauren J

2014-10-07

Vibrational Stark effect (VSE) spectroscopy was used to measure the electrostatic fields present at the interface of the human guanosine triphosphatase (GTPase) Ras docked with the Ras binding domain (RBD) of the protein kinase Raf. Nine amino acids located on the surface of Raf were selected for labeling with a nitrile vibrational probe. Eight of the probe locations were situated along the interface of Ras and Raf, and one probe was 2 nm away on the opposite side of Raf. Vibrational frequencies of the nine Raf nitrile probes were compared both in the monomeric, solvated protein and when docked with wild-type (WT) Ras to construct a comprehensive VSE map of the Ras-Raf interface. Molecular dynamics (MD) simulations employing an umbrella sampling strategy were used to generate a Boltzmann-weighted ensemble of nitrile positions in both the monomeric and docked complexes to determine the effect that docking has on probe location and orientation and to aid in the interpretation of VSE results. These results were compared to an identical study that was previously conducted on nine nitrile probes on the RBD of Ral guanidine dissociation stimulator (RalGDS) to make comparisons between the docked complexes formed when either of the two effectors bind to WT Ras. This comparison finds that there are three regions of conserved electrostatic fields that are formed upon docking of WT Ras with both downstream effectors. Conservation of this pattern in the docked complex then results in different binding orientations observed in otherwise structurally similar proteins. This work supports an electrostatic cause of the known binding tilt angle between the Ras-Raf and Ras-RalGDS complexes.

Structure and dynamics of Penetratin's association and translocation to a lipid bilayer

NASA Astrophysics Data System (ADS)

Ignacio J., General; Asciutto, Eliana K.

2017-03-01

Penetratin belongs to the important class of small and positively charged peptides, capable of entering cells. The determination of the optimal peptidic structure for translocation is challenging; results obtained so far are varied and dependent on several factors. In this work, we review the dynamics of association of Penetratin with a modeled dioleoyl-phosphatidylcholine (DOPC) lipid membrane using molecular dynamics simulations with last generation force fields. Penetratin's structural preferences are determined using a Markov state model. It is observed that the peptide retains a helical form in the membrane associated state, just as in water, with the exception of both termini which lose helicity, facilitating the interaction of terminal residues with the phosphate groups on the membrane's outer layer. The optimal orientation for insertion is found to be with the peptide's axis forming a small angle with the interface, and with R1 stretching toward the bilayer. The interaction between arginine side-chains and phosphate groups is found to be greater than the corresponding to lysine, mainly due to a higher number of hydrogen bonds between them. The free energy profile of translocation is qualitatively studied using Umbrella Sampling. It is found that there are different paths of penetration, that greatly differ in size of free energy barrier. The lowest path is compatible with residues R10 to K13 leading the way through the membrane and pulling the rest of the peptide. When the other side is reached, the C-terminus overtakes those residues, and finally breaks out of the membrane. The peptide's secondary structure during this traversal suffers some changes with respect to the association structure but, overall, conserves its helicity, with both termini in a more disordered state.

Substrate polarization in enzyme catalysis: QM/MM analysis of the effect of oxaloacetate polarization on acetyl-CoA enolization in citrate synthase.

PubMed

van der Kamp, Marc W; Perruccio, Francesca; Mulholland, Adrian J

2007-11-15

Citrate synthase is an archetypal carbon-carbon bond forming enzyme. It promotes the conversion of oxaloacetate (OAA) to citrate by catalyzing the deprotonation (enolization) of acetyl-CoA, followed by nucleophilic attack of the enolate form of this substrate on OAA to form a citryl-CoA intermediate and subsequent hydrolysis. OAA is strongly bound to the active site and its alpha-carbonyl group is polarized. This polarization has been demonstrated spectroscopically, [(Kurz et al., Biochemistry 1985;24:452-457; Kurz and Drysdale, Biochemistry 1987;26:2623-2627)] and has been suggested to be an important catalytic strategy. Substrate polarization is believed to be important in many enzymes. The first step, formation of the acetyl-CoA enolate intermediate, is thought to be rate-limiting in the mesophilic (pig/chicken) enzyme. We have examined the effects of substrate polarization on this key step using quantum mechanical/molecular mechanical (QM/MM) methods. Free energy profiles have been calculated by AM1/CHARMM27 umbrella sampling molecular dynamics (MD) simulations, together with potential energy profiles. To study the influence of OAA polarization, profiles were calculated with different polarization of the OAA alpha-carbonyl group. The results indicate that OAA polarization influences catalysis only marginally but has a larger effect on intermediate stabilization. Different levels of treatment of OAA are compared (MM or QM), and its polarization in the protein and in water analyzed at the B3LYP/6-31+G(d)/CHARMM27 level. Analysis of stabilization by individual residues shows that the enzyme mainly stabilizes the enolate intermediate (not the transition state) through electrostatic (including hydrogen bond) interactions: these contribute much more than polarization of OAA. (c) 2007 Wiley-Liss, Inc.

Effect of Phosphatidic Acid on Biomembrane: Experimental and Molecular Dynamics Simulations Study.

PubMed

Kwolek, Urszula; Kulig, Waldemar; Wydro, Paweł; Nowakowska, Maria; Róg, Tomasz; Kepczynski, Mariusz

2015-08-06

We consider the impact of phosphatidic acid (namely, 1,2-dioleoyl-sn-glycero-3-phosphate, DOPA) on the properties of a zwitterionic (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) bilayer used as a model system for protein-free cell membranes. For this purpose, experimental measurements were performed using differential scanning calorimetry and the Langmuir monolayer technique at physiological pH. Moreover, atomistic-scale molecular dynamics (MD) simulations were performed to gain information on the mixed bilayer's molecular organization. The results of the monolayer studies clearly showed that the DPPC/DOPA mixtures are nonideal and the interactions between lipid species change from attractive, at low contents of DOPA, to repulsive, at higher contents of that component. In accordance with these results, the MD simulations demonstrated that both monoanionic and dianionic forms of DOPA have an ordering and condensing effect on the mixed bilayer at low concentrations. For the DOPA monoanions, this is the result of both (i) strong electrostatic interactions between the negatively charged oxygen of DOPA and the positively charged choline groups of DPPC and (ii) conformational changes of the lipid acyl chains, leading to their tight packing according to the so-called "umbrella model", in which large headgroups of DPPC shield the hydrophobic part of DOPA (the conical shape lipid) from contact with water. In the case of the DOPA dianions, cation-mediated clustering was observed. Our results provide a detailed molecular-level description of the lipid organization inside the mixed zwitterionic/PA membranes, which is fully supported by the experimental data.

