Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Molecular Dynamic 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 91 records · Page 5Linked to original sources
PubMed1994

Molecular dynamics simulations of phospholipid bilayers.

Molecular dynamics (MD) simulations at 37 degrees C have been performed on three phospholipid bilayer systems composed of the lipids DLPE, DOPE, and DOPC. The model used included 24 explicit lipid molecules and explicit waters of solvation in the polar head group regions, together with constant-pressure periodic boundary conditions in three dimensions. Using this model, a MD simulation samples part of an infinite planar lipid bilayer. The lipid dynamics and packing behavior were characterized. Furthermore, using the results of the simulations, a number of diverse properties including bilayer structural parameters, hydrocarbon chain order parameters, dihedral conformations, electron density profile, hydration per lipid, and water distribution along the bilayer normal were calculated. Many of these properties are available for the three lipid systems chosen, making them well suited for evaluating the model and protocols used in these simulations by direct comparisons with experimental data. The calculated MD behavior, chain disorder, and lipid packing parameter, i.e. the ratio of the effective areas of hydrocarbon tails and head group per lipid (a(t)/ah), correctly predict the aggregation preferences of the three lipids observed experimentally at 37 degrees C, namely: a gel bilayer for DLPE, a hexagonal tube for DOPE, and a liquid crystalline bilayer for DOPC. In addition, the model and conditions used in the MD simulations led to good agreement of the calculated properties of the bilayers with available experimental results, demonstrating the reliability of the simulations. The effects of the cis unsaturation in the hydrocarbon chains of DOPE and DOPC, compared to the fully saturated one in DLPE, as well as the effects of the different polar head groups of PC and PE with the same unsaturated chains on the lipid packing and bilayer structure have been investigated. The results of these studies indicate the ability of MD methods to provide molecular-level insights into the structure and dynamics of lipid assemblies.

Algorithms↗
PubMed2000

Molecular dynamics simulation of nucleic acids.

We review molecular dynamics simulations of nucleic acids, including those completed from 1995 to 2000, with a focus on the applications and results rather than the methods. After the introduction, which discusses recent advances in the simulation of nucleic acids in solution, we describe force fields for nucleic acids and then provide a detailed summary of the published literature. We emphasize simulations of small nucleic acids ( approximately 6 to 24 mer) in explicit solvent with counterions, using reliable force fields and modern simulation protocols that properly represent the long-range electrostatic interactions. We also provide some limited discussion of simulation in the absence of explicit solvent. Absent from this discussion are results from simulations of protein-nucleic acid complexes and modified DNA analogs. Highlights from the molecular dynamics simulation are the spontaneous observation of A B transitions in duplex DNA in response to the environment, specific ion binding and hydration, and reliable representation of protein-nucleic acid interactions. We close by examining major issues and the future promise for these methods.

Base Sequence↗
PubMed1995

Structure, thermodynamics and cooperativity of the glucocorticoid receptor DNA-binding domain in complex with different response elements. Molecular dynamics simulation and free energy perturbation studies.

Molecular dynamics simulations and free energy perturbation calculations have been performed on the glucocorticoid receptor DNA-binding domain (GRDBD) in complex with three different half-site response elements (RE). These are the glucocorticoid receptor RE (GREH), the estrogen receptor RE (EREH) and an "intermediate" RE (GRE2H), where the base-pair 6A.T in GREH has been replaced by 6G.C. The molecular dynamics/free energy perturbation calculations reveal the same order of stability of the three complexes, i.e. GREH-GRDBD > GRE2H-GRDBD > EREH-GRDBD, as found experimentally, with reasonable quantitative agreement of the relative stabilities with the experiments. The more favourable entropy in associating GRDBD to GREH than to GRE2H could be explained by the additional non-polar surface that is removed from the solvent in the former complex formation. Part of this additional surface originates from the 6T methyl group in GREH. Sequence-dependent hydration patterns of the DNA major groove, which is interrupted by the GRDBD binding, could also contribute to the relatively more favourable entropy in forming GREH-GRDBD than GRE2H-GRDBD. The tenfold reduced cooperativity in the dimeric GRDBD binding to a partially palindromic ERE (palERE) compared to palGRE/GRE2 could be attributed to conformational changes in the residues of the "D-box" (Cys476 to Cys482) observed in the molecular dynamics simulations of EREH-GRDBD, but not in the other two complexes. Moreover, the conformations of the base-pairs at positions 5 and 6 are distorted (compared to free B-DNA) in GREH and GRE2H, due to the binding of GRDBD. Since the corresponding conformational distortions were not found in EREH-GRDBD, it is plausible that the distortions mediate cooperative binding through a propagation of the distortions to the other half site, thus facilitating binding of the second GRDBD.

