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At least 613 records · Page 34Linked to original sources
PubMed2003

Investigating lipid composition effects on the mechanosensitive channel of large conductance (MscL) using molecular dynamics simulations.

Previous experimental work has shown that the functional properties of the mechanosensitive channel of large conductance (MscL) are affected by variations in lipid composition. Here, we utilize molecular dynamics simulations of Mycobacterium tuberculosis MscL to investigate such lipid composition effects on a molecular level. In particular, two sets of simulations were performed. In the first, trajectories using lipids with different headgroups (phosphatidylcholine and phosphatidylethanolamine) were compared. Protein-lipid interactions were clearly altered by the headgroup changes, leading to conformational differences in the C-terminal region of M. tuberculosis MscL. In the second set of simulations, lipid tails were gradually shortened, thinning the membrane over a molecular dynamics trajectory. These simulations showed evidence of hydrophobic matching between MscL and the lipid membrane, as previously proposed. For all simulations, protein-lipid interaction energies in the second transmembrane region were correlated to mutagenic data, emphasizing the importance of lipid interactions for proper MscL function.

Biophysical Phenomena↗
PubMed2004

Ion motions in molecular dynamics simulations on DNA.

Counterions play a significant role in DNA structure and function, and molecular dynamics (MD) simulations offer the prospect of detailed description of the dynamical structure of ions at the molecular level. However, the motions of mobile counterions are notably slow to converge in MD on DNA. Obtaining accurate and reliable MD simulations requires knowing just how much sampling is required for convergence of each of the properties of interest. To address this issue, MD on a d(CGCGAATTCGCG) duplex in a dilute aqueous solution of water and 22 Na+ counterions was performed until convergence was achieved. The calculated first shell ion occupancies and DNA-Na+ radial distribution functions were computed as a function of time to assess convergence, and compared with relaxation times of the DNA internal parameters shift, slide, rise, tilt, roll, and twist. The sequence dependence of fractional occupancies of ions in the major and minor grooves of the DNA is examined, and the possibility of correlation between ion proximity and DNA minor groove widths is investigated.

Computer Simulation↗
PubMed1992

Conformational regions of Boc-Ala-Aib-Ala-OMe. Sampling with molecular dynamics simulations using time averaging of distance restraints.

The method of time averaging of distance restraints in molecular dynamics simulations is applied to Boc-Ala-Aib-Ala-OMe in order to demonstrate the improved sampling properties of this method compared to conventional distance restraining. Two conformational regions, beta-turn type II and gamma-turn, are seen during MD runs at a simulation temperature of 500 K, while in simulations with conventional distance restraining, no conformational transitions could be observed for temperatures up to 1000 K.

Amino Acid Sequence↗
PubMed2005

A molecular-dynamics simulation study of diffusion of a single model carbonic chain on a graphite (001) surface.

Molecular-dynamics simulations have been used to study the diffusion of a short single model carbonic chain on the graphite (001) surface. The calculated diffusion coefficient (D) first increases, then decreases with increasing chain length (N). This abnormal behavior is similar to polymer lateral diffusion at the solid-liquid interface. Furthermore, we have studied the relation between the mean-square gyration radius and N. [Figure: see text].

Carbon↗
PubMed2005

Structure of liquid formic acid investigated by first principle and classical molecular dynamics simulations.

The structure of liquid formic acid has been investigated by Car-Parrinello and classical molecular dynamics simulations, focusing on the characterization of the H-bond network and on the mutual arrangement of pairs of bonded molecules. In agreement with previous computational studies, two levels of H-bonded structures have been found. Small clusters, characterized by O-H...O bonds, are held together by weak C-H...O bonds to form large branched structures. From the ab initio simulation we infer the importance of cyclic H-bond dimer configurations, typical of the gas phase. Most of these dimer structures are however found to be embedded into H-bonded chains. When only O-H...O bonds are taken into account, linear H-bond chains are detected as basic structures of the liquid. More branched structures occur when C-H...O bonds are also considered. Regarding the arrangement of molecular pairs, we observed that O-H...O bonds favor the occurrence of configurations with parallel molecular planes, whereas no preferential orientation is observed for molecules forming C-H...O bonds.

Journal Article↗
PubMed2006

Molecular dynamics simulation of Leishmania major surface metalloprotease GP63 (leishmanolysin).

