Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “MD simulation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 451 records · Page 25Linked to original sources
PubMed1999

Molecular dynamics studies of axis bending in d(G5-(GA4T4C)2-C5) and d(G5-(GT4A4C)2-C5): effects of sequence polarity on DNA curvature.

Gel retardation studies and other experiments indicate that DNA sequences containing the d(GA4T4C)n motif are curved, whereas those of identical composition but with a reverse sequence polarity, the d(GT4A4C)n motif, are straight. Hydroxyl radical cleavage experiments show that d(GA4T4C)n shows a unique signature, whereas d(GT4A4C)n behaves normally. To explain these results at a molecular level, molecular dynamics (MD) simulations were performed on the DNA duplexes d(G5-(GA4T4C)2-C5) and d(G5-(GT4A4C)2-C5) to 3.0 and 2.5 ns, respectively. The MD simulations are based on the Cornell force field implemented in the AMBER 4.1 modeling package and performed in a neutral solution of anionic DNA with K+, Cl- and Mg2+ at concentrations roughly comparable to a ligase buffer. Long range interactions were treated by the particle mesh Ewald method. Analysis of the results shows that the calculated dynamical structure of d(G5-(GA4T4C)2-C5) exhibits strong gross curvature, consistent with the observed behavior. The most significant locus of curvature in the MD structure is found at the central C15-G16 step, with an average roll angle of 12.8(+/-6.40)deg. The d(G5-(GT4A4C)2-C5) MD structure exhibited significantly less gross curvature. Analysis of results indicates that the reduction in gross curvature in the d(G5-(GT4A4C)2-C5) trajectory originates from the effect of the T10-A11 and T20-A21 steps, which showed average roll angles of 12.5(+/-5)deg. These three steps, T10-A11, C15-G16 and T20-A21, are half-helix turns away from one another, and their contributions to concerted bending cancel out. The A-tracts in the MD structure are essentially straight. The dynamical structure of d(G5-(GA4T4C)2-C5) exhibited minor groove deformation comprised of expansion at the 5' end of A-tracts and progressive narrowing towards the 3' end, consistent with and elaborating the interpretation of hydroxyl radical chemical probing results.

Base Sequence↗
PubMed2005

Ultrafast dynamics of myoglobin without the distal histidine: stimulated vibrational echo experiments and molecular dynamics simulations.

Ultrafast protein dynamics of the CO adduct of a myoglobin mutant with the polar distal histidine replaced by a nonpolar valine (H64V) have been investigated by spectrally resolved infrared stimulated vibrational echo experiments and molecular dynamics (MD) simulations. In aqueous solution at room temperature, the vibrational dephasing rate of CO in the mutant is reduced by approximately 50% relative to the native protein. This finding confirms that the dephasing of the CO vibration in the native protein is sensitive to the interaction between the ligand and the distal histidine. The stimulated vibrational echo observable is calculated from MD simulations of H64V within a model in which vibrational dephasing is driven by electrostatic forces. In agreement with experiment, calculated vibrational echoes show slower dephasing for the mutant than for the native protein. However, vibrational echoes calculated for H64V do not show the quantitative agreement with measurements demonstrated previously for the native protein.

Histidine↗
PubMed1987

Conformational analysis of a cyclic thymopoietin-analogue by 1H n.m.r. spectroscopy and restrained molecular dynamics simulations.

The internuclear distances of the cyclic thymopoietin derivative c[D-Val-Tyr-Arg-Lys-Glu] have been determined using two-dimensional nuclear Overhauser n.m.r. spectroscopy. These distances are used as constraints for a restrained Molecular Dynamics (MD) simulation. The two starting structures used for the calculations consist of a beta and gamma turn for model 1 and two gamma turns for model 2. The rms difference in atomic positions of the two conformations is 0.242 nm. They converge during the restrained MD simulation to the same final structure. The positional rms difference of the time averaged (5-14 ps) conformations is 0.011 nm. The hydrogen bond pattern is similar to that of model 1, but in addition we find three more gamma turns. The vicinal NH-C alpha H couplings agree well with those calculated from the time averaged structures.