Amino Acid Sequence↗
PubMed2003

Plausible interaction of an alpha-fetoprotein cyclopeptide with the G-protein-coupled receptor model GPR30: docking study by molecular dynamics simulated annealing.

In this manuscript, the procedure of molecular dynamics simulated annealing is applied to locate a probable receptor and binding site of a cyclicpeptide that inhibits estrogen-stimulated proliferation of breast cancer. The hydrophilic cyclopeptide EMTOVNOGQ (O = 4-hydroxyproline), derived from alpha-fetoprotein, is an inhibitor of estrogen-stimulated proliferation of human breast cancer. This peptide has been shown to act through a mechanism different from that of estrogen; however, its receptor is unknown. We report computer experiments that suggest that this peptide may execute its actions by interacting with GPR30, a G-protein-coupled receptor. The subject of this work is the simulation, by molecular dynamics simulated annealing, of the interaction of cyclopeptide EMTOVNOGQ with receptor GPR30 protein. A conformational analysis of the cyclopeptide was undertaken and the final structure was docked on several sites of the GPR30 3D model. Our results show that the cyclopeptide interacts on the pocket located between TM6 and TM7 transmembrane helices of the G-protein, triggering a slight conformational change in the secondary structure of the receptor in the complex. Based on differences in accessible surface areas between GPR30 and its ligand, the residues in the interaction zone were identified. The cyclopeptide is stabilized in the active site by forming a network of hydrogen bonds between Glu, Thr, (1)Pro(OH) and GLn residues of the ligand and Arg-259, Cys-271, Asn-316, Asn-320 and Tyr-324 of the G-protein. Moreover, the study of the electrostatic surface potential on the GPR30 receptor shows that the active site is more positively charged than the other sites. Our modeling indicates a plausible interaction of the cyclopeptide with the seven transmembrane GPR30 protein. This may have profound implications for the treatment of breast cancer.

Amino Acid Sequence↗
PubMed2002

Contribution of energy values to the analysis of global searching molecular dynamics simulations of transmembrane helical bundles.

Molecular interactions between transmembrane alpha-helices can be explored using global searching molecular dynamics simulations (GSMDS), a method that produces a group of probable low energy structures. We have shown previously that the correct model in various homooligomers is always located at the bottom of one of various possible energy basins. Unfortunately, the correct model is not necessarily the one with the lowest energy according to the computational protocol, which has resulted in overlooking of this parameter in favor of experimental data. In an attempt to use energetic considerations in the aforementioned analysis, we used global searching molecular dynamics simulations on three homooligomers of different sizes, the structures of which are known. As expected, our results show that even when the conformational space searched includes the correct structure, taking together simulations using both left and right handedness, the correct model does not necessarily have the lowest energy. However, for the models derived from the simulation that uses the correct handedness, the lowest energy model is always at, or very close to, the correct orientation. We hypothesize that this should also be true when simulations are performed using homologous sequences, and consequently lowest energy models with the right handedness should produce a cluster around a certain orientation. In contrast, using the wrong handedness the lowest energy structures for each sequence should appear at many different orientations. The rationale behind this is that, although more than one energy basin may exist, basins that do not contain the correct model will shift or disappear because they will be destabilized by at least one conservative (i.e. silent) mutation, whereas the basin containing the correct model will remain. This not only allows one to point to the possible handedness of the bundle, but can be used to overcome ambiguities arising from the use of homologous sequences in the analysis of global searching molecular dynamics simulations. In addition, because clustering of lowest energy models arising from homologous sequences only happens when the estimation of the helix tilt is correct, it may provide a validation for the helix tilt estimate.

Amino Acid Sequence↗
PubMed2001

Direct comparison of experimental and calculated folding free energies for hydrophobic deletion mutants of chymotrypsin inhibitor 2: free energy perturbation calculations using transition and denatured states from molecular dynamics simulations of unfolding.