One of the molecular factors contributing to Leishmania sp. virulence and pathogenesis is the major surface metalloprotease GP63, alternatively called leishmanolysin, MSP, and PSP (EC 3.4.24.36). Here, the molecular dynamics simulation of Leishmania major GP63 in water at pH 7 is reported. Upon solvation, GP63 undergoes a sharp structural relaxation with respect to the crystal structure. The fluctuation pattern occurs essentially in solvent-exposed nonstructured regions. By contrast, the active site turns out to be rigid. Essential dynamics and dynamic-domain analyses, both carried out on the equilibrated portion of GP63, show that the fingerprint fluctuations of GP63 are practically characterized by the motion of a large part of the N-terminal domain. These results appear to be in line with substrate recognition and (pro)enzyme activation played by the N-terminal domain of GP63. A systematic analysis among a series of 10 homologs of GP63 also shows that the residues involved in the interdomain bending result highly conserved. This finding also suggests possible relationship between the maintainance of proteolytic activity and the similarity of the dynamical properties of the related enzymes.

Animals↗
PubMed2006

Molecular dynamics simulations of gramicidin A in a lipid bilayer: from structure-function relations to force fields.

Molecular dynamics simulations of membrane proteins have become a popular tool for studying their dynamic features, which are not easily accessible by experiments. Whether the force fields developed for globular proteins are adequate this purpose is an important question that is often glossed over. Here we determine the permeation properties of potassium ions in the gramicidin A channel in a lipid bilayer from free energy simulations, and compare the results to experimental data. In particular, we check the dependence of the free energy barriers ions face at the channel center on the membrane size. The results indicate that there is a serious problem with the current rigid force fields independent of the membrane size, and new, possibly polarizable, force fields need to be developed to resolve this problem.

Cations↗
PubMed1997

Insight into signal transduction: structural alterations in transmembrane helices probed by multi-1 ns molecular dynamics simulations.

The hypothesis of structural alteration in transmembrane helices for signal transduction process is viewed by molecular dynamics simulation techniques. For the c-erbB-2 transmembrane domain involved in oncogenicity, the occurrence of conformational changes has been previously described as transition from the alpha to pi helix. This dynamical feature is thoroughly analyzed for the wild phenotype and oncogenic sequences from a series of 18 simulations carried out on one nanosecond time scale. We show that these structural events do not depend upon the conditions of simulations like force field or starting helix coordinates. We demonstrate that the oncogenic mutations Val659 Glu, Gln and Asp do not prevent the transition. Furthermore, we show that beta branched residues, in conjunction with Gly residues in the c-erbB-2 sequence, act as destabilizers for the alpha helix structure, pi deformations are tightly related to other local structural motifs found in soluble and membrane proteins. These structural alterations are discussed in term of structure-activity relationships for the c-erbB-2 activating mechanism mediated by transmembrane domain dimerization.

Amino Acid Sequence↗
PubMed2005

Reproducible polypeptide folding and structure prediction using molecular dynamics simulations.

The folding of a polypeptide from an extended state to a well-defined conformation is studied using microsecond classical molecular dynamics (MD) simulations and replica exchange molecular dynamics (REMD) simulations in explicit solvent and in vacuo. It is shown that the solvated peptide folds many times in the REMD simulations but only a few times in the conventional simulations. From the folding events in the classical simulations we estimate an approximate folding time of 1-2 micros. The REMD simulations allow enough sampling to deduce a detailed Gibbs free energy landscape in three dimensions. The global minimum of the energy landscape corresponds to the native state of the peptide as determined previously by nuclear magnetic resonance (NMR) experiments. Starting from an extended state it takes about 50 ns before the native structure appears in the REMD simulations, about an order of magnitude faster than conventional MD. The calculated melting curve is in good qualitative agreement with experiment. In vacuo, the peptide collapses rapidly to a conformation that is substantially different from the native state in solvent.

Computer Simulation↗
PubMed2000

One nanosecond molecular dynamics simulation of the N-terminal domain of the lambda repressor protein.

We have carried out molecular dynamics simulation of the N-terminal domain of the lambda repressor protein in a surrounding environment including explicit waters and ions. We observe two apparent dynamics substates in the nanosecond protein simulation, the transition occurring around 500 ps. The existence of these two apparent substates results from a high flexibility of the arm in each monomer, a relative flexibility of both arms with respect to each other, and a relative displacement of the recognition helices from 30 to 40 A of interhelical distance. Many amino acid residues, including those involved in DNA recognition, undergo a simultaneous transition in their side-chain conformations, consistent with the relationship between side-chain conformation and secondary structural elements, as observed in protein crystal structures. This result suggests plausible conformational changes experienced by the protein upon DNA binding. On the whole, the non-consensus monomer appears to be more flexible than its consensus counterpart.

