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 235 records · Page 13Linked to original sources
PubMed2003

Understanding the Hofmeister effect in interactions between chaotropic anions and lipid bilayers: molecular dynamics simulations.

A set of all-atom molecular dynamics simulations have been performed to better understand critical phenomena regarding a Hofmeister series of anions and lipid bilayers. The simulations isolate the effect of anion size and show clear differences in the interactions with the dipolar phoshpatidylcholine headgroup. Cl- anions penetrate into the headgroup region of the bilayer, but the simulations confirm theories which predict that larger anions penetrate more deeply, into a more heterogeneous and hydrophobic molecular region. That anion size leads to such differences in partitioning in the bilayer provides atomic-level support to hypotheses inspired by several experimental studies. The ability of larger anions to bury deep within the bilayer is correlated with a less well-structured hydration shell, shedding of which upon penetration incurs a smaller penalty for the larger anions than for Cl-.

Anions↗
PubMed2005

Molecular dynamics simulations and 2H NMR study of the GalCer/DPPG lipid bilayer.

Molecular dynamics simulations were performed on a two-component lipid bilayer system in the liquid crystalline phase at constant pressure and constant temperature. The lipid bilayers were composed of a mixture of neutral galactosylceramide (GalCer) and charged dipalmitoylphosphatidylglycerol (DPPG) lipid molecules. Two lipid bilayer systems were prepared with GalCer:DPPG ratio 9:1 (10%-DPPG system) and 3:1 (25%-DPPG system). The 10%-DPPG system represents a collapsed state lipid bilayer, with a narrow water space between the bilayers, and the 25%-DPPG system represents an expanded state with a fluid space of approximately 10 nm. The number of lipid molecules used in each simulation was 1024, and the length of the production run simulation was 10 ns. The simulations were validated by comparing the results with experimental data for several important aspects of the bilayer structure and dynamics. Deuterium order parameters obtained from (2)H NMR experiments for DPPG chains are in a very good agreement with those obtained from molecular dynamics simulations. The surface area per GalCer lipid molecule was estimated to be 0.608 +/- 0.011 nm(2). From the simulated electron density profiles, the bilayer thickness defined as the distance between the phosphorus peaks across the bilayer was calculated to be 4.21 nm. Both simulation systems revealed a tendency for cooperative bilayer undulations, as expected in the liquid crystalline phase. The interaction of water with the GalCer and DPPG oxygen atoms results in a strong water ordering in a spherical hydration shell and the formation of hydrogen bonds (H-bonds). Each GalCer lipid molecule makes 8.6 +/- 0.1 H-bonds with the surrounding water, whereas each DPPG lipid molecule makes 8.3 +/- 0.1 H-bonds. The number of water molecules per GalCer or DPPG in the hydration shell was estimated to be 10-11 from an analysis of the radial distribution functions. The formation of the intermolecular hydrogen bonds was observed between hydroxyl groups from the opposing GalCer sugar headgroups, giving an energy of adhesion in the range between -1.0 and -3.4 erg/cm(2). We suggest that this value is the contribution of the hydrogen-bond component to the net adhesion energy between GalCer bilayers in the liquid crystalline phase.

Animals↗
PubMed1997

Helix bending in alamethicin: molecular dynamics simulations and amide hydrogen exchange in methanol.

Molecular dynamics simulations of alamethicin in methanol were carried out with either a regular alpha-helical conformation or the x-ray crystal structure as starting structures. The structures rapidly converged to a well-defined hydrogen-bonding pattern with mixed alpha-helical and 3(10)-helical hydrogen bonds, consistent with NMR structural characterization, and did not unfold throughout the 1-ns simulation, despite some sizable backbone fluctuations involving reversible breaking of helical hydrogen bonds. Bending of the helical structure around residues Aib10-Aib13 was associated with reversible flips of the peptide bonds involving G11 (Aib10-G11 or G11-L12 peptide bonds), yielding discrete structural states in which the Aib10 carbonyl or (rarely) the G11 carbonyl was oriented away from the peptide helix. These peptide bond reversals could be accommodated without greatly perturbing the adjacent helical structure, and intramolecular hydrogen bonding was generally maintained in bent states through the formation of new (non-alpha or 3[10]) hydrogen bonds with good geometries: G11 NH-V9 CO (inverse gamma turn), Aib13 NH-Aib8 CO (pi-helix) and, rarely, L12 NH- Q7 NH (pi-helix). These observations may reconcile potentially conflicting NMR structural information for alamethicin in methanol, in which evidence for conformational flexibility in the peptide sequence before P14 (G11-Aib13) contrasts with the stability of backbone amide NH groups to exchange with solvent. Similar reversible reorientation of the Thr11-Gly12 peptide bond of melittin is also observed in dynamics simulations in methanol (R. B. Sessions, N. Gibbs, and C. E. Dempsey, submitted). This phenomenon may have some role in the orientation of the peptide carbonyl in solvating the channel lumen in membrane ion channel states of these peptides.