Previous molecular dynamics (MD) simulations of thermal denaturation of chymotrypsin inhibitor 2 (CI2) have provided transition-state models in good agreement with experiment. Unfortunately, however, the comparisons have been necessarily indirect. The simulations have provided detailed structural information but not energetics, while from experiment, structure is inferred from a ratio of free energy changes upon mutation (Phi values). Here, direct comparison with experimental free energies is obtained by performing free energy perturbation calculations of hydrophobic deletion mutants of CI2 using transition- and denatured-state structures from various denaturation MD simulations. The agreement between the calculated and experimental DeltaDeltaG and Phi values is quite good (R = 0.8-0.9). In addition, given the availability of realistic atomic models for the denatured protein, the common approach of using small peptides to represent the denatured state in stability calculations can now be evaluated. To this end, two different extended tripeptide models were used: one using the sequence from the protein with the residue to be mutated in the center and the other with this residue surrounded by Ala residues. The results for the two peptides agree neither with one another nor with the different full-length denatured-state models, which do provide results in good agreement with experiment. This finding is noteworthy because the denatured state of CI2 is very disrupted with little residual structure, such that the peptides might have been expected to serve as reasonable models. Overall the calculations presented here validate our previous MD-generated transition- and denatured-state models and therefore the simulated unfolding pathways and their relevance to refolding.

Alanine↗
PubMed1998

Molecular dynamics simulations of biomembrane models.

A molecular force field dedicated to molecular dynamics simulation of biomembranes was developed. It was parameterized on model compounds related to phospholipids and was able to reproduce at the same time structures, energies, and vibrational spectra. Cross terms in the potential energy function were introduced by solving the redundancy problem among internal coordinates. This force field was used in the 400-ps molecular dynamics simulation of a hydrated bilayer in the gel and liquid crystal phases. The conformational properties of the polar head groups were in particular agreement with the experimental observations using Raman scattering.

Gels↗
PubMed2000

Hydration of beta-cyclodextrin: a molecular dynamics simulation study.

We study by molecular dynamics simulations the hydration of beta-cyclodextrin. Our simulations show that within these barrel-shaped molecules hydrophobicity dominates, while at the top and bottom sides of the barrel interactions with water are mostly hydrophilic in nature. These results agree with crystallographic data at 120 K and, in particular, with the spontaneous hydration process of a cyclodextrin crystal in wet atmosphere. The predicted structure of the hydration shells is discussed and compared with previous molecular mechanics calculations which report an overall hydrophobic behavior. Moreover, the temperature dependence of the hydration process is discussed.

Crystallography↗
PubMed1997

Conformations, orientations and time scales characterising dimyristoylphosphatidylcholine bilayer membrane. Molecular dynamics simulation studies.

The results of molecular dynamics simulation of fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayer membrane in the liquid-crystalline phase are presented. They show that the probability of a gauche conformation varies periodically along the chain with only a slight increase towards the end of the chain. However, the frequency of transition between conformations increases, due to a decrease in the lifetime of the trans conformation, along the chain. The average lifetimes for trans conformations are in the range of 1-2 x 10(-10) s and for gauche conformations in the range of 4-7 x 10(-11) s. The alpha-chain of the DMPC head group has mainly an extended conformation, due to predominantly trans conformation of alpha5 torsion. The rotational correlation time for the P-N vector is 3.7 ns. The C2-C1-O11-P fragment of the DMPC head group (theta1, alpha1, alpha2 torsions) is rigid while the P-O12-C11-C12 fragment (alpha3, alpha4, alpha5 torsions) is flexible. The lateral diffusion coefficient for DMPC self-diffusion in the membrane is 2 x 10(-7) cm2/s; the rate of transverse diffusion is the same. Large differences in the calculated rotational correlation times for the alpha-, beta-, gamma-chains and for the O21-C1 vector indicate that in the liquid-crystalline bilayer each segment of the DMPC molecule exhibits its own rotational freedom, in addition to its internal flexibility resulting from rotational isomerism. The results obtained in these calculations, although in general agreement with some experimental data, shed new light on the dynamical behaviour of phosphatidylcholine molecules in the bilayer membrane in the liquid-crystalline phase.

Dimyristoylphosphatidylcholine↗
PubMed2000

Stress domains in Si(111)/a-Si3N4 nanopixel: ten-million-atom molecular dynamics simulations on parallel computers

Parallel molecular dynamics simulations are performed to determine atomic-level stresses in Si(111)/Si(3)N4(0001) and Si(111)/a-Si3N4 nanopixels. Compared to the crystalline case, the stresses in amorphous Si3N4 are highly inhomogeneous in the plane of the interface. In silicon below the interface, for a 25 nm square mesa stress domains with triangular symmetry are observed, whereas for a rectangular, 54 nmx33 nm, mesa tensile stress domains ( approximately 300 A) are separated by Y-shaped compressive domain wall. Maximum stresses in the domains and domain walls are -2 GPa and +2 GPa, respectively.