Amino Acid Sequence↗
PubMed1992

Molecular dynamics simulation of the DNA triplex d(TC)5.d(GA)5.d(C+T)5.

A molecular dynamics simulation of the DNA triple helix d(TC)5.d(GA)5.d(C+T)5 is described (C+ represents a protonated cytosine residue). The simulation has been performed using the program AMBER 3.1 and includes counterions and explicit solvent under periodic boundary conditions. Both the dynamic and time-averaged behaviour of the system has been analysed. Considerable deviations from the fibre-diffraction model for DNA triple helix structure are observed, including the repuckering of the purine strand sugars that has been identified in some nuclear magnetic resonance (n.m.r.) studies. The simulation suggests that this conformational change may be driven by the possibility of improved interactions between the phosphate groups of this strand and both the solvent and counterions. Several examples of a particular conformational transition are observed, involving correlated changes in the backbone angles alpha and gamma. These transitions provide a possible explanation for some unusual n.m.r. data that have been reported. The structure of the triple helix major groove also suggests an explanation for the observed stabilization of DNA triplexes by polyvalent cations, and their ability to interact with drugs that bind in the minor groove of DNA duplexes.

Base Sequence↗
PubMed1996

Identification and characterization of the unfolding transition state of chymotrypsin inhibitor 2 by molecular dynamics simulations.

Temperature-induced unfolding of chymotrypsin inhibitor 2 (CI2) in water has been investigated using molecular dynamics simulations. One simulation (2.2 ns) has been analyzed in detail and three additional simulations (each > or = 1 ns) were performed to check the generality of the results. Concurrent loss of secondary and tertiary structure during unfolding was observed in all the simulations. For each simulation, the major transition state of unfolding was identified based on conformational analysis of protein structures along the unfolding trajectory. The transition state has a considerably weakened hydrophobic core and disrupted secondary structure. Nevertheless, the overall structure of the transition state is closer to the native state than to the unfolded state. The disruption of the hydrophobic core appears to be rate limiting. However, other energy barriers have to be overcome before reaching the major transition state. A method is described to quantitatively compare the structure of the simulated transition state with that characterized by protein engineering experiments. Good agreement with the experimental data is obtained for all four transition state models (the correlation coefficient R = 0.80 to 0.93) and the average over all four models gives the best correlation (R = 0.94). These simulations provide the first comprehensive atomic-level view of what the unfolding transition state of C12 may look like.

Chymotrypsin↗
PubMed1998

Importance of explicit salt ions for protein stability in molecular dynamics simulation.

The accurate and efficient treatment of electrostatic interactions is one of the challenging problems of molecular dynamics simulation. Truncation procedures such as switching or shifting energies or forces lead to artifacts and significantly reduced accuracy. The particle mesh Ewald (PME) method is one approach to overcome these problems by providing a computationally efficient means of calculating all long-range electrostatic interactions in a periodic simulation box by use of fast Fourier transformation techniques. For the application of the PME method to the simulation of a protein with a net charge in aqueous solution, counterions are added to neutralize the system. The usual procedure is to add charge-balancing counterions close to charged residues to neutralize the protein surface. In the present article, we show that for MD simulation of a small protein of marginal stability, the YAP-WW domain, explicit modeling of 0.2 M ionic strength (in addition to the charge-balancing counterions) is necessary to maintain a stable protein structure. Without explicit ions throughout the periodic simulation box, the charge-balancing counterions on the protein surface diffuse away from the protein, resulting in destruction of the beta-sheet secondary structure of the WW domain.

Computer Simulation↗
PubMed2001

Nonequilibrium Molecular Dynamics Simulations of Steady-State Heat and Mass Transport in Condensation. II. Transfer Coefficients.