Alamethicin↗
PubMed2004

Molecular-dynamics simulations of sputtering.

The use of molecular-dynamics simulations to understand the ejection processes of particles from surfaces after energetic ion bombardment is discussed. Substrates considered include metals, covalent and ionic materials, polymers and molecular solids. It is shown how the simulations can be used to aid interpretation of experimental results by providing the underlying mechanisms behind the ejection processes.

Journal Article↗
PubMed2004

OmpT: molecular dynamics simulations of an outer membrane enzyme.

Five molecular dynamics simulations (total duration >25 ns) have been performed on the Escherichia coli outer membrane protease OmpT embedded in a dimyristoylphosphatidylcholine lipid bilayer. Globally the protein is conformationally stable. Some degree of tilt of the beta-barrel is observed relative to the bilayer plane. The greatest degree of conformational flexibility is seen in the extracellular loops. A complex network of fluctuating H-bonds is formed between the active site residues, such that the Asp210-His212 interaction is maintained throughout, whereas His212 and Asp83 are often bridged by a water molecule. This supports a catalytic mechanism whereby Asp83 and His212 bind a water molecule that attacks the peptide carbonyl. A configuration yielded by docking calculations of OmpT simulation snapshots and a model substrate peptide Ala-Arg-Arg-Ala was used as the starting point for an extended Huckel calculation on the docked peptide. These placed the lowest unoccupied molecular orbital mainly on the carbon atom of the central C=O in the scissile peptide bond, thus favoring attack on the central peptide by the water held by residues Asp83 and His212. The trajectories of water molecules reveal exchange of waters between the intracellular face of the membrane and the interior of the barrel but no exchange at the extracellular mouth. This suggests that the pore-like region in the center of OmpT may enable access of water to the active site from below. The simulations appear to reveal the presence of specific lipid interaction sites on the surface of the OmpT barrel. This reveals the ability of extended MD simulations to provide meaningful information on protein-lipid interactions.

Binding Sites↗
PubMed1998

Molecular dynamics simulation of a synthetic ion channel.

A molecular dynamics simulation has been performed on a synthetic membrane-spanning ion channel, consisting of four alpha-helical peptides, each of which is composed of the amino acids leucine (L) and serine (S), with the sequence Ac-(LSLLLSL)3-CONH2. This four-helix bundle has been shown experimentally to act as a proton-conducting channel in a membrane environment. In the present simulation, the channel was initially assembled as a parallel bundle in the octane portion of a phase-separated water/octane system, which provided a membrane-mimetic environment. An explicit reversible multiple-time-step integrator was used to generate a dynamical trajectory, a few nanoseconds in duration for this composite system on a parallel computer, under ambient conditions. After more than 1 ns, the four helices were found to adopt an associated dimer state with twofold symmetry, which evolved into a coiled-coil tetrameric structure with a left-handed twist. In the coiled-coil state, the polar serine side chains interact to form a layered structure with the core of the bundle filled with H2O. The dipoles of these H2O molecules tended to align opposite the net dipole of the peptide bundle. The calculated dipole relaxation function of the pore H2O molecules exhibits two reorientation times. One is approximately 3.2 ps, and the other is approximately 100 times longer. The diffusion coefficient of the pore H2O is about one-third of the bulk H2O value. The total dipole moment and the inertia tensor of the peptide bundle have been calculated and reveal slow (300 ps) collective oscillatory motions. Our results, which are based on a simple united atom force-field model, suggest that the function of this synthetic ion channel is likely inextricably coupled to its dynamical behavior.

Amino Acid Sequence↗
PubMed1990

Restrained and unrestrained molecular dynamics simulations in the NVT ensemble of alamethicin.

