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PubMed2001

Molecular dynamics simulations of B '-DNA: sequence effects on A-tract-induced bending and flexibility.

Molecular dynamics (MD) simulations including water and counterions are reported on five examples of A-tract DNA oligonucleotide dodecamer duplexes for which crystal structures are available, the homopolymeric duplex sequences poly(dA) and poly(dG), and two related sequences that serve as controls. MD was performed using the AMBER suite of programs for 3 ns on each sequence. These results, combined with previously reported MDs on 25-mer and 30-mer oligonucleotides on sequences with phased A-tracts carried out under a similar simulation protocol, are used to examine salient issues in the structural chemistry of ApA steps and A-tract induced axis bending. MD modeling successfully describes the distinctive B' structure of A-tracts in solution as essentially straight (wedge angles of <1 degrees ), more rigid than generic B-form DNA, with slight base-pair inclination, high propeller twist and a minor groove narrowing 5' to 3'. The MD structures in solution agree closely with corresponding crystal structures, supporting the idea that crystal structures provide a good model for A-tract DNA structure in solution. From the collective MD results, bending and flexibility are calculated by step. Pyrimidine-purine steps are predicted to be most intrinsically bent and also most bendable, i.e. susceptible to bending. Pyrimidine-pyrimidine ( approximately purine-purine) and purine-pyrimidine steps show less intrinsic deformation and deformability. The MD calculated flexibility correlates well with the protein-induced bendability derived independently from the protein DNA crystal structures. The MD results indicate that bending and flexibility of base-pair steps in DNA are highly correlated, i.e. steps that exhibit the most intrinsic deformation from B-form DNA turn are also the most dynamically deformable. The MD description of A-tract-induced axis bending shows most consistency with the non A-tract, general-sequence model, in which the sequence curvature originates primarily in base-pair roll towards the major groove in non-A-tract regions of the sequence, particularly pyrimidine-purine steps. The direction of curvature is towards the minor groove viewed from opposite the A-tracts, but the A-tracts per se exhibit only minor deformation. The MD results are found to be consistent with the directionality of bending inferred for DNA sequences from gel retardation and cyclization experiments.

Base Pairing↗
PubMed2004

Bilayer conformation of fusion peptide of influenza virus hemagglutinin: a molecular dynamics simulation study.

Unraveling the conformation of membrane-bound viral fusion peptides is essential for understanding how those peptides destabilize the bilayer topology of lipids that is important for virus-cell membrane fusion. Here, molecular dynamics (MD) simulations were performed to investigate the conformation of the 20 amino acids long fusion peptide of influenza hemagglutinin of strain X31 bound to a dimyristoyl phosphatidylcholine (DMPC) bilayer. The simulations revealed that the peptide adopts a kinked conformation, in agreement with the NMR structures of a related peptide in detergent micelles. The peptide is located at the amphipathic interface between the headgroups and hydrocarbon chains of the lipid by an energetically favorable arrangement: The hydrophobic side chains of the peptides are embedded into the hydrophobic region and the hydrophilic side chains are in the headgroup region. The N-terminus of the peptide is localized close to the amphipathic interface. The molecular dynamics simulations also revealed that the peptide affects the surrounding bilayer structure. The average hydrophobic thickness of the lipid phase close to the N-terminus is reduced in comparison with the average hydrophobic thickness of a pure dimyristoyl phosphatidylcholine bilayer.

Computer Simulation↗
PubMed1992

Molecular dynamics simulations of helix denaturation.

An understanding of the structural transitions that an alpha-helix undergoes will help to elucidate such motions in proteins and their role in protein folding. We present the results of molecular dynamics simulations to investigate these transitions in a short polyalanine peptide (13 residues) both in vacuo and in the presence of solvent. The denaturation of this peptide was monitored as a function of temperature (ranging from 5 to 200 degrees C). In vacuo, the helical state predominated at all temperatures, whereas in solution the helix melted with increasing temperature. The peptide was predominantly helical at low temperature in solution, while at intermediate temperatures the peptide spent the bulk of the time fluctuating between different conformations with intermediate amounts of helix, e.g. not completely helical nor entirely non-helical. Many of these conformations consisted of short helical segments with intervening non-helical residues. At high temperature the peptide unfolded and adopted various collapsed unstructured states. The intrahelical hydrogen bonds that break at high temperature were not fully compensated by hydrogen bonds with water molecules in the partially unfolded forms of the peptide. Increases in temperature disrupted both the helical structure and the peptide-water interactions. Water played a major but indirect role in facilitating unfolding, as opposed to specifically competing for the intrapeptide hydrogen bonds. The implications of our results to protein folding are discussed.

