PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Molecular dynamics”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed2005

Flexibility of prolyl oligopeptidase: molecular dynamics and molecular framework analysis of the potential substrate pathways.

The flexibility of prolyl oligopeptidase has been investigated using molecular dynamics (MD) and molecular framework approaches to delineate the route of the substrate to the active site. The selectivity of the enzyme is mediated by a seven-bladed beta-propeller that in the crystal structure does not indicate the possible passage for the substrate to the catalytic center. Its open topology however, could allow the blades to move apart and let the substrate into the large central cavity. Flexibility analysis of prolyl oligopeptidase structure using the FIRST (Floppy Inclusion and Rigid Substructure Topology) approach and the atomic fluctuations derived from MD simulations demonstrated the rigidity of the propeller domain, which does not permit the substrate to approach the active site through this domain. Instead, a smaller tunnel at the inter-domain region comprising the highly flexible N-terminal segment of the peptidase domain and a facing hydrophilic loop from the propeller (residues 192-205) was identified by cross-correlation analysis and essential dynamics as the only potential pathway for the substrate. The functional importance of the flexible loop has been also verified by kinetic analysis of the enzyme with a split loop. Catalytic effect of engineered disulfide bridges was rationalized by characterizing the concerted motions of the two domains.

Animals↗
PubMed2004

Accurate and efficient description of protein vibrational dynamics: comparing molecular dynamics and Gaussian models.

Current all-atom potential based molecular dynamics (MD) allows the identification of a protein's functional motions on a wide-range of timescales, up to few tens of nanoseconds. However, functional, large-scale motions of proteins may occur on a timescale currently not accessible by all-atom potential based MD. To avoid the massive computational effort required by this approach, several simplified schemes have been introduced. One of the most satisfactory is the Gaussian network approach based on the energy expansion in terms of the deviation of the protein backbone from its native configuration. Here, we consider an extension of this model that captures in a more realistic way the distribution of native interactions due to the introduction of effective side-chain centroids. Since their location is entirely determined by the protein backbone, the model is amenable to the same exact and computationally efficient treatment as previous simpler models. The ability of the model to describe the correlated motion of protein residues in thermodynamic equilibrium is established through a series of successful comparisons with an extensive (14 ns) MD simulation based on the AMBER potential of HIV-1 protease in complex with a peptide substrate. Thus, the model presented here emerges as a powerful tool to provide preliminary, fast yet accurate characterizations of protein near-native motion.

Computer Simulation↗
PubMed2005

A comparative study between dissipative particle dynamics and molecular dynamics for simple- and complex-geometry flows.

The purpose of this study is to compare the results from molecular-dynamics and dissipative particle dynamics (DPD) simulations of Lennard-Jones (LJ) fluid and determine the quantitative effects of DPD coarse graining on flow parameters. We illustrate how to select the conservative force coefficient, the cut-off radius, and the DPD time scale in order to simulate a LJ fluid. To show the effects of coarse graining and establish accuracy in the DPD simulations, we conduct equilibrium simulations, Couette flow simulations, Poiseuille flow simulations, and simulations of flow around a periodic array of square cylinders. For the last flow problem, additional comparisons are performed against continuum simulations based on the spectral/hp element method.

Journal Article↗
PubMed2006

Prediction of binding affinities between the human amphiphysin-1 SH3 domain and its peptide ligands using homology modeling, molecular dynamics and molecular field analysis.

The SH3 domain of the human protein amphiphysin-1, which plays important roles in clathrin-mediated endocytosis, actin function and signaling transduction, can recognize peptide motif PXRPXR (X is any amino acid) with high affinity and specificity. We have constructed a complex structure of the amphiphysin-1 SH3 domain and a high-affinity peptide ligand PLPRRPPRA using homology modeling and molecular docking, which was optimized by molecular dynamics (MD). Three-dimensional quantitative structure-affinity relationship (3D-QSAR) analyses on the 200 peptides with known binding affinities to the amphiphysin-1 SH3 domain was then performed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best CoMSIA model showed promising predictive power, giving good predictions for about 95% of the peptides in the test set (absolute prediction errors less than 1.0). It was used to validate peptide-SH3 binding structure and provide insight into the structural requirements for binding of peptides to SH3 domains. Finally, MD simulations were performed to analyze the interaction between the SH3 domain and another peptide GFPRRPPPRG that contains with the PXRPXsR (s represents residues with small side chains) motif. MD simulations demonstrated that the binding conformation of GFPRRPPPRG is quite different from that of PLPRRPPRAA especially the four residues at the C terminal, which may explain why the CoMSIA model cannot give good predictions on the peptides of the PXRPXsR motif. Because of its efficiency and predictive power, the 3D-QSAR model can be used as a scoring filter for predicting peptide sequences bound to SH3 domains.