Molecular dynamics simulations on the transmembrane antibiotic peptide alamethicin have been performed in the NVT ensemble (i.e., the number of particles N, the volume V, and the temperature T of the system are kept constant). Results on the structure and conformational flexibility of this molecule are discussed and compared with previous experimental CD, x-ray, nmr data and theoretical computations on fragments analogues. An extensive study of structural and dynamic properties from H-bonding pattern analysis is presented. Evidences for a largely alpha-helix structure with some extent of freedom in the C-terminal region are found. Further, a partition of the molecule into three regions on the base of structural features and dynamic behavior has been proposed, and the correlation among the motions of the three regions is described.

Alamethicin↗
PubMed2001

Analysis of a 10-ns molecular dynamics simulation of mouse acetylcholinesterase.

A 10-ns molecular dynamics simulation of mouse acetylcholinesterase was analyzed, with special attention paid to the fluctuation in the width of the gorge and opening events of the back door. The trajectory was first verified to ensure its stability. We defined the gorge proper radius as the measure for the extent of gorge opening. We developed an expression of an inter-atom distance representative of the gorge proper radius in terms of projections on the principal components. This revealed the fact that collective motions of many scales contribute to the opening behavior of the gorge. Covariance and correlation results identified the motions of the protein backbone as the gorge opens. In the back-door region, side-chain dihedral angles that define the opening were identified.

Acetylcholinesterase↗
PubMed2006

HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations.

We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease that sample large conformational changes of the active site flaps. In particular, the unliganded protease undergoes multiple conversions between the "closed" and "semiopen" forms observed in crystal structures of inhibitor-bound and unliganded protease, respectively, including reversal of flap "handedness." Simulations in the presence of a cyclic urea inhibitor yield stable closed flaps. Furthermore, we observe several events in which the flaps of the unliganded protease open to a much greater degree than observed in crystal structures and subsequently return to the semiopen state. Our data strongly support the hypothesis that the unliganded protease predominantly populates the semiopen conformation, with closed and fully open structures being a minor component of the overall ensemble. The results also provide a model for the flap opening and closing that is considered to be essential to enzyme function.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Protein unfolding pathways explored through molecular dynamics simulations.

Herein we describe the results of molecular dynamics simulations of the bovine pancreatic trypsin inhibitor (BPTI) in solution at a variety of temperatures both with and without disulfide bonds. The reduced form of the protein unfolded at high temperature to an ensemble of conformations with all the properties of the molten globule state. In this account we outline the structural details of the actual unfolding process between the native and molten globule states. The first steps of unfolding involved expansion of the protein, which disrupted packing interactions. The solvent-accessible surface area also quickly increased. The unfolding was localized mostly to the turn and loop regions of the molecule, while leaving the secondary structure intact. Then, there was more gradual unfolding of the secondary structure and non-native turns became prevalent. This same trajectory was continued and more drastic unfolding occurred that resulted in a relatively compact state devoid of stable secondary structure.

Aprotinin↗
PubMed1998

The early stage of folding of villin headpiece subdomain observed in a 200-nanosecond fully solvated molecular dynamics simulation.

A new approach in implementing classical molecular dynamics simulation for parallel computers has enabled a simulation to be carried out on a protein with explicit representation of water an order of magnitude longer than previously reported and will soon enable such simulations to be carried into the microsecond time range. We have used this approach to study the folding of the villin headpiece subdomain, a 36-residue small protein consisting of three helices, from an unfolded structure to a molten globule state, which has a number of features of the native structure. The time development of the solvation free energy, the radius of gyration, and the mainchain rms difference from the native NMR structure showed that the process can be seen as a 60-nsec "burst" phase followed by a slow "conformational readjustment" phase. We found that the burial of the hydrophobic surface dominated the early phase of the folding process and appeared to be the primary driving force of the reduction in the radius of gyration in that phase.

Biophysical Phenomena↗
PubMed1993

Molecular dynamics simulation of NO recombination to myoglobin mutants.

Molecular dynamics simulations on two coupled electronic surfaces are employed to investigate the geminate recombination of nitric oxide to mutants of sperm whale myoglobin. A model for the ground and the excited states is constructed based on experimental data. The crossing between the surfaces is treated using the Landau-Zener formula. The reaction probability and the recombination curves are calculated directly by histogramming the results of an ensemble of trajectories. The experimental trend is reproduced in which the picosecond recombination rate of different mutants increases in the order Phe29 > Leu29 > Val29 > Ala29. Furthermore, in accord with the experiment on significantly longer time scales an opposite trend is obtained, in which the recombination rate for Ala29 is larger than for Phe29. These results are explained by constrained diffusion of the ligand in the heme pocket. The average and the transient volume of the heme pocket is modified by the 29 mutants.