Journal Article↗
PubMed1997

Insight into the stabilization of A-DNA by specific ion association: spontaneous B-DNA to A-DNA transitions observed in molecular dynamics simulations of d[ACCCGCGGGT]2 in the presence of hexaamminecobalt(III).

BACKGROUND: Duplex DNA is more than a simple information carrier. The sequence-dependent structure and its inherent deformability, in concert with the subtle modulating effects of the environment, play a crucial role in the regulation and packaging of DNA. Recent advances in force field and simulation methodologies allow molecular dynamics simulations to now represent the specific effects of the environment. An understanding of the environmental dependence of DNA structure gives insight into how histones are able to package DNA, how various proteins are able to bind and modulate nucleic acid structure and will ultimately aid the design of molecules to package DNA for more effective gene therapy. RESULTS: Molecular dynamics simulations of d[ACCCGCGGGT]2 in solution in the presence of hexaamminecobalt(III) [Co(NH3)6(3+)] show stabilization of A-DNA and spontaneous B-DNA to A-DNA transitions, which is consistent with experimental results from NMR and Raman spectroscopic and X-ray crystallographic studies. In the absence of Co(NH3)6(3+), A-DNA to B-DNA transitions are observed instead. In addition to their interaction with the guanines in the major groove, Co(NH3)6(3+) ions bridge opposing strands in the bend across the major groove, probably stabilizing A-DNA. CONCLUSIONS: The simulation methods and force fields have advanced to a sufficient level that some representation of the environment can be seen in nanosecond length molecular dynamics simulations. These simulations suggest that, in addition to the general explanation of A-DNA stabilization by dehydration, hydration and ion association in the major groove stabilize A-DNA.

Cobalt↗
PubMed1993

Molecular dynamics simulation of Pf1 coat protein.

The results of molecular dynamics simulations of Pf1 coat protein are described and compared to experimental NMR data on both the membrane bound and structural forms of this viral coat protein. Molecular dynamics simulations of the 46 residue coat protein and related model sequences were performed according to a simple protocol. The simulations were initiated with the polypeptides in a completely uniform alpha helical conformation in a dielectric continuum (epsilon = 2) and the motions of individual residues were followed as a function of time by monitoring the angular fluctuations of amide NH bond vectors. The simulations of Pf1 coat protein were able to identify the same mobile and structured segments found in experimental NMR studies of the membrane bound form of the protein (Shon, K.-J., Y. Kim, L. A. Colnago, and S. J. Opella. 1991. Science (Wash. DC). 252:1303-1305). Significantly, in addition to mobile amino and carboxyl terminal regions, a mobile internal loop was found that connects the rigid hydrophobic and amphipathic helices in the protein. NMR experiments show that this mobile loop is present in both the viral and membrane bound forms of the protein and that it plays a role in viral assembly (Nambudripad, R., W. Stark, S. J. Opella, and L. Makowski. 1991. Science (Wash. DC) 252:1305-1308). The results of simulations of several alanine based 46 residue polypeptides with some of the charged residues present in the Pf1 coat protein sequence suggest that interactions between the Asp 14 and Asp 18 sidechains and the peptide backbone are responsible for the formation of the mobile loop. The agreement between the results of the calculations presented here and the previously reported NMR experiments suggest that molecular dynamics simulations might be useful in the prediction of the secondary structure and dynamics of individual residues in membrane and structural proteins with predominantly alpha helical secondary structure.

Bacteriophages↗
PubMed1994

Molecular dynamics simulations of HIV-1 protease with peptide substrate.