Alanine↗
PubMed2005

Fatty acid binding proteins: same structure but different binding mechanisms? Molecular dynamics simulations of intestinal fatty acid binding protein.

Fatty acid binding proteins (FABPs) carry fatty acids (FAs) and other lipids in the cellular environment, and are thus involved in processes such as FA uptake, transport, and oxidation. These proteins bind either one or two ligands in a binding site, which appears to be inaccessible from the bulk. Thus, the entry of the substrate necessitates a conformational change, whose nature is still unknown. A possible description of the ligand binding process is given by the portal hypothesis, which suggests that the FA enters the protein through a dynamic area known as the portal region. On the other hand, recent simulations of the adipocyte lipid binding protein (ALBP) suggested a different entry site (the alternative portal). In this article, we discuss molecular dynamics simulations of the apo-intestinal-FABP (I-FABP) in the presence of palmitate molecule(s) in the simulation box. The simulations were carried out to study whether the FA can enter the protein during the simulations (as in the ALBP) and where the ligand entry site is (the portal region, the alternative portal or a different domain). The analysis of the simulations revealed a clear difference between the ALBP and the I-FABP. In the latter case, the palmitate preferentially adsorbed to the portal region, which was more mobile than the rest of the protein. However, no ligand entry was observed in the multi-nanosecond-long simulations, in contrast to ALBP. These findings suggest that, although the main structural motif of the FABPs is common, the fine details of each individual protein structure grossly modulate its reactivity.

Adsorption↗
PubMed1996

Molecular dynamics simulations of small DNA plasmids: effects of sequence and supercoiling on intramolecular motions.

Small (600 base pair) DNA plasmids were modeled with a simplified representation (3DNA) and the intramolecular motions were studied using molecular mechanics and molecular dynamics techniques. The model is detailed enough to incorporate sequence effects. At the same time, it is simple enough to allow long molecular dynamics simulations. The simulations revealed that large-scale slithering occurs in a homogeneous sequence. In a heterogeneous sequence, containing numerous small intrinsic curves, the centers of the curves are preferentially positioned at the tips of loops. With more curves than loop tips (two in unbranched supercoiled DNA), the heterogeneous sequence plasmid slithers short distances to reposition other curves into the loop tips. However, the DNA is immobilized most of the time, with the loop tips positioned over a few favored curve centers. Branching or looping also appears in the heterogeneous sequence as a new method of repositioning the loop tips. Instead of a smooth progression of increasing writhing with increasing linking difference, theoretical studies have predicted that there is a threshold between unwrithed and writhed DNA at a linking difference between one and two. This has previously been observed in simulations of static structures and is demonstrated here for dynamic homogeneous closed DNA. Such an abrupt transition is not found in the heterogeneous sequence in both the static and dynamic cases.

DNA, Superhelical↗
PubMed2000

Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers.

The structural properties of the endogenous opioid peptide dynorphin A(1-17) (DynA), a potential analgesic, were studied with molecular dynamics simulations in dimyristoylphosphatidylcholine bilayers. Starting with the known NMR structure of the peptide in dodecylphosphocholine micelles, the N-terminal helical segment of DynA (encompassing residues 1-10) was initially inserted in the bilayer in a perpendicular orientation with respect to the membrane plane. Parallel simulations were carried out from two starting structures, systems A and B, that differ by 4 A in the vertical positioning of the peptide helix. The complex consisted of approximately 26,400 atoms (dynorphin + 86 lipids + approximately 5300 waters). After >2 ns of simulation, which included >1 ns of equilibration, the orientation of the helical segment of DynA had undergone a transition from parallel to tilted with respect to the bilayer normal in both the A and B systems. When the helix axis achieved a approximately 50 degrees angle with the bilayer normal, it remained stable for the next 1 ns of simulation. The two simulations with different starting points converged to the same final structure, with the helix inserted in the bilayer throughout the simulations. Analysis shows that the tilted orientation adopted by the N-terminal helix is due to specific interactions of residues in the DynA sequence with phospholipid headgroups, water, and the hydrocarbon chains. Key elements are the "snorkel model"-type interactions of arginine side chains, the stabilization of the N-terminal hydrophobic sequence in the lipid environment, and the specific interactions of the first residue, Tyr. Water penetration within the bilayer is facilitated by the immersed DynA, but it is not uniform around the surface of the helix. Many water molecules surround the arginine side chains, while water penetration near the helical surface formed by hydrophobic residues is negligible. A mechanism of receptor interaction is proposed for DynA, involving the tilted orientation observed from these simulations of the peptide in the lipid bilayer.