Digital Video and Writing with Priority Learners

ERIC Educational Resources Information Center

Diglin, Peter

2016-01-01

Digital technology has become more ubiquitous in classrooms across the western world. Literacy learning is topical in New Zealand education under the umbrella of the current National Standards policy, a policy introduced on the basis of rhetoric around improving achievement for priority learners. The study presented in this paper would then appear…

Endowment Investing: Time for a Sustainability Play?

ERIC Educational Resources Information Center

Pelletier, Stephen G.

2010-01-01

Managers of university endowment funds are paying closer attention to investing in "green" industries, commonly bundled under the umbrella "cleantech." Cleantech offers the possibility of buying in while prices are low "and" making a "green" investment play, but it also harbors the risks inherent in any emerging industry. Cleantech has varying…

Adapting Unconventional Warfare Doctrine to Cyberspace Operations: An Examination of Hacktivist Based Insurgencies

DTIC Science & Technology

2015-06-12

Unconventional Warfare, Cyberspace Operations, Cyber Warfare , Hacktivism, China, Russia, Georgia, Estonia, Umbrella Revolution, UW, Cyber, Guerilla, Hacktivist...6 Cyber Warfare ............................................................................................................. 7...Internet, and cyber warfare , the nature of the human element in cyberspace exhibits only a scientific advancement in the evolution of warfare, not a

Perspectives Regarding Classroom Management Style: Differences between Elementary and Secondary Level Teachers.

ERIC Educational Resources Information Center

Martin, Nancy K.; Baldwin, Beatrice

This study represents a continuation of research efforts to further refine the Inventory of Classroom Management Style, an instrument designed to measure teachers' perceptions of their classroom management beliefs and practices. "Classroom management" is an umbrella term describing teacher efforts to oversee a multitude of activities in…

The Changing Atmosphere: UNEP Environment Brief No. 1.

ERIC Educational Resources Information Center

United Nations Environment Programme, Nairobi (Kenya).

Discussed are the following topics: (1) the greenhouse problem, including the processes involved and some possible resulting scenarios; (2) ozone, the "umbrella" protecting the earth from lethal concentrations of ultraviolet rays and the problem of decreasing ozone levels; (3) what could happen as the earth gets warmer (including…

CLIL Implementation: From Policy-Makers to Individual Initiatives

ERIC Educational Resources Information Center

de Zarobe, Yolanda Ruiz

2013-01-01

Since Do Coyle and Hugo Baetens Beardsmore published their Special Issue on "Research on Content and Language Integrated Learning (CLIL)" in the "International Journal of Bilingual Education and Bilingualism" in 2007, there has been a great deal of interest and debate about the approach, which under the umbrella term of Content…

The Reactivation of the Western European Union

DTIC Science & Technology

1989-06-02

position under the US nuclear umbrella. Meanwhile, it seeks to conserve its 14 David Kramer and Glenn Yago , ŕ West Germany Contends with the Alliance...Kramer and Glenn Yago , "West Germany Contends with the Alliance Crisis": p. 133. 64 RELEVANT ACTORS ECONOMY. Figure 4 compares the GDPs of the WEU

A Collaborative Group Method of Inclusive Research

ERIC Educational Resources Information Center

Bigby, Christine; Frawley, Patsie; Ramcharan, Paul

2014-01-01

Background: Funding bodies in Australia and the United Kingdom require research on issues that affect the lives of people with intellectual disability to be inclusive. Debate continues about the nature and benefits of inclusive research, which has become an umbrella term encompassing a broad spectrum of approaches. Method: This study proposes one…

Service, Sex Work, and the Profession

ERIC Educational Resources Information Center

Potts, Donna L.

2012-01-01

The author serves as the chair of the American Association of University Professors' (AAUP) Assembly of State Conferences, the umbrella organization for individual state AAUP conferences; a moderator for Pandora's Project, a website for survivors of sexual abuse and assault; a volunteer for Veronica's Voice, a support program for women and girls…

Current uses of 2.0 applications in transportation : case studies of select state departments of transportation.

DOT National Transportation Integrated Search

2010-03-01

Web 2.0 is an umbrella term for websites or online applications that are user-driven and emphasize collaboration and user interactivity. The trend away from static web pages to a more user-driven Internet model has also occurred in the public s...

Students' Development of Representational Competence through the Sense of Touch

ERIC Educational Resources Information Center

Magana, Alejandra J.; Balachandran, Sadhana

2017-01-01

Electromagnetism is an umbrella encapsulating several different concepts like electric current, electric fields and forces, and magnetic fields and forces, among other topics. However, a number of studies in the past have highlighted the poor conceptual understanding of electromagnetism concepts by students even after instruction. This study aims…

30 CFR Appendix to Part 553 - List of U.S. Geological Survey Topographic Maps

Code of Federal Regulations, 2013 CFR

2013-07-01

...; Three Mile Bay; Tigre Lagoon; Timbalier Island; Triumph; Venice; Weeks; West of Johnson Bayou; Western... Islands; Tivoli SE; Turtle Bay; Umbrella Point; Virginia Point; West of Johnson Bayou; Whites Ranch...; Hollingers Island; Isle Aux Herbes; Kreole; Lillian; Little Dauphin Island; Little Point Clear; Magnolia...

30 CFR Appendix to Part 553 - List of U.S. Geological Survey Topographic Maps

Code of Federal Regulations, 2012 CFR

2012-07-01

...; Three Mile Bay; Tigre Lagoon; Timbalier Island; Triumph; Venice; Weeks; West of Johnson Bayou; Western... Islands; Tivoli SE; Turtle Bay; Umbrella Point; Virginia Point; West of Johnson Bayou; Whites Ranch...; Hollingers Island; Isle Aux Herbes; Kreole; Lillian; Little Dauphin Island; Little Point Clear; Magnolia...