Amino Acid Sequence↗
PubMed1997

CAMDAS: an automated conformational analysis system using molecular dynamics. Conformational Analyzer with Molecular Dynamics And Sampling.

We present an automated conformational analysis program, CAMDAS (Conformational Analyzer with Molecular Dynamics And Sampling). CAMDAS performs molecular dynamics (MD) calculations for a target molecule and samples conformers from the trajectory of the MD. The program then evaluates the similarities between each of the sampled conformers in terms of the root-mean-square deviations of the atomic positions, clusters similar conformers, and finally prints out the clustered conformers. This MD-based conformational analysis is a broadly used method, and CAMDAS is intended to provide a convenient framework for the method. CAMDAS has the ability to find the representative conformers automatically from an arbitrarily given structure of the molecule. The accuracy of the program was examined using N-acetylalanine-N'-methylamide, and the obtained result was consistent with that of the systematic search method. In the test calculation of cyclodecane, CAMDAS could identify most of the known conformers and their conformational enantiomers by examining only 5000 conformers. In addition, the potential-scaled method, which we have developed previously as an accelerating technique for MD, could find two additional conformers of cyclodecane that have not been reported. CAMDAS presents a convenient way to find the energetically possible conformers of a molecule, which is needed especially in the early stage of drug design.

Alanine↗
PubMed2004

Comparison of molecular dynamics with hybrid continuum-molecular dynamics for a single tethered polymer in a solvent.

We compare a newly developed hybrid simulation method which combines classical molecular dynamics (MD) and computational fluid dynamics (CFD) to a simulation consisting only of molecular dynamics. The hybrid code is composed of three regions: a classical MD region, a continuum domain where the dynamical equations are solved by standard CFD methods, and an overlap domain where transport information from the other two domains is exchanged. The exchange of information in the overlap region ensures that momentum, energy, and mass are conserved. The validity of the hybrid code is demonstrated by studying a single polymer tethered to a hard wall immersed in explicit solvent and undergoing shear flow. In classical molecular dynamics simulation a great deal of computational time is devoted to simulating solvent molecules, although the solvent itself is of no direct interest. By contrast, the hybrid code simulates the polymer and surrounding solvent explicitly, whereas the solvent farther away from the polymer is modeled using a continuum description. In the hybrid simulations the MD domain is an open system whose number of particles is controlled to filter the perturbative density waves produced by the polymer motion. We compare conformational properties of the polymer in both simulations for various shear rates. In all cases polymer properties compare extremely well between the two simulation scenarios, thereby demonstrating that this hybrid method is a useful way to model a system with polymers and under nonzero flow conditions. There is also good agreement between the MD and hybrid schemes and experimental data on tethered DNA in flow. The computational cost of the hybrid protocol can be reduced to less than 6% of the cost of updating the MD forces, confirming the practical value of the method.

Journal Article↗
PubMed1992

Molecular-dynamics investigation of molecular flexibility in ligand binding.