Biophysical Phenomena↗
PubMed2002

Hydration structure of human lysozyme investigated by molecular dynamics simulation and cryogenic X-ray crystal structure analyses: on the correlation between crystal water sites, solvent density, and solvent dipole.

The hydration structure of human lysozyme was studied with cryogenic X-ray diffraction experiment and molecular dynamics simulations. The crystal structure analysis at a resolution of 1.4 A provided 405 crystal water molecules around the enzyme. In the simulations at 300 K, the crystal structure was immersed in explicit water molecules. We examined correlations between crystal water sites and two physical quantities calculated from the 1-ns simulation trajectories: the solvent density reflecting the time-averaged distribution of water molecules, and the solvent dipole measuring the orientational ordering of water molecules around the enzyme. The local high solvent density sites were consistent with the crystal water sites, and better correlation was observed around surface residues with smaller conformational fluctuations during the simulations. Solvent dipoles around those sites exhibited coherent and persistent ordering, indicating that the hydration water molecules at the crystal water sites were highly oriented through the interactions with hydrophilic residues. Those water molecules restrained the orientational motions of adjoining water molecules and induced a solvent dipole field, which was persistent during the simulations around the enzyme. The coherent ordering was particularly prominent in and around the active site cleft of the enzyme. Because the ordering was significant up to the third to fourth solvent layer region from the enzyme surface, the coherently ordered solvent dipoles likely contributed to the molecular recognition of the enzyme in a long-distance range. The present work may provide a new approach combining computational and the experimental studies to understand protein hydration.

Chemical Phenomena↗
PubMed2005

Density functional theory and empirical derived force fields for the delocalized polaron form of polyaniline. Application to properties determination of an isolated oligomer using molecular dynamics simulations.

Normal mode analyses obtained from quantum chemical calculations at the DFT level of theory have been performed for the repetitive unit of the delocalized bipolaron form of polyaniline (PANI). Empirical molecular mechanics force field parameters were consecutively refined using the SPASIBA software and applied to the molecular dynamics properties of an isolated dodeca oligomer model of the leucoemeraldine form of PANI. It is shown that effects of protonation of the emeraldine base spread over the four rings constituting the repeating unit. Molecular dynamics simulations reveal alternative bendings of the whole chain with a time period of 18-20 ps for the model of PANI under study.

Aniline Compounds↗
PubMed2005

Thermodynamic and kinetic characterization of a beta-hairpin peptide in solution: an extended phase space sampling by molecular dynamics simulations in explicit water.

The folding of the amyloidogenic H1 peptide MKHMAGAAAAGAVV taken from the syrian hamster prion protein is explored in explicit aqueous solution at 300 K using long time scale all-atom molecular dynamics simulations for a total simulation time of 1.1 mus. The system, initially modeled as an alpha-helix, preferentially adopts a beta-hairpin structure and several unfolding/refolding events are observed, yielding a very short average beta-hairpin folding time of approximately 200 ns. The long time scale accessed by our simulations and the reversibility of the folding allow to properly explore the configurational space of the peptide in solution. The free energy profile, as a function of the principal components (essential eigenvectors) of motion, describing the main conformational transitions, shows the characteristic features of a funneled landscape, with a downhill surface toward the beta-hairpin folded basin. However, the analysis of the peptide thermodynamic stability, reveals that the beta-hairpin in solution is rather unstable. These results are in good agreement with several experimental evidences, according to which the isolated H1 peptide adopts very rapidly in water beta-sheet structure, leading to amyloid fibril precipitates [Nguyen et al., Biochemistry 1995;34:4186-4192; Inouye et al., J Struct Biol 1998;122:247-255]. Moreover, in this article we also characterize the diffusion behavior in conformational space, investigating its relations with folding/unfolding conditions.

Computer Simulation↗
PubMed2002

Molecular dynamics simulations of biological reactions.

This review considers the author perspective on the emergence of molecular dynamics (MD) simulations of biological processes. It starts with the 1976 simulation of the primary event in rhodopsin, moves to the earliest simulations of enzymatic reactions and electron transfer reactions and ends up with recent simulations of proton translocations and ion transport in proteins. The emphasis is placed on our progress in simulations of actual biological reactions and functional properties, rather than on studies of general properties such as structure and thermal motions. In most cases it has been possible to develop special strategies that capture the relevant dynamics of the given biological process. The predictive power of our early simulations of fast biological process (e.g. vision and photosynthesis) and the insight obtained from these studies is pointed out. Critical examinations of dynamical effects in different biological processes is reviewed. This includes the finding that dynamical effects are unlikely to contribute significantly to enzyme catalysis or to other processes with significant activation barriers. Even in the case of ion channels it is found that the most important effects are associated with energetics rather than dynamics. Nevertheless, MD simulations provide what is probably the most realistic description of the actual reactive events. The resulting insight is crucial in studies of fast photobiological reactions and instructive in cases of slower processes.