Magnetic Resonance Spectroscopy↗
PubMed2004

Local order and dynamics in supercooled water: a study by IR spectroscopy and molecular dynamic simulations.

Micron-sized water droplets in a cryogenic flow tube were probed by IR spectroscopy. The analysis of the IR spectra suggests that there is a relative increase of about 30% in the fraction, f(L), of low density domains in water on cooling over the temperature range between 300 and 240 K. The results derived from the experiments agree qualitatively with those of molecular dynamics (MD) simulations in terms of the increase in the f(L) values. The MD simulations show that the intensities of the mode at about 100 cm(-1) for the molecules in the low density domains are reduced in comparison to the average, while the intensities and frequencies of the librational mode at 600 cm(-1) are increased. Furthermore, the reorientations (dielectric relaxation times) in these domains are found to be somewhat slower, pointing to the fact that these low density "cages" live longer than the average local molecular environments in supercooled water.

Journal Article↗
PubMed2006

Structure of poly(propyl ether imine) dendrimer from fully atomistic molecular dynamics simulation and by small angle x-ray scattering.

We study the structure of carboxylic acid terminated neutral poly(propyl ether imine) (PETIM) dendrimer from generations 1-6 (G1-G6) in a good solvent (water) by fully atomistic molecular dynamics (MD) simulations. We determine as a function of generation the structural properties such as radius of gyration, shape tensor, asphericity, fractal dimension, monomer density distribution, and end-group distribution functions. The sizes obtained from the MD simulations have been validated by small angle x-ray scattering experiment on dendrimer of generations 2-4 (G2-G4). A good agreement between the experimental and theoretical value of radius of gyration has been observed. We find a linear increase in radius of gyration with the generation. In contrast, Rg scales as approximately Nx with the number of monomers. We find two distinct exponents depending on the generations, x=0.47 for G1-G3 and x=0.28 for G3-G6, which reveal their nonspace filling nature. In comparison with the amine terminated poly(amidoamine) (PAMAM) dendrimer, we find that Rg of Gth generation PETIM dendrimer is nearly equal to that of (G+1)th generation of PAMAM dendrimer as observed by Maiti et al. [Macromolecules 38, 979 (2005)]. We find substantial back folding of the outer subgenerations into the interior of the dendrimer. Due to their highly flexible nature of the repeating branch units, the shape of the PETIM dendrimer deviates significantly from the spherical shape and the molecules become more and more spherical as the generation increases. The interior of the dendrimer is quite open with internal cavities available for accommodating guest molecules, suggesting the use of PETIM dendrimer for guest-host applications. We also give a quantitative measure of the number of water molecules present inside the dendrimer.

Journal Article↗
PubMed2006

Molecular dynamics study of conformational changes in human serum albumin by binding of fatty acids.

Human serum albumin (HSA) binds with fatty acids under normal physiologic conditions. To date, there is little published information on the tertiary structure of HSA-fatty acid complex in aqueous solution. In the present study, we used molecular dynamics (MD) simulations to elucidate possible structural changes of HSA brought about by the binding of fatty acids. Both unliganded HSA and HSA-fatty acid complex models for MD calculations were constructed based on the X-ray crystal structures. Five myristates (MYRs) were bound in the HSA-fatty acid complex model. In the present MD study, the motion of domains I and III caused by the binding of MYR molecules increased the radius of gyration of HSA. Root-mean-square fluctuations from the MD simulations revealed that the atomic fluctuations of the specific amino acids at drug-binding site I that can regulate the drug-binding affinity were increased by the binding of MYR molecules. Primary internal motions, characterized by the first three principal components, were observed mainly at domains I and III in the principal component analysis for trajectory data. The directional motion projected on the first principal component of unliganded HSA was conserved in HSA-MYR complex as the third principal directional motion with higher frequency. However, the third principal directional motion in unliganded HSA turned into the first principal directional motion with lower frequency in the HSA-MYR complex. Thus, the present MD study provides insights into the possible conformational changes of HSA caused by the binding of fatty acids.