The molecular flexibility of an inhibitor in ligand-binding process has been investigated by the mass-weighted molecular-dynamics simulation, a computational method adopted from the standard molecular-dynamics simulation and one by which the conformational space of a biomolecular system over potential energy barriers can be sampled effectively. The bimolecular complex of the aspartyl proteinase from Rhizopus chinensis, rhizopuspepsin, and an octapeptide inhibitor was previously studied in a mass-weighted molecular-dynamics simulation; the study has been extended for investigating the molecular flexibility in ligand binding. A series of mass-weighted molecular-dynamics simulations was carried out in which libration of the inhibitor dihedral angles was parametrically controlled, and threshold values of dihedral angle libration amplitudes were observed from monitoring the sampling of the enzyme binding pocket by the inhibitor in the simulations. The computational results are consistent with the general notion of molecular-flexibility requirement for ligand binding; the freedom of dihedral rotations of side-chain groups was found to be particularly important for ligand binding. Thus the critical degree of molecular flexibility which would contribute to effective enzyme inhibition can be obtained precisely from the modified molecular-dynamics simulations; the procedure described herein represents a first step toward providing quantitative measures of such a molecular-flexibility index for inhibitor molecules that have been otherwise targeted for optimal protein-ligand interactions.

Amino Acid Sequence↗
PubMed2005

Molecular dynamics and protein function.

A fundamental appreciation for how biological macromolecules work requires knowledge of structure and dynamics. Molecular dynamics simulations provide powerful tools for the exploration of the conformational energy landscape accessible to these molecules, and the rapid increase in computational power coupled with improvements in methodology makes this an exciting time for the application of simulation to structural biology. In this Perspective we survey two areas, protein folding and enzymatic catalysis, in which simulations have contributed to a general understanding of mechanism. We also describe results for the F(1) ATPase molecular motor and the Src family of signaling proteins as examples of applications of simulations to specific biological systems.

Animals↗
PubMed1997

Length scales of lipid dynamics and molecular dynamics.

Following a brief overview of length scales and system size in computer simulation, it is demonstrated that a simulation sized lipid bilayer (typically a 50 x 50 A2 patch) is in the regime where stretching dominates undulation, while the reverse holds for a flaccid macroscopic membrane. Then it is estimated that current system sizes of membrane simulations must be increased by at least a factor of 10 before thermodynamic limits are approached for quantities such as surface tension.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2002

Ultrafast spectroscopy reveals subnanosecond peptide conformational dynamics and validates molecular dynamics simulation.

Femtosecond time-resolved spectroscopy on model peptides with built-in light switches combined with computer simulation of light-triggered motions offers an attractive integrated approach toward the understanding of peptide conformational dynamics. It was applied to monitor the light-induced relaxation dynamics occurring on subnanosecond time scales in a peptide that was backbone-cyclized with an azobenzene derivative as optical switch and spectroscopic probe. The femtosecond spectra permit the clear distinguishing and characterization of the subpicosecond photoisomerization of the chromophore, the subsequent dissipation of vibrational energy, and the subnanosecond conformational relaxation of the peptide. The photochemical cis/trans-isomerization of the chromophore and the resulting peptide relaxations have been simulated with molecular dynamics calculations. The calculated reaction kinetics, as monitored by the energy content of the peptide, were found to match the spectroscopic data. Thus we verify that all-atom molecular dynamics simulations can quantitatively describe the subnanosecond conformational dynamics of peptides, strengthening confidence in corresponding predictions for longer time scales.

Computer Simulation↗
PubMed2005

Selectivity of bis(calix[4]diquinone) ionophores towards metal ions in solvent dimethylsulfoxide: a molecular mechanics and molecular dynamics study.