We present coefficients for transfer of heat and mass across the liquid-vapor interface of a one-component fluid. The coefficients are defined for the Gibbs surface from nonequilibrium thermodynamics and determined by nonequilibrium molecular dynamics simulations. The main conductivity coefficients are found to become large near the critical point, consistent with the disappearance of the surface in this limit. The resistivities of transfer found by molecular dynamics simulations are compared to the values predicted by kinetic theory. The main resistivity to heat transfer is found to agree from the triple point to about halfway to the critical point. The resistivity to mass transfer was used to determine the condensation coefficient, which was found to be practically constant with a value of about 0.82. The resistivity coupling coefficient predicted by simulations also agrees with values predicted by kinetic theory from the triple point until about halfway to the critical point. Copyright 2001 Academic Press.

Journal Article↗
PubMed2005

Effect of filling on the compressibility of carbon nanotubes: predictions from molecular dynamics simulations.

The compressibility of filled and empty (10, 10) carbon nanotubes (CNTs) is examined using classical molecular dynamics simulations. The filled nanotubes contain C60, CH4, Ne, n-C4H10, and n-C4H7 molecules that are covalently cross-linked to the inner CNT walls. In addition, nanotubes filled with either a hydrogen-terminated carbon nanowire or a carbon nanotube of comparable diameter is also considered. The forces on the atoms are calculated using a many-body reactive empirical bond-order potential and the adaptive intermolecular reactive empirical bond-order potential for hydrocarbons. The butane-filled system shows a unique yielding behavior prior to buckling that has not been observed previously. Cross-linking the molecules to the inner CNT walls is not predicted to affect the stiffness of the filled nanotube systems and removes the yielding response. The mechanical response of the nanowire filled CNT is remarkably similar to the response of the similarly sized multiwalled CNT.

Butanes↗
PubMed2003

Molecular dynamics simulations of the unfolding of the starch binding domain from Aspergillus niger glucoamylase.

The 600 ps molecular dynamics simulations to investigate the unfolding of the starch binding domain from Aspergillus niger glucoamylase were conducted in vacuum as well as in an external field with the dielectric constant of 80 with temperature jump technique. Electrostatic interactions play an important role in determining the stability of the beta-strands in this domain. The starch binding site 1 is less stable than site 2 since it is more exposed to the surface. The disulfide bond between C509 and C604 is unstable since these two residues are located near the flexible linker domain and in the mobile loop region between beta-strands 6 and 7, respectively. The melting temperature, at which the total residual beta-strand content is 50% that of the solution structure, is about 544K for the simulations with dielectric constant of 80, leading to the estimated unfolding timescale of 0.48 ms in vitro. In addition, the unfolding of the starch binding domain is proposed to initiate from the interior region by the lost of the integrity of the secondary structure.

Animals↗
PubMed2005

Relating kinetic rates and local energetic roughness by accelerated molecular-dynamics simulations.

We show that our accelerated molecular-dynamics (MD) approach can extend the time scale in all-atom MD simulations of biopolymers. We also show that this technique allows for the kinetic rate information to be recaptured. In deducing the kinetic rates, the relationship between the local energetic roughness of the potential-energy landscape and the effective diffusion coefficient is established. These are demonstrated on a very slow but important biomolecular process: the dynamics of cis-trans-isomerization of Ser-Pro motifs. We do not only recapture the slow kinetic rates, which is difficult in traditional MD, but also obtain the underlying roughness of the energy landscape of proteins at atomistic resolution.

Algorithms↗
PubMed2004

Mimicking the action of folding chaperones in molecular dynamics simulations: Application to the refinement of homology-based protein structures.

A novel method for the refinement of misfolded protein structures is proposed in which the properties of the solvent environment are oscillated in order to mimic some aspects of the role of molecular chaperones play in protein folding in vivo. Specifically, the hydrophobicity of the solvent is cycled by repetitively altering the partial charges on solvent molecules (water) during a molecular dynamics simulation. During periods when the hydrophobicity of the solvent is increased, intramolecular hydrogen bonding and secondary structure formation are promoted. During periods of increased solvent polarity, poorly packed regions of secondary structures are destabilized, promoting structural rearrangement. By cycling between these two extremes, the aim is to minimize the formation of long-lived intermediates. The approach has been applied to the refinement of structural models of three proteins generated by using the ROSETTA procedure for ab initio structure prediction. A significant improvement in the deviation of the model structures from the corresponding experimental structures was observed. Although preliminary, the results indicate computationally mimicking some functions of molecular chaperones in molecular dynamics simulations can promote the correct formation of secondary structure and thus be of general use in protein folding simulations and in the refinement of structural models of small- to medium-size proteins.

Bacillus↗