Binding Sites↗
PubMed2005

Interpreting NMR data for beta-peptides using molecular dynamics simulations.

NMR is one of the most used techniques to resolve structure of proteins and peptides in solution. However, inconsistencies may occur due to the fact that a polypeptide may adopt more than one conformation. Since the NOE distance bounds and (3)J-values used in such structure determination represent a nonlinear average over the total ensemble of conformers, imposition of NOE or (3)J-value restraints to obtain one unique conformation is not an appropriate procedure in such cases. Here, we show that unrestrained MD simulation of a solute in solution using a high-quality force field yields a conformational ensemble that is largely compatible with the experimental NMR data on the solute. Four 100 ns MD simulations of two forms of a nine-residue beta-peptide in methanol at two temperatures produced conformational ensembles that were used to interpret the NMR data on this molecule and resolve inconsistencies between the experimental NOEs. The protected and unprotected forms of the beta-peptide adopt predominantly a 12/10-helix in agreement with the qualitative interpretation of the NMR data. However, a particular NOE was not compatible with this helix indicating the presence of other conformations. The simulations showed that 3(14)()-helical structures were present in the ensemble of the unprotected form and that their presence correlates with the fulfillment of the particular NOE. Additionally, all inter-hydrogen distances were calculated to compare NOEs predicted by the simulations to the ones observed experimentally. The MD conformational ensembles allowed for a detailed and consistent interpretation of the experimental data and showed the small but specific conformational differences between the protected and unprotected forms of the peptide.

Computer Simulation↗
PubMed2000

Wave dispersion relations in Yukawa fluids.

The wave dispersion relations in the fluid phase of Yukawa systems are obtained from molecular dynamics (MD) simulations for a wide range of the parameters. The Yukawa system is a collection of particles interacting through Yukawa (i.e., screened Coulomb) potentials, which can serve as a simple model for dusty plasmas. Our simulations have clearly shown that the transverse wave dispersion has a cutoff at a long wavelength even in the case of weak screening. The MD simulation data are compared with earlier theoretical predictions of the Yukawa dispersion relations and the validity of these theories is clarified.

Journal Article↗
PubMed2006

Molecular simulation study of adsorption and diffusion on silicalite for a benzene/CO2 mixture.

The adsorption and diffusion of a binary mixture of supercritical CO2 and benzene on silicalite (MFI-type) have been studied through the grand canonical Monte Carlo and molecular dynamics (MD) simulations. The adsorption behavior of pure CO2 on silicalite was discussed in detail from the adsorption isotherms, adsorption sites, interaction energies, and isosteric heats of adsorption. For the mixture, the influences of temperature, pressure and composition on the adsorption isotherms have been examined. The adsorption site behavior of the mixture has been analyzed, and benzene molecules get adsorbed preferentially in the more spacious channel intersection positions. These simulation results suggest that SC-CO2 fluid can be used as an efficient desorbent of larger aromatics in the zeolite material. The diffusion characteristic for the benzene/CO2 mixture was studied on the basis of MD simulation. It was found that the large coadsorbed benzene molecule has a pronounced effect on the CO2 diffusion in the mixture, while the mobility of benzene molecules is very small due to geometrical restrictions.

Adsorption↗
PubMed1999

Analysis of affinities of penicillins for a class C beta-lactamase by molecular dynamics simulations.

We present a calculation for the binding free energy difference between two complexes of the class C beta-lactamase from Enterobacter cloacae with foramidocillin (FOPC) and with piperacillin (PIPC). The calculation was carried out by means of the thermodynamic integration (TI) method implemented with molecular dynamics (MD). By use of the available crystal structure of the class C beta-lactamase from E. cloacae, the structures of the beta-lactamase-FOPC (FOPC complex) and beta-lactamase-PIPC (PIPC complex) complexes were built by molecular modeling and equilibrated with MD simulations. FOPC were gradually converted into PIPC in both the solution and the enzyme system by means of MD/TI methods during the MD simulation. The structure of the PIPC complex as derived by the MD/TI simulation was similar to that of the PIPC complex obtained from molecular modeling. The calculated difference in the free energy of binding (deltadeltaGbind) was -2.2 kcal/mol. This compares well with the experimental value of -1.5 kcal/mol. The results indicate that the binding affinity of FOPC is lower than that of PIPC because of the greater difficulty of desolvation for FOPC upon binding to the enzyme. This calculation suggests that the desolvation of the ligand, as well as its interaction with the beta-lactamase, is important in understanding the relative affinity of the ligands with beta-lactamase.