30 CFR Appendix to Part 553 - List of U.S. Geological Survey Topographic Maps

Code of Federal Regulations, 2014 CFR

2014-07-01

...; Three Mile Bay; Tigre Lagoon; Timbalier Island; Triumph; Venice; Weeks; West of Johnson Bayou; Western... Islands; Tivoli SE; Turtle Bay; Umbrella Point; Virginia Point; West of Johnson Bayou; Whites Ranch...; Hollingers Island; Isle Aux Herbes; Kreole; Lillian; Little Dauphin Island; Little Point Clear; Magnolia...

The New School Collaborates: Organization and Communication in Immersive International Field Programs with Artisan Communities

ERIC Educational Resources Information Center

Lawson, Cynthia

2010-01-01

Under the umbrella terms of "humanitarian design," "social design" and "social responsibility," educational institutions and specifically design programs are more and more searching for opportunities to engage their students in critical and hands-on learning via collaborations between students, faculty, communities in…

Systematic Thinking on Dialogical Education

ERIC Educational Resources Information Center

Sarid, Ariel

2012-01-01

Dialogic or dialogical education is an umbrella term that encompasses a myriad of different and at times conflicting approaches. As there is no agreed-upon definition of "dialogue" (not that there is or should be one unified definition), and even fewer clear and systematic guidelines for application, researchers and practitioners in the DE field…

Everything Is Connected: Giftedness within a Broad Framework for Cognition

ERIC Educational Resources Information Center

Woolcott, Geoff

2012-01-01

Ziegler and Phillipson (Z&P) have provided a valuable discussion of the identification and development of giftedness under a systemic umbrella, including issues of differing theoretical approaches and efficacy. This commentary considers their discussion within a novel systemic framework that links also individuals and environment, but in terms of…

Understanding Horizontal Governance. Research Brief

ERIC Educational Resources Information Center

Ferguson, Daniel

2009-01-01

Horizontal governance is an umbrella term that covers a range of approaches to policy development, service delivery issues, and management practices. A horizontal initiative may take place across levels of government, across boundaries between units of a single department or agency or among multiple departments or agencies, or across public,…

A Ghetto Land Pedagogy: An Antidote for Settler Environmentalism

ERIC Educational Resources Information Center

Paperson, La

2014-01-01

A ghetto land pedagogy begins with two axioms that align it with land education more broadly, and that distinguish it from the general umbrella of environmental education. First, ghetto colonialism is a specialization of settler colonialism. Second, land justice requires decolonization, not just environmental justice. A ghetto land pedagogy thus…

Urban Education: A Model for Leadership and Policy

ERIC Educational Resources Information Center

Gallagher, Karen Symms, Ed.; Goodyear, Rodney, Ed.; Brewer, Dominic, Ed.; Rueda, Robert, Ed.

2011-01-01

Many factors complicate the education of urban students. Among them have been issues related to population density; racial, ethnic, cultural, and linguistic diversity; poverty; racism (individual and institutional); and funding levels. Although urban educators have been addressing these issues for decades, placing them under the umbrella of "urban…

Improving Girls' Education in Guatemala. Impact Evaluation.

ERIC Educational Resources Information Center

Agency for International Development (IDCA), Washington, DC. Center for Development Information and Evaluation.

In Guatemala, many girls attend no school. A project by the United States Agency for International Development (USAID), Basic Education Strengthening (BEST), demonstrated that improving educational quality is the best approach to enhancing girls' participation. BEST included a Girls Education Program (GEP) activity. Under the BEST/GEP umbrella,…

A Multidimensional Needs Assessment of Social Emotional Learning Skill Areas

ERIC Educational Resources Information Center

Yopp, Ashley; McKim, Billy R.; Moore, Lori L.; Odom, Summer F.; Hanagriff, Roger

2017-01-01

Social and Emotional Learning (SEL) has often been an umbrella term for a wide range of competencies, including emotional processes, social and interpersonal skills, and cognitive regulation (Jones, Bouffard, & Weissbourd, 2013). We used the Borich (1980) needs assessment model to assess the professional development needs of Texas agricultural…

Analyzing Sustainability Themes in State Science Standards: Two Case Studies

ERIC Educational Resources Information Center

Miller, Hannah K.; Jones, Linda Cronin

2014-01-01

Due to the interdisciplinary nature of environmental education, addressing the range of socioscientific issues included under the umbrella of sustainability can be challenging for educators working within the context of mandated state subject area standards. Two states (Washington and Vermont) have been recognized as leaders in incorporating…

Developing Psychological Literacy: Is There a Role for Reflective Practice?

ERIC Educational Resources Information Center

Coulson, Debra; Homewood, Judi

2016-01-01

Psychological literacy is an umbrella term that is widely used to describe the attributes or capabilities of psychology graduate (Cranney & Dunn 2011). This article explores some of the complexities inherent in the learning and teaching of psychological literacy by exploring challenges to the development of self-awareness and cultural…

LIFE CYCLE IMPACT ASSESSMENT WORKSHOP SUMMARY - MIDPOINTS VERSUS ENDPOINTS: THE SACRIFICES AND BENEFITS

EPA Science Inventory

On 5/25-26/2000 in Brighton, England, the third international workshop was held under the umbrella of UNEP addressing issues in Life Cycle Impact Assessment (LCIA). The workshop provided a forum for experts to discuss midpoint vs. endpoint modeling. Midpoints are considered to be...