Molecular modelling studies have been carried out on two bis(calix[4]diquinone) ionophores, each created from two (calix[4]diquinone)arenes bridged at their bottom rims via alkyl chains (CH(2))(n), 1: n = 3, 2; n = 4, in order to understand the reported selectivity of these ligands towards different sized metal ions such as Na(+), K(+), Rb(+), and Cs(+) in dmso solution. Conformational analyses have been carried out which show that in the lowest energy conformations of the two macrocycles, the individual calix[4]diquinones exhibit a combination of partial cone, 1,3-alternate and cone conformations. The interactions of these alkali metals with the macrocycles have been studied in the gas phase and in a periodic box of solvent dmso by molecular mechanics and molecular dynamics calculations. Molecular mechanics calculations have been carried out on the mode of entry of the ions into the macrocycles and suggest that this is likely to occur from the side of the central cavity, rather than through the main axis of the calix[4]diquinones. There are energy barriers of ca. 19 kcal mol(-1) for this entry path in the gas phase, but in solution no energy barrier is found. Molecular dynamics simulations show that in both 1 and 2, though particularly in the latter macrocycle, one or two solvent molecules are bonded to the metal throughout the course of the simulation, often to the exclusion of one or more of the ether oxygen atoms. By contrast the carbonyl oxygen atoms remain bonded to the metal atoms throughout with bond lengths that remain significantly less than those to the ether oxygen atoms. Free energy perturbation studies have been carried out in dmso and indicate that for 1, the selectivity follows the order Rb(+) approximately K(+) > Cs(+) >> Na(+), which is partially in agreement with the experimental results. The energy differences are small and indeed the ratio between stability constants found for Cs(+) and K(+) complexes is only 0.60, showing that has only a slight preference for K(+). For the larger receptor , which is better suited to metal complexation, the binding affinity follows the pattern Cs(+) >> Rb(+) >> K(+) >> Na(+), with energy differences of 5.75, 2.61, 2.78 kcal mol(-1) which is perfectly consistent with experimental results.

Calixarenes↗
PubMed2004

Ab initio centroid path integral molecular dynamics: application to vibrational dynamics of diatomic molecular systems.

An ab initio centroid molecular dynamics (CMD) method is developed by combining the CMD method with the ab initio molecular orbital method. The ab initio CMD method is applied to vibrational dynamics of diatomic molecules, H2 and HF. For the H2 molecule, the temperature dependence of the peak frequency of the vibrational spectral density is investigated. The results are compared with those obtained by the ab initio classical molecular dynamics method and exact quantum mechanical treatment. It is shown that the vibrational frequency obtained from the ab initio CMD approaches the exact first excitation frequency as the temperature lowers. For the HF molecule, the position autocorrelation function is also analyzed in detail. The present CMD method is shown to well reproduce the exact quantum result for the information on the vibrational properties of the system.

Journal Article↗
PubMed2006

Energy-flow dynamics in the molecular channel of propanal photodissociation, C2H5CHO --> C2H6 + CO: direct ab initio molecular dynamics study.

Direct ab initio molecular dynamics calculations have been carried out for the molecular channel of the photodissociation of propanal, C2H5CHO --> C2H6 + CO, at the RMP2(full)/cc-pVDZ level of ab initio molecular orbital theory. The initial conditions were generated using the microcanonical sampling to put the excess energy randomly into all vibrational modes of the TS. Starting from the TS, a total of approximately 700 trajectories were numerically integrated for 100 fs. The obtained final energy distributions for the C2H6 and CO fragments and their relative translational motion were found to be quite similar to those obtained for the acetaldehyde reaction, CH3CHO --> CH4 + CO, in our previous study (Chem. Phys. Lett. 2006, 421, 549) despite the fact that the number of degree of freedom for C2H6 is larger than that for CH4. The coupling between the intrinsic reaction coordinate and one of the generalized normal modes orthogonal to it was predicted substantially strong around s = 1.4 amu(1/2) bohr, and it is expected that the energy flow out of C2H6 proceeds through this coupling. However, the obtained energy distributions strongly suggest that the coupling among the modes in C2H6 is quite small and the intramolecular energy redistribution does not occur efficiently in this molecule.

Journal Article↗
PubMed2006

Calculation of the entropy and free energy of peptides by molecular dynamics simulations using the hypothetical scanning molecular dynamics method.

Hypothetical scanning (HS) is a method for calculating the absolute entropy S and free energy F from a sample generated by any simulation technique. With this approach each sample configuration is reconstructed with the help of transition probabilities (TPs) and their product leads to the configuration's probability, hence to the entropy. Recently a new way for calculating the TPs by Monte Carlo (MC) simulations has been suggested, where all system interactions are taken into account. Therefore, this method--called HSMC--is in principle exact where the only approximation is due to insufficient sampling. HSMC has been applied very successfully to liquid argon, TIP3P water, self-avoiding walks on a lattice, and peptides. Because molecular dynamics (MD) is considered to be significantly more efficient than MC for a compact polymer chain, in this paper HSMC is extended to MD simulations as applied to peptides. Like before, we study decaglycine in vacuum but for the first time also a peptide with side chains, (Val)(2)(Gly)(6)(Val)(2). The transition from MC to MD requires implementing essential changes in the reconstruction process of HSMD. Results are calculated for three microstates, helix, extended, and hairpin. HSMD leads to very stable differences in entropy TDeltaS between these microstates with small errors of 0.1-0.2 kcal/mol (T=100 K) for a wide range of calculation parameters with extremely high efficiency. Various aspects of HSMD and plans for future work are discussed.