Crystallography↗
PubMed1998

Predicting drug absorption from molecular surface properties based on molecular dynamics simulations.

PURPOSE: To develop an efficient method for generating representative conformations for calculation of the conformationally dependent molecular surface area, and to investigate the relation between this parameter and the permeability in Caco-2 cells. METHODS: High temperature molecular dynamics (MD) simulations were used to obtain 1000 conformations of six beta-blocking agents and their prodrugs. The Boltzmann averaged (B.a.) polar surface area of the 1000 conformations was correlated to the apparent permeability coefficients (Papp) for transport across filter-grown Caco-2 cells. RESULTS: Sampling of 1000 conformations during the MD simulations was sufficient for obtaining a representative set of conformations. The B.a. polar water accessible surface area (PWASA) yielded an excellent linear correlation with Papp for both series of compounds under study (R2 = 0.98). Thus, the improved permeability of the prodrugs could be explained by a reduced PWASA. The improvement of permeability after derivatization correlated positively with the size of the non-polar water accessible surface area-suggesting a synergistic effect of the cyclopropyl and the non-polar parts of the molecule to shield the polar parts from contact with water. CONCLUSIONS: An efficient method for generating the representative conformations for calculation of the B.a. polar surface area has been established. An excellent linear correlation explaining the improved permeability of the prodrugs was obtained.

Adrenergic beta-Antagonists↗
PubMed2006

Molecular simulation studies of the structure of phosphorylcholine self-assembled monolayers.

We report a study of the structure of phosphorylcholine self-assembled monolayers (PC-SAMs) on Au(111) surfaces using both molecular mechanics (MM) and molecular dynamics (MD) simulation techniques. The lattice structure (i.e., packing densities and patterns) of the PC chains was determined first, by examining the packing energies of different structures by MM simulations in an implicit solvent. The chain orientation (i.e., antiparallel and parallel arrangements of the PC head groups) was then evaluated. The initial azimuthal angles of the PC chains were also adjusted to ensure that the optimal lattice structure was found. Finally, the two most probable lattice structures were solvated with explicit water molecules and their energies were compared after 1.5 ns of MD simulations to verify the optimal structures obtained from MM. We found that the optimal lattice structure of the PC-SAM corresponds to a radical7 x radical7 R19degree lattice structure (i.e., surface coverage of 50.4 A(2)molecule) with a parallel arrangement of the head groups. The corresponding thickness of the optimal PC-SAM is 13.4 A which is in agreement with that from experiments. The head groups of the PC chains are aligned on the surface in such a way that their dipole components are minimized. The P-->N vector of the head groups forms an angle of 82 degrees with respect to the surface normal. The tilt direction of molecular chains was observed to be towards their next nearest neighbor.

Adsorption↗
PubMed2004

Molecular dynamics simulations of papilloma virus E2 DNA sequences: dynamical models for oligonucleotide structures in solution.