Distance Education for Technology Teachers

ERIC Educational Resources Information Center

Williams, P. John

2004-01-01

A typical definition of distance education is the delivery of instruction in a format that separates the teacher and learner, often both in time and space. It tends to be an umbrella term that may encompass more specific forms of education such as distributed learning, independent study, correspondence education, satellite education, etc. This…

BRIDGES: Connecting with Families to Facilitate and Enhance Involvement

ERIC Educational Resources Information Center

Sawyer, Mary

2015-01-01

"Parent involvement" is an umbrella term for activities characterized by varying levels of frequency, response effort, and types of settings in which they occur. Parent involvement in a child's education can occur in a variety of school-related contexts, including helping with homework and supporting academic development at home. It…

Mathematical models in simulation process in rehabilitation of persons with disabilities

NASA Astrophysics Data System (ADS)

Gorie, Nina; Dolga, Valer; Mondoc, Alina

2012-11-01

The problems of people with disability are varied. A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these. The major disabilities which can appear in people's lives are: the blindness, the deafness, the limb-girdle muscular dystrophy, the orthopedic impairment, the visual impairment. A disability is an umbrella term, covering impairments, activity limitations and participation restrictions. A disability may occur during a person's lifetime or may be present from birth. The authors conclude that some of these disabilities like physical, cognitive, mental, sensory, emotional, developmental can be rehabilitated. Starting from this state of affairs the authors present briefly the possibility of using certain mechatronic systems for rehabilitation of persons with different disabilities. The authors focus their presentation on alternative calling the Stewart platform in order to achieve the proposed goal. The authors present a mathematical model of systems theory approach under the parallel system and described its contents can. The authors analyze in a meaningful mathematical model describing the procedure of rehabilitation process. From the affected function biomechanics and taking into account medical recommendations the authors illustrate the mathematical models of rehabilitation work. The authors assemble a whole mathematical model of parallel structure and the rehabilitation process and making simulation and highlighting the results estimated. The authors present in the end work the results envisaged in the end analysis work, conclusions and steps for future work program..

Potential of Mean Force Calculations of Solute Permeation Across UT-B and AQP1: A Comparison between Molecular Dynamics and 3D-RISM.

PubMed

Ariz-Extreme, Igor; Hub, Jochen S

2017-02-23

Membrane channels facilitate the efficient and selective flux of various solutes across biological membranes. A common approach to investigate the selectivity of a channel has been the calculation of potentials of mean force (PMFs) for solute permeation across the pore. PMFs have been frequently computed from molecular dynamics (MD) simulations, yet the three-dimensional reference interaction site model (3D-RISM) has been suggested as a computationally efficient alternative to MD. Whether the two methods yield comparable PMFs for solute permeation has remained unclear. In this study, we calculated potentials of mean force for water, ammonia, urea, molecular oxygen, and methanol across the urea transporter B (UT-B) and aquaporin-1 (AQP1), using 3D-RISM, as well as using MD simulations and umbrella sampling. To allow direct comparison between the PMFs from 3D-RISM and MD, we ensure that all PMFs refer to a well-defined reference area in the bulk or, equivalently, to a well-defined density of channels in the membrane. For PMFs of water permeation, we found reasonable agreement between the two methods, with differences of ≲3 kJ mol -1 . In contrast, we found stark discrepancies for the PMFs for all other solutes. Additional calculations confirm that discrepancies between MD and 3D-RISM are not explained by the choice for the closure relation, the definition the reaction coordinate (center of mass-based versus atomic site-based), details of the molecule force field, or fluctuations of the protein. Comparison of the PMFs suggests that 3D-RISM may underestimate effects from hydrophobic solute-channel interactions, thereby, for instance, missing the urea binding sites in UT-B. Furthermore, we speculate that the orientational averages inherent to 3D-RISM might lead to discrepancies in the narrow channel lumen. These findings suggest that current 3D-RISM solvers provide reasonable estimates for the PMF for water permeation, but that they are not suitable to study the selectivity of membrane channels with respect to uncharged nonwater solutes.

Free energy of conformational transition paths in biomolecules: The string method and its application to myosin VI

PubMed Central

Ovchinnikov, Victor; Karplus, Martin; Vanden-Eijnden, Eric

2011-01-01

A set of techniques developed under the umbrella of the string method is used in combination with all-atom molecular dynamics simulations to analyze the conformation change between the prepowerstroke (PPS) and rigor (R) structures of the converter domain of myosin VI. The challenges specific to the application of these techniques to such a large and complex biomolecule are addressed in detail. These challenges include (i) identifying a proper set of collective variables to apply the string method, (ii) finding a suitable initial string, (iii) obtaining converged profiles of the free energy along the transition path, (iv) validating and interpreting the free energy profiles, and (v) computing the mean first passage time of the transition. A detailed description of the PPS↔R transition in the converter domain of myosin VI is obtained, including the transition path, the free energy along the path, and the rates of interconversion. The methodology developed here is expected to be useful more generally in studies of conformational transitions in complex biomolecules. PMID:21361558

Solvent, Temperature And Concentration Effects on the Optical Activity of Chiral FIVE-And-SIX Membered Ring Ketones Conformers

NASA Astrophysics Data System (ADS)

Al-Basheer, Watheq

2017-06-01

Chiral five-and-six membered ring ketones are important molecules that are found in many biological systems and can exist in many possible conformers. In this talk, experimental and computational investigation of solvent, temperature and concentration effects on the circular dichroism (CD) and optical rotation (OR) of (R)-3 -methylcyclohexanone (R3MCH), (R)-3-methylcyclopentanone (R3MCP) and carvone conformers will be discussed. CD and OR measurements of these ketones gaseous samples and in ten common solvents of wide polarity range for different concentrations and sample temperatures were recorded and related to molecular conformation. Density functional theoretical calculations were performed using Gaussian09 at B3LYP functions with aug-cc-pVDZ level of theory. Also, CD and OR spectra for the optimized geometries of the ketones dominant conformers were computed over the ultraviolet and visible region in the gas phase as well as in ten solvents of varying polarity range, and under the umbrella of the polarizable continuum model (PCM). By comparing theoretical and experimental results, few thermodynamic parameters were deduced for the individual equatorial and axial conformers of each molecule in gas phase and in solvation.

Educating Professional Musicians: Lessons Learned from School Music

ERIC Educational Resources Information Center

Carruthers, Glen

2008-01-01

Music in Canadian schools at one time focused on skills development. Building on talent, aptitude, prior learning and physical coordination, students would become better at singing or playing an instrument by studying it at school. Over time, new approaches to music teaching and learning opened the umbrella to a more comprehensive range of…

Identifying Risk and Promoting Resilience in Infants and Toddlers with Fetal Alcohol Spectrum Disorders

ERIC Educational Resources Information Center

Shah, Prachi; Milgrom, Tedi; Munzer, Tiffany; Hoyme, H. Eugene

2015-01-01

Fetal alcohol spectrum disorders (FASDs) is an umbrella term that describes a variety of conditions characterized by a pattern of atypical facial features, growth restriction, structural physical abnormalities, and brain dysfunction resulting from prenatal alcohol exposure. Studies suggest that the prevalence of FASDs ranges between 2-5% (of the…

Should I Pack My Umbrella? Clinical versus Statistical Prediction of Mental Health Decisions

ERIC Educational Resources Information Center

Aegisdottir, Stefania; Spengler, Paul M.; White, Michael J.