Amino Acid Sequence↗
PubMed1994

A connected-cluster of hydration around myoglobin: correlation between molecular dynamics simulations and experiment.

An analysis of a molecular dynamics simulation of metmyoglobin in an explicit solvent environment of 3,128 water molecules has been performed. Both statics and dynamics of the protein-solvent interface are addressed in a comparison with experiment. Three-dimensional density distributions, temperature factors, and occupancy weights are computed for the solvent by using the trajectory coordinates. Analysis of the hydration leads to the localization of more than 500 hydration sites distributed into multiple layers of solvation located between 2.6 and 6.8 A from the atomic protein surface. After locating the local solvent density maxima or hydration sites we conclude that water molecules of hydration positions and hydration sites are distinct concepts. Both global and detailed properties of the hydration cluster around myoglobin are compared with recent neutron and X-ray data on myoglobin. Questions arising from differences between X-ray and neutron data concerning the locations of the protein-bound water are investigated. Analysis of water site differences found from X-ray and neutron experiments compared with our simulation shows that the simulation gives a way to unify the hydration picture given by the two experiments.

Amino Acid Sequence↗
PubMed1996

Structural consequences of heme removal: molecular dynamics simulations of rat and bovine apocytochrome b5.

Molecular dynamics simulations of rat and bovine apocytochrome b5 were performed to investigate the structural and dynamical consequences of heme removal. A crystal structure is available for the bovine holoprotein, while experimental studies of apocytochrome b5 have focused on the rat protein. The rat and bovine proteins are 93% homologous by sequence, and the sequence differences (six residues) appear to have no effect on the structure of the native holoprotein, as seen by the correlation of a bovine simulation with rat holocytochrome b5 experimental data (Storch & Daggett, 1995). There was a marked effect, however, on the structure and dynamics of the apo form. The bovine apocytochrome b5 simulation displayed subtle inconsistencies when compared to the experimental results on the rat apoprotein. Therefore, the rat protein was constructed from the bovine crystal structure coordinates. The MD simulation of the rat apoprotein displayed greater deviations from the crystal structure, yet it was in much closer agreement to the experimental data for the apoprotein. Additionally, the six variant residues fall in the regions where the bovine protein deviated from experiment. The two hydrophobic cores of the rat protein behaved very differently. Core 2 was well maintained, retained native-like structure, and is in good agreement with NMR data (Moore & Lecomte, 1990). Conversely, core 1, which is normally constrained by the prosthetic heme group, exhibited conformational heterogeneity, increased mobility, and some loss of secondary structure. Thus, the model of rat apocytochrome b5 complements past studies by providing structural information about core 1 that has proved difficult to obtain by experiment. The bovine simulation serves as a prediction, since little to no experimental data exist for this form of the apoprotein.

Animals↗
PubMed2004

The transmembrane domain of Neu in a lipid bilayer: molecular dynamics simulations.

The results of full-atom molecular dynamics simulations of the transmembrane domains (TMDs) of both native, and Glu664-mutant (either protonated or unprotonated) Neu in an explicit fully hydrated dimyristoylphosphatidylcholine (DMPC) lipid bilayer are presented. For the native TMD peptide, a 10.05 ns trajectory was collected, while for the mutant TMD peptides 5.05 ns trajectories were collected for each. The peptides in all three simulations display stable predominantly alpha-helical hydrogen bonding throughout the trajectories. The only significant exception occurs near the C-terminal end of the native and unprotonated mutant TMDs just outside the level of the lipid headgroups, where pi-helical hydrogen bonding develops, introducing a kink in the backbone structure. However, there is no indication of the formation of a pi bulge within the hydrophobic region of either native or mutant peptides. Over the course of the simulation of the mutant peptide, it is found that a significant number of water molecules penetrate the hydrophobic region of the surrounding lipid molecules, effectively hydrating Glu664. If the energy cost of such water penetration is significant enough, this may be a factor in the enhanced dimerization affinity of Glu664-mutant Neu.