The specificity of papilloma virus E2 protein-DNA binding depends critically upon the sequence of a region of the DNA not in direct contact with the protein, and represents one of the simplest known examples of indirect readout. A detailed characterization of this system in solution is important to the further investigation hypothesis of a structural code for DNA recognition by regulatory proteins. In the crystalline state, the E2 DNA oligonucleotide sequence, d(ACCGAATTCGGT), exhibits three different structural forms. We report herein studies of the structure of E2 DNA in solution based on a series of molecular dynamics (MD) simulations including counterions and water, utilizing both the canonical and various crystallographic structures as initial points of departure. All MDs converged on a single dynamical structure of d(ACCGAATTCGGT) in solution. The predicted structure is in close accord with two of the three crystal structures, and indicates that a significant kink in the double helix at the central ApT step in the other crystal molecule may be a packing effect. The dynamical fine structure was analyzed on the basis of helicoidal parameters. The calculated curvature in the sequence was found to originate primarily from YPR steps in the regions flanking the central AATT tract. In order to study the role of structural adaptation of the DNA in the binding process, a subsequent simulation on the 16-mer cognate sequence d(CAACCGAATTCGGTTG) was initiated from the crystallographic coordinates of the bound DNA in the crystal structure of the protein DNA complex. MD simulations starting with the protein-bound form relaxed rapidly back to the dynamical structure predicted from the previous simulations on the uncomplexed DNA. The MD results show that the bound form E2 DNA is a dynamically unstable structure in the absence of protein, and arises as a consequence of both structural changes intrinsic to the sequence and induced by the interaction with protein.

Animals↗
PubMedDate not supplied

A link between sequence conservation and domain motion within the AAA+ family.

The AAA+ family of proteins play fundamental roles in all three kingdoms of life. It is thought that they act as molecular chaperones in aiding the assembly or disassembly of proteins or protein complexes. Recent structural studies on a number of AAA+ family proteins have revealed that they share similar structural elements. These structures provide a possible link between nucleotide binding/hydrolysis and the conformational changes which are then amplified to generate mechanical forces for their specific functions. However, from these individual studies it is far from clear whether AAA+ proteins in general share properties in terms of nucleotide induced conformational changes. In this study, we analyze sequence conservation within the AAA+ family and identify two subfamilies, each with a distinct conserved linker sequence that may transfer conformational changes upon ATP binding/release to movements between subdomains and attached domains. To investigate the relation of these linker sequences to conformational changes, molecular dynamics (MD) simulations on X-ray structures of AAA+ proteins from each subfamily have been performed. These simulations show differences in both the N-linker peptide, subdomain motion, and cooperativity between elements of quaternary structure. Extrapolation of subdomain movements from one MD simulation enables us to produce a structure in close agreement with cryo-EM experiments.

Adenosine Triphosphatases↗
PubMed2004

Molecular recognition in purinergic receptors. 1. A comprehensive computational study of the h-P2Y1-receptor.

P2Y receptors (P2Y-Rs) are attractive pharmaceutical targets due to their involvement in the modulation of many tissues and organs. The lack of experimental structural data on P2Y-Rs impedes structure-based drug design. The need to elucidate the receptor's molecular recognition, together with the limitations of previous receptor models, triggered the construction of a new molecular model for the h-P2Y1-R. Therefore, a h-P2Y1-R model was constructed by homology modeling using the 2.6 A crystal structure of bovine rhodopsin as a template and subsequently refined by constrained molecular dynamics (MD) simulations in a fully hydrated lipid bilayer environment. ATP was docked into the receptor binding site, followed by binding site refinement using Monte Carlo and MD simulations. Analysis of the h-P2Y1-R-ATP complex suggests that the triphosphate moiety is tightly bound by a multitude of interactions possibly including a Mg2+ ion, the ribose ring is not involved in specific interactions, and the adenine ring is bound via N1, N7, and N6. The molecular recognition of the h-P2Y1-R was further probed by ATP derivatives modified on the adenine ring, and correlated with EC50 values for these derivatives. Analysis of receptor:ligand complexes and quantum mechanical studies on model compounds support the role of both steric and electronic effects in improving H-bonding (via N1 and N6) and pi-stacking interactions. The computed h-P2Y1-R model was validated with respect to our previous biochemical results. We believe that this new model of the h-P2Y1-R provides the means for understanding phenomena such as the ligand's potency and receptor subtype selectivity.

Adenosine Triphosphate↗
PubMed1988

On the occurrence of three-center hydrogen bonds in cyclodextrins in crystalline form and in aqueous solution: comparison of neutron diffraction and molecular dynamics results.