Molecular dynamics simulations of human immunodeficiency virus (HIV)-1 protease with a model substrate were used to test if there is a stable energy minimum for a proton that is equidistant from the four delta oxygen atoms of the two catalytic aspartic acids. The crystal structure of HIV-1 protease with a peptidic inhibitor was modified to model the peptide substrate Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln for the starting geometry. A proton was positioned between the two closet oxygen atoms of the two catalytic aspartic acids, and close to the carbonyl oxygen of the scissile bond in the substrate. All crystallographic water molecules were included. Two molecular dynamics simulations were run: 30 ps with united-atom potentials and 40 ps using the more accurate all-atom potentials. The molecular dynamics used a new algorithm that increased the speed and allowed the elimination of a cut-off for non-bonded interactions and the inclusion of an 8 A shell of water molecules in the calculations. The overall structure of the protease dimer, including the catalytic aspartic acids, was stable during the course of the molecular dynamics simulations. The substrate and a water molecule, that is an important component of the binding site, were stable during the simulation using all-atom potentials, but more mobile when united-atom potentials were used. A Poincare map representation showed that the positions of the proton and its coordinating oxygen atoms were stable for 93% of both simulations, although many of the buried and poorly accessible water molecules exchanged with solvent. The proton has a stable minimum energy position and maintains coordination with all four delta oxygen atoms of the two catalytic aspartic acids and the carbonyl oxygen of the scissile bond of the substrate. Therefore, a loosely bound hydrogen ion at this position will not be rapidly exchanged with solvent, and will rebond to either a catalytic aspartic acid or possibly the substrate. The implications for the reaction mechanism are discussed.

Amino Acid Sequence↗
PubMed1995

Conformational modeling of elastin tetrapeptide Boc-Gly-Leu-Gly-Gly-NMe by molecular dynamics simulations with improvements to the thermalization procedure.

Molecular Dynamics Simulations (MD) at Constant-Temperature or Constant-total Energy for the conformational Global-Minimum (GM) of elastin tetrapeptide Boc-Gly-Leu-Gly-Gly-NMe have been performed. The thermalization problem concerning the initial state of Constant-Temperature MD has been solved developing two effective strategies. In the first one, the run starts from the room-temperature state reached by Molecular Dynamics Simulated Annealing (SA). In the second one, one starts from the annealed-state at low-temperature and performs a long constant-low-temperature run until the initial conformer is perfectly equilibrated. Then, the low-temperature equilibrated-state is used as initial state for MD at room-temperature. heuristic criteria on order to define the onset of steady-state have been established monitoring the hystories of collective parameters (e.g., the total energy, temperature, end-to-end distance, etc.) and their amplitude fluctuations. Moreover, the equilibrium between the system and the heat bath is verified analyzing the total linear momentum conservation by the time evolution of center mass velocity. The slow drift of total energy during Constant-total Energy MD has been corrected using a loose coupling between the system and the heat bath. Moreover, we have verified that the roto-translational motions do not affect significantly the properties of molecular vibrations. The librations of peptide unit inside the type II beta-turn [Gly1]C = 0 ... HN[Gly4], previously detected, were confirmed. Large -Gly-Gly- chain motions were identified and modeled as fluctuations occurring between the tetratepeptide GM and the saddle-point corresponding to the transition state of the conversion toward the extended-chain conformation. All these peptide motions could contribute to the elasticity mechanism of elastin.

Amino Acid Sequence↗
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↗
PubMed2026

Validating the potential mechanism and therapeutic effect of Qinlian Jiangxia decoction in the treatment of type 2 diabetes mellitus complicated with hyperlipidemia through network pharmacology, molecular docking, molecular dynamics simulation, andexperiments.

OBJECTIVE: To investigate the mechanism of action of Qinlian Jiangxia decoction (, QLJXD) in the treatment of type 2 diabetes mellitus (T2DM) complicated by hyperlipidemia using network pharmacology, molecular docking, molecular dynamics simulation and in vivo experiments. METHODS: Drug components, targets and disease targets were identified using databases such as TCM systems pharmacology database and analysis platform and GeneCards. The intersecting targets were subjected to protein-protein interaction analysis using the search tool for the retrieval of interacting genes/proteins database. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the intersecting targets were conducted using the Metascape platform to identify core components and targets. The results were validated using molecular docking, molecular dynamics simulations and in vivo experiments. RESULTS: QLJXD contains 76 active ingredients and 136 disease targets. The core ingredients are quercetin, β-sitosterol, wogonin and baicalein, while the core targets are fatty acid binding protein 4 (FABP4) and peroxisome proliferative activated receptor gamma (PPARG). Molecular docking and molecular dynamics simulations revealed that the core ingredients bound well to the core targets. Animal experiments demonstrated that QLJXD effectively inhibited the expression of FABP4 and increased the expression of PPARG, thereby enhancing disorders of glycolipid metabolism. CONCLUSION: The putative therapeutic efficacy of QLJXD in the management of T2DM complicated with hyperlipidemia may be ascribed to the synergistic actions of multiple components, such as quercetin, β-sitosterol, wogonin, and baicalein, which collectively modulate FABP4 and PPARG molecular targets.

Molecular Docking Simulation↗