2006-01-01

In this rejoinder, the authors respond to the insightful commentary of Strohmer and Arm, Chwalisz, and Hilton, Harris, and Rice about the meta-analysis on statistical versus clinical prediction techniques for mental health judgments. The authors address issues including the availability of statistical prediction techniques for real-life psychology…

A strategic systems perspective of organizational learning theory: models for a case study at the Jet Propulsion Laboratory

NASA Technical Reports Server (NTRS)

Neece, O.

2000-01-01

Organizational learning is an umbrella term that covers a variety of topics including; learning curves, productivity, organizational memory, organizational forgetting, knowledge transfer, knowledge sharing and knowledge creation. This treatise will review some of these theories in concert with a model of how organizations learn.

Cyber Forensics and Security as an ABET-CAC Accreditable Program

ERIC Educational Resources Information Center

Wood, David F.; Kohun, Frederick G.; Ali, Azad; Paullet, Karen; Davis, Gary A.

2010-01-01

This paper frames the recent ABET accreditation model with respect to the balance between IS programs and innovation. With the current relaxation of the content of the information systems requirement by ABET, it is possible to include innovation into the accreditation umbrella. To this extent this paper provides a curricular model that provides…

Writing in the Workplace: Implications for Human Resource Development

ERIC Educational Resources Information Center

Akdere, Mesut; Azevedo, Ross E.

2005-01-01

Writing in the workplace is among the understudied business topics in the field of HRD. Yet, the impacts of writing in today's workplace are significant, and organizations making it a priority benefit from it. Furthermore, writing is related to the issue of workplace literacy which is the umbrella term for basic communication skills. This…

PROCSEE: Policy Challenges for Professional Higher Education in Central and South-Eastern Europe

ERIC Educational Resources Information Center

Policnik, Jasmina; Sauli Miklavcic, Alicia Leonor; Alupei-Durach, Flavia; Nožica, Žarko; Chrást, Ondrej; Voldánová, Iva; Karpíšek, Michal; Dinya, László; Medve, Anna; Wéber, György; Racsko, Réka; Perényi, Petra; Camilleri, Anthony F.

2016-01-01

PROCSEE is a policy-oriented project, aimed at strengthening the provision of professional higher education, by strengthening the policy-work conducted by umbrella organizations representing professional higher education institutions in Central and South-Eastern in Europe. Working together over three years, the project intends to: (1) identify the…

Education as a Spectral Technology: Corporate Culture at Work in Ontario's Schools

ERIC Educational Resources Information Center

Martin, Susan Marie

2012-01-01

This paper addresses the sweeping neoliberal reforms implemented in Ontario's schools in 2000, and conceptualises them within the terms of "millennial capitalism" (Comaroff & Comaroff, 2000). A close reading of secondary school curriculum documents and the umbrella policies that shape education from ages 5 to 18 years reveals how…

Emotional Disturbance. NICHCY Disability Fact Sheet #5

ERIC Educational Resources Information Center

National Dissemination Center for Children with Disabilities, 2010

2010-01-01

The mental health of our children is a natural and important concern for us all. The fact is, many mental disorders have their beginnings in childhood or adolescence, yet may go undiagnosed and untreated for years. "Umbrella" terms such as emotional disturbance, behavioral disorders, or mental illness are used to refer to mental…

Outcome Assessment of the Visiting Fulbright Scholar Program

ERIC Educational Resources Information Center

US Department of State, 2005

2005-01-01

The Office of Policy and Evaluation of the Bureau of Educational and Cultural Affairs of the U.S. Department of State contracted with SRI International to conduct a series of assessments of outcomes and impacts of various specialized exchange programs under the overall umbrella of the Fulbright Educational Exchange Program, the U.S. government's…

Multi-taxa population connectivity in the northern Rocky Mountains

Treesearch

Samuel A. Cushman; Erin L. Landguth

2012-01-01

Effective broad-spectrum biodiversity conservation requires that conservation strategies simultaneously meet the needs of multiple species. However, little is known about how maintaining habitat connectivity for one species or species group may also act as an umbrella for other species. We evaluated the degree to which predicted connected habitat for each of 144...

BDSM Disclosure and Stigma Management: Identifying Opportunities for Sex Education

ERIC Educational Resources Information Center

Bezreh, Tanya; Weinberg, Thomas S.; Edgar, Timothy

2012-01-01

While participation in the activities like bondage, domination, submission/sadism, masochism that fall under the umbrella term BDSM is widespread, stigma surrounding BDSM poses risks to practitioners who wish to disclose their interest. We examined risk factors involved with disclosure to posit how sex education might diffuse stigma and warn of…

Measuring the Test-Wiseness of Medical Students.

ERIC Educational Resources Information Center

Harvill, Leo M.

The objectives for this study were to: (1) develop a valid, reliable measure of test-wiseness with equivalent forms for use with students in the health sciences; and (2) determine the level of test-wiseness of entering medical students. The test-wiseness areas included in this study were: similar options, umbrella term, item give-away, convergence…

Unintended Revelations in History Textbooks: The Precarious Authenticity and Historical Continuity of the Slovak Nation

ERIC Educational Resources Information Center

Šulíková, Jana

2016-01-01

Purpose: This article proposes an analytical framework that helps to identify and challenge misconceptions of ethnocentrism found in pre-tertiary teaching resources for history and the social sciences in numerous countries. Design: Drawing on nationalism studies, the analytical framework employs ideas known under the umbrella terms of…

Making It Personal: The Importance of Student Experience in Creating Autonomy-Supportive Classrooms for Millennial Learners

ERIC Educational Resources Information Center

Conklin, Thomas A.