Amino Acid Substitution↗
PubMed2004

Modeling the alpha-helix to beta-hairpin transition mechanism and the formation of oligomeric aggregates of the fibrillogenic peptide Abeta(12-28): insights from all-atom molecular dynamics simulations.

In this paper, all-atom molecular dynamics simulations in explicit solvent are used to investigate the structural and dynamical determinants of the alpha-helical to beta-hairpin conformational transition of the 12-28 fragment from the full length Abeta Alzheimer's peptide. The transition from alpha-helical to beta-structure requires the peptide to populate intermediate beta-bend geometries in which several mainly hydrophobic interactions are partially formed. This is followed by the sudden collapse to ordered beta-hairpin structures and the simultaneous disruption of the hydrophobic side-chain interactions with a consequent increase in solvent exposure. The solvent exposure of hydrophobic side-chains belonging to a sequence of five consecutive residues in the beta-hairpin defines a possible starting point for the onset of the aggregation mechanisms. Several different conformations of model oligomeric (dimeric and tetrameric) aggregates are then investigated. These simulations show that while hydrophobic contacts are important to bring together different monomers with a beta-hairpin like conformation, more specific interactions such as hydrogen-bonding and coulombic interactions, should be considered necessary to provide further stabilization and ordering to the nascent fibrillar aggregates.

Alzheimer Disease↗
PubMed2005

Cofactor activation and substrate binding in pyruvate decarboxylase. Insights into the reaction mechanism from molecular dynamics simulations.

We have performed long-term molecular dynamics simulations of pyruvate decarboxylase from Zymomonas mobilis. Nine structures were modeled to investigate mechanistic questions related to binding of the cofactor, thiamin diphosphate (ThDP), and the substrate in the active site. The simulations reveal that the proposed three ThDP-tautomers all can bind in the active site and indicate that the equilibrium is shifted toward 4'-aminopyrimidine ThDP in the absence of substrate. 4'-Aminopyrimidinium ThDP is found to be a likely intermediate in the equilibrium. Mutations of important active site residues, Glu473Ala and Glu50Ala, were modeled to further elucidate their catalytic role. Formation of the catalytic important ylide by deprotonation of ThDP(C2) is investigated. Only the less favored tautomer, 1',4'-iminopyrimidine ThDP (imino-ThDP), could be deprotonated. The two other tautomers of ThDP could not be activated at the C2-position, thus, explaining the mechanistic importance of the less stable imino-ThDP. Finally, binding of pyruvate in the active site with the cofactor modeled as the nucleophilic ylide (ylide-ThDP) is studied. The carbonyl group of the substrate forms a hydrogen bond to Tyr290(OH). No hydrogen bond could be identified between ThDP(N4') and the substrate. The geometry of the substrate binding is well-suited for a nucleophilic attack by ylide-ThDP(C2). We propose that a proton relay from His113 via Asp27 and Tyr290 to the carbonyl oxygen atom of the substrate may be involved in the mechanism.

Binding Sites↗
PubMed2004

The stabilizing effects of O-glycosylation on the secondary structural integrity of the designed alpha-loop-alpha motif by molecular dynamics simulations.

In this study, various 400 ps molecular dynamics simulations were conducted to determine the stabilizing effect of O-glycosylation on the secondary structural integrity of the design alpha-loop-alpha motif, which has the optimal loop length of 7 Gly residues (denoted as N-A16G7A16-C). In general, O-glycosylation stabilizes the structural integrity of the model peptide regardless of the length and position of glycosylation sites because it decreases the opportunity for water molecules to compete for the intramolecular hydrogen bonds. The designed peptide exhibits the highest helicity when residues 11 and 31 are replaced with Ser residues followed by O-linked with 3 galactose residues, representing the "face-to-face" glycosylation near the loop. In this case, the loop exhibits an extended conformation and several new hydrogen bonds are observed between the main chain of the loop and the galactose residues, resulting in decreasing the fluctuation and increasing the stability of the entire peptide. When the glycosylation are made close to the loop, the secondary structural integrity of the alpha-loop-alpha motif increases with the number of galactose residues. In addition, "face-to-face" glycosylation increases the structural integrity of this motif to a greater extent than "back-to-back" glycosylation. However, when the glycosylation are created away from the loop and near the N- and C-termini, no general rule is found for the stabilizing effect.

Amino Acid Motifs↗