Carrier Proteins↗
PubMed2005

Molecular dynamics simulations of nanocomposites based on poly(epsilon-caprolactone) grafted on montmorillonite clay.

Intercalated and exfoliated models of polymer nanocomposites based on poly(epsilon-caprolactone) and functionalized montmorillonite clay are studied by means of molecular dynamics simulations. Intercalated and exfoliated models are considered for probing the structural characteristics of the corresponding nanocomposites prepared by melt intercalation and in situ polymerization, respectively. In the exfoliated system, the organization of the polymer chains onto the clay surface is examined in terms of the density profiles and the order parameter function. A layered structure can clearly be seen to form near the surface with density maxima higher than in amorphous poly(epsilon-caprolactone). This can be viewed as an increase in effective particle thickness, which can contribute to the outstanding gas barrier properties of the exfoliated nanocomposites. The comparison of the structures and energetics of the intercalated model with those of a nanocomposite model based on a nonfunctionalized clay indicates nearly similar characteristics. Nevertheless, the slight differences observed for the interfacial polymer density and clay- and surfactant-polymer binding energies can account for the differences in rheological measurements. The results also suggest that the difference in morphology obtained for the nanocomposites prepared by the two synthetic approaches can be ascribed to both a difference in interfacial polymer density and the formation of bridging polymer chain structures that hinder the exfoliation process.

Journal Article↗
PubMed2006

Molecular dynamics simulation study of the structural characteristics of water molecules confined in functionalized carbon nanotubes.

Molecular dynamics (MD) simulations were performed to study the structural properties of water molecules confined in functionalized carbon nanotubes (CNTs). Four CNTs, two armchair-type (6, 6), (7, 7) and two zigzag-type (10, 0), (12, 0) CNTs, representing different helicities and different diameters, were chosen and functionalized at their open ends by the hydrophilic -COOH and the hydrophobic -CH3 groups. The structural properties of water molecules inside the functionalized CNTs, including the orientation distributions of dipole moment and O-H bonds, the length of the single-file water chain, and the average number of hydrogen bonds, were analyzed during a process of simulations. MD simulation results in this work showed that the -CH3 functional groups exert little special effects on the structural properties of water molecules. It is mainly due to the relatively small size of the -CH3 group and its hydrophobic nature, which is consistent with hydrophobic CNTs. For CNTs functionalized by -COOH groups, the configurations of -COOH groups, incurvature or excurvature, determine whether water molecules can enter the CNTs. The incurvature or excurvature configurations of -COOH groups are the results of synergy effects of the CNTs' helicity and diameter and control the flow direction of water molecules in CNTs.

Journal Article↗
PubMed2005

Kinetic theory of gas separation in a nanopore and comparison to molecular dynamics simulation.

Kinetic mesoscopic theory derived from an atomistic model is applied to study permeation and separation of gases in a single rectangular pore. The goal is to judge the analytical method against the results of molecular dynamics simulation and to demonstrate the ease and relevance of analytical theories to calculate density profiles, flux, permeance, and separation factors. The permeance is linked to the amount of gas adsorbed in the pore and the effect of the effective gas-wall interaction on adsorption is explored. The effects of pore size, temperature, and the parameters of the pore wall interaction are investigated and reproduce the trends found in the numerical simulation of permeation of a mixture of methane and carbon dioxide in a carbon nanopore.

Journal Article↗
PubMed2005

Measure of accuracy for multicanonical molecular-dynamics simulation.

A measure of the flatness of the energy probability distribution for multicanonical molecular-dynamics (MMD) simulation is presented. It (the flatness measure) can be introduced by a slight change in the renewing scheme of the MMD potential energy. Our proposed measure is applied to liquid Ar with a Lennard-Jones potential system in order to investigate the influence of flatness on the simulation results such as internal energy and specific heat at constant volume. We find that the accuracy of MMD simulation is influenced not only by the flatness of the energy probability distribution but also by the width of the energy region that is accessible during the MMD simulation.

Algorithms↗
PubMed2006

Diffusion of acetylene inside Na-Y zeolite: molecular dynamics simulation studies.

Dynamics of acetylene molecules adsorbed in Na-Y zeolite cages is investigated using molecular dynamics simulation. The translational motion of the acetylene molecules is shown to involve three different time scales. "Free particle" type diffusion is observed in short time and small length scale. At long time and large length scale, center of mass motion of acetylene is determined by the zeolitic pore topology. Rotational motion of the acetylene is found to be very fast. Detailed analysis of the intermediate scattering function corresponding to the rotational motion showed large-angle jumps that could be described by an m-diffusion model.