Chemistry, Physical↗
PubMed1990

Accessible conformations of melanin-concentrating hormone: a molecular dynamics approach.

Molecular dynamics simulations have been used to search for the accessible conformations of the melanin-concentrating hormone (MCH). The studies have been performed on native MCH and two of its peptide fragments, a cyclic MCH(5-14) fragment and a linear MCH(5-14) fragment. An analysis of the molecular dynamics trajectories of the three peptides indicates that two regions of the peptide have characteristic conformational properties that may be important for the biological activity. One is a region around Gly8, which is conformationally mobile, and the other is around Pro13, which shows unusual rigidity. The molecular dynamics simulation results are discussed in terms of backbone structural features like beta turns, side-chain interactions, and orientations of the disulfide bridge. The results of this analysis are used to suggest new analogues that will modify the conformational features of the peptide and further define the conformational requirements for activity. Finally, the results are related to nmr studies of the peptide and reveal agreements between the experimental nuclear Overhauser effect constraints and some of the accessible conformations obtained from the simulation.

Amino Acid Sequence↗
PubMed2006

Simulation of phase separation in alcohol/water mixtures using two-body force field and standard molecular dynamics.

Standard molecular dynamics simulations have been carried out on pure alcohols and alcohol/water mixtures. A simple atom-atom force field consisting of Lennard-Jones potentials plus coulombic terms over atomic point charges, but without explicit polarization terms, has been specifically fitted to reproduce several experimental properties of the pure alcohols, and has been used for mixtures by developing combination rules with the TIP3P water model. Densities, enthalpies of vaporization, radial distribution functions, self-diffusion coefficients, and rotational correlation functions of the pure alcohols are well reproduced and compare favorably with those from more sophisticated force fields. Some key aspects of the phase behaviour are correctly reproduced by the molecular dynamics simulation, showing a distinct demixing process for the n-butanol/water mixture as opposed to the stability of the t-butanol/water mixtures. The results demonstrate the ability of a molecular dynamics simulation, even in its standard form and with easily accessible time ranges, but with a carefully optimized force field, to simulate and, to a certain extent, predict the properties of binary mixtures.

Journal Article↗
PubMed1995

Dramatic differences in the motions of the mouth of open and closed cytochrome P450BM-3 by molecular dynamics simulations.

Molecular dynamics trajectories were calculated separately for each of the two molecules in the asymmetric unit of the crystal structure of the hemoprotein domain of cytochrome P450BM-3. Each simulation was 200 ps in length and included a 10 A layer of explicit solvent. The simulated time-average structure of each P450BM-3 molecule is closer to its crystal structure than the two molecular dynamics time-averaged structures are to each other. In the crystal structure, molecule 2 has a more accessible substrate binding pocket than molecule 1, and this difference is maintained throughout the simulations presented here. In particular, the substrate docking regions of molecule 1 and molecule 2 diverge in the solution state simulations. The mouth of the substrate binding pocket is significantly more mobile in the simulation of molecule 2 than in the simulation of molecule 1. For molecule 1, the width of the mouth is only slightly larger than its X-ray value of 8.7 A and undergoes fluctuations of about 1 A. However, in molecule 2, the mouth of the substrate binding pocket is dramatically more open in the time-average molecular dynamics structure (14.7 A) than in the X-ray structure (10.9 A). Furthermore, this region of the protein undergoes large amplitude motions during the trajectory that are not seen in the trajectory of molecule 1, repeatedly opening and closing up to 7 A. Presumably, the binding of different substrates will induce the mouth region to adopt different conformations from within the wide range of structures that are accessible.

Binding Sites↗