2013-01-01

This article reviews andragogy as the philosophy resident in the broad arena of experience-based learning. Beneath the umbrella of experience-based learning lie the specific classroom orientations of student-centered learning, problem-based learning, and classrooms as organizations. These orientations contribute to the creation of…

The Changing World of Higher Education: Where Do Language Centres Fit in?

ERIC Educational Resources Information Center

Dijk, Anje; Engelen, Christine; Korebrits, Liesbet

2014-01-01

This article assesses the current trends in language centre (LC) management in the Netherlands and Dutch-speaking Belgium. Twenty-five LCs are united under the umbrella of NUT, which offers its members the possibility to meet and discuss concrete professional subjects. Solutions, strategies and decisions emphasise the importance of national…

Current uses of Web 2.0 applications in transportation : case studies of select state departments of transportation

DOT National Transportation Integrated Search

2010-03-01

Web 2.0 is an umbrella term for websites or online applications that are user-driven and emphasize collaboration and user interactivity. The trend away from static web pages to a more user-driven Internet model has also occurred in the public s...

Divergence and Convergence within Greek Library Education: An Applied vs a Theoretical Approach

ERIC Educational Resources Information Center

Kyriaki-Manessi, Daphne

2008-01-01

This paper explores the differences and similarities of the three library schools educating librarians and information professionals in Greece. The structure of higher education in Greece has recently undergone major changes (2002) integrating technological institutions and universities under one umbrella that of higher education. As a result,…

Evaluating the Theory of Executive Dysfunction in Autism

ERIC Educational Resources Information Center

Hill, Elisabeth L.

2004-01-01

In this paper studies of executive function in autism spectrum disorder are reviewed. Executive function is an umbrella term for functions such as planning, working memory, impulse control, inhibition, and shifting set, as well as for the initiation and monitoring of action. In this review, the focus will be on planning, inhibition, shifting set,…

Parent Abuse: A Review

ERIC Educational Resources Information Center

Kennair, Nicola; Mellor, David

2007-01-01

A recent focus of research and clinical practice has been on the issue of abuse of parents by their children (parent abuse). This paper reviews the literature on this phenomenon. While parent abuse falls under the umbrella of family violence, it appears to be qualitatively different from other forms of intra-family abuse. Research has primarily…

Building a Blended Learning Program

ERIC Educational Resources Information Center

McLester, Susan

2011-01-01

"Online learning" often serves as an umbrella term that includes the subcategory of blended learning, which might also be referred to as hybrid learning, and comprises some combination of online and face-to-face time. Spurred in part by a 2009 U.S. Department of Education study, "Evaluation of Evidence-Based Practices in Online Learning," which…

Education in Action, School Year 1975-1976.

ERIC Educational Resources Information Center

Robin, Fay

This report is an evaluation of selected New York City Umbrella Programs funded under a special grant from the New York State Legislature. The 1975-76 Education in Action Program, a community health education program, served 427 elementary and junior high school students and 105 community parents in the Harlem and East Harlem communities. The…

Media Storytelling, Curriculum, and the Next 100 Years

ERIC Educational Resources Information Center

Lipschultz, Jeremy Harris

2012-01-01

Journalism as an academic field in the United States has frequently changed and grown through new professions and new industries coming under its umbrella (sometimes but not always driven by technological and/or economic changes) and academic developments such as cultural studies and media studies. But journalism is still rooted in good…

Investigation of the Relationship between Learning Process and Learning Outcomes in E-Learning Environments

ERIC Educational Resources Information Center

Yurdugül, Halil; Menzi Çetin, Nihal

2015-01-01

Problem Statement: Learners can access and participate in online learning environments regardless of time and geographical barriers. This brings up the umbrella concept of learner autonomy that contains self-directed learning, self-regulated learning and the studying process. Motivation and learning strategies are also part of this umbrella…

When Technology, Science and Culture Meet: Insights from Ancient Chinese Technology

ERIC Educational Resources Information Center

Lee, Yeung Chung

2018-01-01

This paper draws together two important agendas in science education. The first is making science education more inclusive such that students from non-Western or indigenous cultures can benefit from culturally relevant curricula. The second is integrating technology into the curriculum under the umbrella of Science-Technology-Society (STS)…

The Impact of Tougher Education Standards: Evidence from Florida

ERIC Educational Resources Information Center

Clark, Damon; See, Edward

2011-01-01

Many of the policies that fall under the school accountability umbrella are designed to incentivize students. Prominent among these are high school exit exams, standardized tests that, in some states, students must pass to earn a high school diploma. Proponents of these tests argue that by incentivizing students, they induce them to work harder…

Report from the European Prison Education Association

ERIC Educational Resources Information Center

Behan, Cormac

2008-01-01

Since the last edition of the Journal, the European Prison Education Association (EPEA) has been officially elected a member of the European Association for the Education of Adults (EAEA) at EAEA's General Assembly held at the University of Latvia in Riga. The EAEA is the largest umbrella organization in Europe advocating lifelong learning. It is…

APPA Promotes Leadership in Energy and Sustainability with New FPI Tool

ERIC Educational Resources Information Center

Boyce, Darryl K.

2012-01-01

Although sustainability best practices for buildings are generally well understood, campuses face unique challenges because they are developed to support a diverse community with a variety of facilities. From academic facilities and labs to residences and sports facilities, all operate under one organizational umbrella. This can make it difficult…

Understanding and Implementing the CLT (Communicative Language Teaching) Paradigm

ERIC Educational Resources Information Center

Jacobs, George M.; Farell, Thomas S. C.

2003-01-01

The call to change seems to be a constant in education. In second language education, a constellation of changes have been proposed and, to some extent, implemented. This constellation of interconnected changes can perhaps best be termed a paradigm shift, with this paradigm fitting under the general umbrella of Communicative Language Teaching…

Digital Media, Technologies and Scholarship: Some Shapes of eResearch in Educational Inquiry

ERIC Educational Resources Information Center

Markauskaite, Lina

2010-01-01

This paper discusses some recent developments in digital media, research technologies and scholarly practices that are known under the umbrella term of "eResearch". Drawing on conceptual ideas of digital materialism, epistemic artefacts and epistemic tools, this paper discusses how the digital inscription of knowledge and knowing could…

Socially Indigenous Help: The Community Cares for Itself.