Journal Article↗
PubMed2004

Large-scale molecular dynamics simulation of DNA: implementation and validation of the AMBER98 force field in LAMMPS.

Molecular modelling played a central role in the discovery of the structure of DNA by Watson and Crick. Today, such modelling is done on computers: the more powerful these computers are, the more detailed and extensive can be the study of the dynamics of such biological macromolecules. To fully harness the power of modern massively parallel computers, however, we need to develop and deploy algorithms which can exploit the structure of such hardware. The Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) is a scalable molecular dynamics code including long-range Coulomb interactions, which has been specifically designed to function efficiently on parallel platforms. Here we describe the implementation of the AMBER98 force field in LAMMPS and its validation for molecular dynamics investigations of DNA structure and flexibility against the benchmark of results obtained with the long-established code AMBER6 (Assisted Model Building with Energy Refinement, version 6). Extended molecular dynamics simulations on the hydrated DNA dodecamer d(CTTTTGCAAAAG)(2), which has previously been the subject of extensive dynamical analysis using AMBER6, show that it is possible to obtain excellent agreement in terms of static, dynamic and thermodynamic parameters between AMBER6 and LAMMPS. In comparison with AMBER6, LAMMPS shows greatly improved scalability in massively parallel environments, opening up the possibility of efficient simulations of order-of-magnitude larger systems and/or for order-of-magnitude greater simulation times.

Algorithms↗
PubMed1992

Molecular dynamics studies of a DNA-binding protein: 2. An evaluation of implicit and explicit solvent models for the molecular dynamics simulation of the Escherichia coli trp repressor.

Although aqueous simulations with periodic boundary conditions more accurately describe protein dynamics than in vacuo simulations, these are computationally intensive for most proteins. Trp repressor dynamic simulations with a small water shell surrounding the starting model yield protein trajectories that are markedly improved over gas phase, yet computationally efficient. Explicit water in molecular dynamics simulations maintains surface exposure of protein hydrophilic atoms and burial of hydrophobic atoms by opposing the otherwise asymmetric protein-protein forces. This properly orients protein surface side chains, reduces protein fluctuations, and lowers the overall root mean square deviation from the crystal structure. For simulations with crystallographic waters only, a linear or sigmoidal distance-dependent dielectric yields a much better trajectory than does a constant dielectric model. As more water is added to the starting model, the differences between using distance-dependent and constant dielectric models becomes smaller, although the linear distance-dependent dielectric yields an average structure closer to the crystal structure than does a constant dielectric model. Multiplicative constants greater than one, for the linear distance-dependent dielectric simulations, produced trajectories that are progressively worse in describing trp repressor dynamics. Simulations of bovine pancreatic trypsin were used to ensure that the trp repressor results were not protein dependent and to explore the effect of the nonbonded cutoff on the distance-dependent and constant dielectric simulation models. The nonbonded cutoff markedly affected the constant but not distance-dependent dielectric bovine pancreatic trypsin inhibitor simulations. As with trp repressor, the distance-dependent dielectric model with a shell of water surrounding the protein produced a trajectory in better agreement with the crystal structure than a constant dielectric model, and the physical properties of the trajectory average structure, both with and without a nonbonded cutoff, were comparable.

Amino Acid Sequence↗
PubMed2002

Molecular dynamics simulation of the ice nucleation and growth process leading to water freezing.

Upon cooling, water freezes to ice. This familiar phase transition occurs widely in nature, yet unlike the freezing of simple liquids, it has never been successfully simulated on a computer. The difficulty lies with the fact that hydrogen bonding between individual water molecules yields a disordered three-dimensional hydrogen-bond network whose rugged and complex global potential energy surface permits a large number of possible network configurations. As a result, it is very challenging to reproduce the freezing of 'real' water into a solid with a unique crystalline structure. For systems with a limited number of possible disordered hydrogen-bond network structures, such as confined water, it is relatively easy to locate a pathway from a liquid state to a crystalline structure. For pure and spatially unconfined water, however, molecular dynamics simulations of freezing are severely hampered by the large number of possible network configurations that exist. Here we present a molecular dynamics trajectory that captures the molecular processes involved in the freezing of pure water. We find that ice nucleation occurs once a sufficient number of relatively long-lived hydrogen bonds develop spontaneously at the same location to form a fairly compact initial nucleus. The initial nucleus then slowly changes shape and size until it reaches a stage that allows rapid expansion, resulting in crystallization of the entire system.

Journal Article↗