Three-center (bifurcated) hydrogen bonds may play a role by serving as an intermediate state between different dynamically changing hydrogen bonding patterns. Hydrogen bonding configurations can be studied experimentally by neutron diffraction and theoretically by computer simulation techniques. Here, both methods are used to analyse the occurrence of three-center hydrogen bonds in crystals of cyclodextrins. Almost all experimentally observed three-center hydrogen bonds in the crystal are reproduced in the molecular dynamics (MD) simulations, even as far as the detailed asymmetric geometry is concerned. On the basis of this result a MD simulation of cyclodextrin in aqueous solution is searched for the occurrence of three-center hydrogen bonds. Significant differences are found. In solution more different three-center hydrogen bonds per alpha-cyclodextrin molecule are observed than in the crystal but the population (existence as percent of the simulation period) of each three-center hydrogen bond is lower in solution than in crystal. These may indeed serve as intermediate states in the process of changing one hydrogen bonding pattern into another.

Chemical Phenomena↗
PubMed1999

Exploring the dynamic information content of a protein NMR structure: comparison of a molecular dynamics simulation with the NMR and X-ray structures of Escherichia coli ribonuclease HI.

The multiconformer nature of solution nuclear magnetic resonance (NMR) structures of proteins results from the effects of intramolecular dynamics, spin diffusion and an uneven distribution of structural restraints throughout the molecule. A delineation of the former from the latter two contributions is attempted in this work for an ensemble of 15 NMR structures of the protein Escherichia coli ribonuclease HI (RNase HI). Exploration of the dynamic information content of the NMR ensemble is carried out through correlation with data from two crystal structures and a 1.7-ns molecular dynamics (MD) trajectory of RNase HI in explicit solvent. Assessment of the consistency of the crystal and mean MD structures with nuclear Overhauser effect (NOE) data showed that the NMR ensemble is overall more compatible with the high-resolution (1.48 A) crystal structure than with either the lower-resolution (2.05 A) crystal structure or the MD simulation. Furthermore, the NMR ensemble is found to span more conformational space than the MD simulation for both the backbone and the sidechains of RNase HI. Nonetheless, the backbone conformational variability of both the NMR ensemble and the simulation is especially consistent with NMR relaxation measurements of two loop regions that are putative sites of substrate recognition. Plausible side-chain dynamic information is extracted from the NMR ensemble on the basis of (i) rotamericity and syn-pentane character of variable torsion angles, (ii) comparison of the magnitude of atomic mean-square fluctuations (msf) with those deduced from crystallographic thermal factors, and (iii) comparison of torsion angle conformational behavior in the NMR ensemble and the simulation. Several heterogeneous torsion angles, while adopting non-rotameric/syn-pentane conformations in the NMR ensemble, exist in a unique conformation in the simulation and display low X-ray thermal factors. These torsions are identified as sites whose variability is likely to be an artifact of the NMR structure determination procedure. A number of other torsions show a close correspondence between the conformations sampled in the NMR and MD ensembles, as well as significant correlations among crystallographic thermal factors and atomic msf calculated from the NMR ensemble and the simulation. These results indicate that a significant amount of dynamic information is contained in the NMR ensemble. The relevance of the present findings for the biological function of RNase HI, protein recognition studies, and previous investigations of the motional content of protein NMR structures are discussed.

Cluster Analysis↗
PubMed2001

Classical molecular interaction potentials: improved setup procedure in molecular dynamics simulations of proteins.

The latest version of the classical molecular interaction potential (CMIP) has the ability to predict the position of crystallographic waters in several proteins with great accuracy. This article analyzes the ability of the CMIP functional to improve the setup procedure of the molecular system in molecular dynamics (MD) simulations of proteins. To this end, the CMIP strategy is used to include both water molecules and counterions in different protein systems. The structural details of the configurations sampled from trajectories obtained using the CMIP setup procedure are compared with those obtained from trajectories derived from a standard equilibration process. The results show that standard MD simulations can lead to artifactual results, which are avoided using the CMIP setup procedure. Because the CMIP is easy to implement at a low computational cost, it can be very useful in obtaining reliable MD trajectories.

Acetylcholinesterase↗