ERIC Educational Resources Information Center

Curry, Ronald; Young, Richard D.

Recently, interest has increased in self-help groups, lay referral networks, social support networks, natural helpers, and others which may be placed under a single conceptual umbrella--socially indigenous help--because they all deal with the issue of how people use other people, social groups, and lay institutions to alleviate problems in living,…

Morbidity and Mortality: Building the Culture for Professional Growth and Innovation

ERIC Educational Resources Information Center

Howland, Jonathan

2011-01-01

Like their counterparts in law and medicine, teachers are professionals whose habits and techniques and strategies--whose "practices"--must be derived and customized and refined from a panoply of available prospects. So, while there are surely some pedagogies they might gather under the umbrella of "worst practices," one effective teacher's "best…

Technology-Supported Orchestration Matters: Outperforming Paper-Based Scripting in a Jigsaw Classroom

ERIC Educational Resources Information Center

Balestrini, Mara; Hernandez-Leo, Davinia; Nieves, Raul; Blat, Josep

2014-01-01

Under the umbrella of ubiquitous technologies, many computational artifacts have been designed to enhance the learning experience in physical settings such as classrooms or playgrounds, but few of them focus on aiding orchestration. This paper presents a systematic evaluation of the signal orchestration system (SOS) used by students for a jigsaw…

One for Autism: A Powerful Formula for Success

ERIC Educational Resources Information Center

Caroff, Maria

2007-01-01

One for Autism is a thriving and ever-growing facility for children with autism and other developmental delays. One for Autism, Inc., umbrellas One for Autism Academy, which offers a classroom setting, as well as One for Autism Center, which provides one-on-one comprehensive therapies, including behavioral therapy, occupational therapy and speech…

The relieving effects of shelter modes on physiological stress of traffic police in summer

NASA Astrophysics Data System (ADS)

Zheng, G. Z.; Wang, Y. J.; Bu, W. T.; Lu, Y. Z.; Li, Ke; Li, Z. H.

2018-03-01

In summer, high temperature and strong sun radiation last for a long time. However, traffic police still stick to their positions to ensure normal traffic order. Therefore, the health and safety of traffic police are challenged by the high temperature weather. To protect the safety of the traffic police in the outdoor high temperature environment, some shelter modes, such as sun hat and sun umbrella are selected for duty traffic police. The relieving effects on the physiological stress of the shelter modes are analyzed by comparison of the physiological parameters in these shelter modes. The results show that sun umbrella has a good effect on relieving physiological stress. And sun hat has no effect on relieving physiological stress, although it avoids the direct sunlight on the face. However, it causes the increase of the thermal sensation. This study can provide important methods for health protecting of traffic police in the outdoor high temperature environment. It also provides a theoretical support for the revision of the outdoor high temperature labour protection standard.

Power attenuation characteristics as switch-over criterion in personal satellite mobile communications

NASA Technical Reports Server (NTRS)

Castro, Jonathan P.

1993-01-01

A third generation mobile system intends to support communications in all environments (i.e., outdoors, indoors at home or office and when moving). This system will integrate services that are now available in architectures such as cellular, cordless, mobile data networks, paging, including satellite services to rural areas. One way through which service integration will be made possible is by supporting a hierarchical cellular structure based on umbrella cells, macro cells, micro and pico cells. In this type of structure, satellites are part of the giant umbrella cells allowing continuous global coverage, the other cells belong to cities, neighborhoods, and buildings respectively. This does not necessarily imply that network operation of terrestrial and satellite segments interconnect to enable roaming and spectrum sharing. However, the cell concept does imply hand-off between different cell types, which may involve change of frequency. Within this propsective, the present work uses power attenuation characteristics to determine a dynamic criterion that allows smooth transition from space to terrestrial networks. The analysis includes a hybrid channel that combines Rician, Raleigh and Log Normal fading characteristics.

Coffee, Caffeine, and Health Outcomes: An Umbrella Review.

PubMed

Grosso, Giuseppe; Godos, Justyna; Galvano, Fabio; Giovannucci, Edward L

2017-08-21

To evaluate the associations between coffee and caffeine consumption and various health outcomes, we performed an umbrella review of the evidence from meta-analyses of observational studies and randomized controlled trials (RCTs). Of the 59 unique outcomes examined in the selected 112 meta-analyses of observational studies, coffee was associated with a probable decreased risk of breast, colorectal, colon, endometrial, and prostate cancers; cardiovascular disease and mortality; Parkinson's disease; and type-2 diabetes. Of the 14 unique outcomes examined in the 20 selected meta-analyses of observational studies, caffeine was associated with a probable decreased risk of Parkinson's disease and type-2 diabetes and an increased risk of pregnancy loss. Of the 12 unique acute outcomes examined in the selected 9 meta-analyses of RCTs, coffee was associated with a rise in serum lipids, but this result was affected by significant heterogeneity, and caffeine was associated with a rise in blood pressure. Given the spectrum of conditions studied and the robustness of many of the results, these findings indicate that coffee can be part of a healthful diet.

An umbrella review of garlic intake and risk of cardiovascular disease.

PubMed

Schwingshackl, Lukas; Missbach, Benjamin; Hoffmann, Georg

2016-10-15

To gain further insight into the strength of evidence and extent of possible biases in the scope of studies investigating the impact of garlic and garlic supplement intake on biomarkers of cardiovascular disease, we performed an umbrella review of all published meta-analyses synthesizing data from both observational studies and randomized controlled trials. Electronic database PubMed (between 1966 and June 2015) was searched for systematic reviews and meta-analyses using following search terms: ("garlic" OR "allium sativum" OR "allicin" OR "organosulfur") AND ("cardiovascular" OR "coronary" OR "cholesterol" OR "triglyceride" OR "atherosclerosis" OR "blood pressure" OR "hypertension" OR "blood glucose") AND ("systematic review" OR "meta-analysis"), with no restriction to calendar data and language. Hand-search of reference lists and relevant clinical guidelines was performed as well. Nine systematic reviews investigated the effects of garlic on lipid parameters and eight systematic reviews analyzed the effects on blood pressure parameters were identified. Eight of nine meta-analyses synthesizing the effect of garlic on blood lipids reported significantly decreased total cholesterol levels. Inconsistent results could be detected for HDL-cholestrol, LDL-cholesterol, and triacylglycerols. The effect of garlic on systolic blood pressure showed consistent results across publications with 7 out of 8 meta-analyses demonstrating a substantial decrease in systolic blood pressure. Similar results could be reported regarding the effect of garlic on diastolic blood pressure, i.e. 6 out of 8 meta-analyses detected significant reductions in diastolic blood pressure levels following interventions with garlic. According to the data summarized in the present umbrella review, garlic preparations as well as garlic exerted some positive effects on indicators and biomarkers of cardiovascular disease, typically without causing any serious side effects. However, with regard to the substantial heterogeneities between the different trials enrolled in the various meta-analyses of this review, a conservative interpretation of the outcome seems to be appropriate. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cross-sector Service Provision in Health and Social Care: An Umbrella Review.

PubMed

Winters, Shannon; Magalhaes, Lilian; Anne Kinsella, Elizabeth; Kothari, Anita

2016-04-08

Meeting the complex health needs of people often requires interaction among numerous different sectors. No one service can adequately respond to the diverse care needs of consumers. Providers working more effectively together is frequently touted as the solution. Cross-sector service provision is defined as independent, yet interconnected sectors working together to better meet the needs of consumers and improve the quality and effectiveness of service provision. Cross-sector service provision is expected, yet much remains unknown about how it is conceptualised or its impact on health status. This umbrella review aims to clarify the critical attributes that shape cross-sector service provision by presenting the current state of the literature and building on the findings of the 2004 review by Sloper. Literature related to cross-sector service provision is immense, which poses a challenge for decision makers wishing to make evidence-informed decisions. An umbrella review was conducted to articulate the overall state of cross-sector service provision literature and examine the evidence to allow for the discovery of consistencies and discrepancies across the published knowledge base. Sixteen reviews met the inclusion criteria. Seven themes emerged: Focusing on the consumer, developing a shared vision of care, leadership involvement, service provision across the boundaries, adequately resourcing the arrangement, developing novel arrangements or aligning with existing relationships, and strengthening connections between sectors. Future research from a cross-organisational, rather than individual provider, perspective is needed to better understand what shapes cross-sector service provision at the boundaries. Findings aligned closely with the work done by Sloper and raise red flags related to reinventing what is already known. Future researchers should look to explore novel areas rather than looking into areas that have been explored at length. Evaluations of out-comes related to cross-sector service provision are still needed before any claims about effectiveness can be made.

Is chocolate consumption associated with health outcomes? An umbrella review of systematic reviews and meta-analyses.

PubMed

Veronese, Nicola; Demurtas, Jacopo; Celotto, Stefano; Caruso, Maria Gabriella; Maggi, Stefania; Bolzetta, Francesco; Firth, Joseph; Smith, Lee; Schofield, Patricia; Koyanagi, Ai; Yang, Lin; Solmi, Marco; Stubbs, Brendon

2018-06-01

The literature regarding the potential health benefits of chocolate consumption are unclear and the epidemiological credibility has not been systematically scrutinized, while the strength of the evidence is undetermined. We therefore aimed to map and grade the diverse health outcomes associated with chocolate consumption using an umbrella review of systematic reviews. Umbrella review of systematic reviews of observational and intervention studies (randomized placebo-controlled trials, RCTs). For each association, random-effects summary effect size, 95% confidence interval, and 95% prediction interval were estimated. We also assessed heterogeneity, evidence for small-study effect and evidence for excess significance bias. For significant outcomes of the RCTs, the GRADE assessment was furtherly used. From 240 articles returned, 10 systematic reviews were included (8 of which included a meta-analysis), including a total of 84 studies (36 prospective observational studies and 48 interventional). Nineteen different outcomes were included. Among observational studies, including a total of 1,061,637 participants, the best available evidence suggests that chocolate consumption is associated with reduced risk of cardiovascular disease (CVD) death (n = 4 studies), acute myocardial infarction (n = 6), stroke (n = 5) and diabetes (n = 6), although this was based on a weak evidence of credibility. Across meta-analyses of intervention studies, chocolate consumption was positively associated with flow-mediated dilatation at 90-150 min (n = 3) and at 2-18 weeks (n = 3), and insulin resistance markers (n = 2). However, using the GRADE assessment, the evidence for these outcomes was low or very low. Data from two systematic reviews, reported that chocolate consumption was not associated with better depressive mood or cognitive function. There is weak evidence to suggest that chocolate consumption may be associated with favorable health outcomes. Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Cross-sector Service Provision in Health and Social Care: An Umbrella Review

PubMed Central

Magalhaes, Lilian; Anne Kinsella, Elizabeth; Kothari, Anita

2016-01-01

Introduction: Meeting the complex health needs of people often requires interaction among numerous different sectors. No one service can adequately respond to the diverse care needs of consumers. Providers working more effectively together is frequently touted as the solution. Cross-sector service provision is defined as independent, yet interconnected sectors working together to better meet the needs of consumers and improve the quality and effectiveness of service provision. Cross-sector service provision is expected, yet much remains unknown about how it is conceptualised or its impact on health status. This umbrella review aims to clarify the critical attributes that shape cross-sector service provision by presenting the current state of the literature and building on the findings of the 2004 review by Sloper. Methods: Literature related to cross-sector service provision is immense, which poses a challenge for decision makers wishing to make evidence-informed decisions. An umbrella review was conducted to articulate the overall state of cross-sector service provision literature and examine the evidence to allow for the discovery of consistencies and discrepancies across the published knowledge base. Findings: Sixteen reviews met the inclusion criteria. Seven themes emerged: Focusing on the consumer, developing a shared vision of care, leadership involvement, service provision across the boundaries, adequately resourcing the arrangement, developing novel arrangements or aligning with existing relationships, and strengthening connections between sectors. Future research from a cross-organisational, rather than individual provider, perspective is needed to better understand what shapes cross-sector service provision at the boundaries. Conclusion: Findings aligned closely with the work done by Sloper and raise red flags related to reinventing what is already known. Future researchers should look to explore novel areas rather than looking into areas that have been explored at length. Evaluations of out-comes related to cross-sector service provision are still needed before any claims about effectiveness can be made. PMID:27616954