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Results for “Molecular Dynamic simulation”

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PubMed1991

Mass-weighted molecular dynamics simulation of the protein-ligand complex of rhizopuspepsin and inhibitor.

The mass-weighted molecular dynamics simulation method was developed previously for sampling the multidimensional conformational space of linear and cyclic polypeptides and studying their conformational flexibility. Herein results from molecular dynamics simulations of the protein-ligand complex of the aspartyl protease rhizopuspepsin and a polypeptide inhibitor are reported. The dihedral conformational space sampling for the linear peptide inhibitor in situ was found to be increased in the mass-weighted simulation as in other molecular systems previously studied. More significantly, the physical space of the enzyme binding pocket was also sampled efficiently in the simulations and multiple binding sites were identified for the inhibitor. These results suggest that it may be possible now to study, by computer simulations, the putative initial enzyme-inhibitor complex suggested experimentally from the time-dependent kinetics of enzyme inhibition by slow-binding inhibitors (Morrison, J. F., and C. T. Walsh. 1988. Adv. Enzymol. 61:201), and/or conformational substates in protein-ligand complexes suggested in the study of reassociation dynamics of myoglobin and carbon monoxide following photolysis (Austin, R. H., K. W. Beeson, L. Eisenstein, H. Frauenfelder, and I. C. Gunsalus. 1975. Biochemistry. 14:5355). Moreover, the intermediate binding steps and the molecular flexibility of the inhibitor shown in the MWMD simulation may have crucial roles in the ligand binding process.

Amino Acid Sequence↗

PubMed2002

Molecular dynamics simulation of brittle fracture in silicon.

Brittle fracture in silicon is simulated with molecular dynamics utilizing a modified embedded atom method potential. The simulations produce propagating crack speeds that are in agreement with previous experimental results over a large range of fracture energy. The dynamic fracture toughness is found to be equal to the energy consumed by creating surfaces and lattice defects in agreement with theoretical predictions. The dynamic fracture toughness is approximately 1/3 of the static strain energy release rate, which results in a limiting crack speed of 2/3 of the Rayleigh wave speed.

Journal Article↗

PubMed2006

Multiple molecular dynamics simulations of human p450 monooxygenase CYP2C9: the molecular basis of substrate binding and regioselectivity toward warfarin.

To examine the molecular basis of activity and regioselectivity of the clinically important human microsomal cytochrome P450 (CYP) monooxygenase 2C9 toward its substrate warfarin, 22 molecular dynamics simulations (3-5 ns each) were performed in the presence and absence of warfarin. The resulting trajectories revealed a stable protein core and mobile surface elements. This mobility leads to the formation of two surface channels in the region between F-G loop, B' helix/B-B' loop, beta(1)-sheet, and between helices F and I and the turn in the C-terminal antiparallel beta-sheet in the presence of warfarin. Besides the nonproductive state of the CYP2C9 warfarin complex captured in the crystal structure, three additional states were observed. These states differ in the shape of the substrate binding cavity and the position of the warfarin molecule relative to heme. In one of these states, the 7- and 6-positions of warfarin contact the heme with a marked geometrical preference for position 7 over position 6. This modeling result is consistent with experimentally determined regioselectivity (71 and 22% hydroxylation in positions 7 and 6, respectively). Access to the heme group is limited by the core amino acids Ala297, Leu362, Leu366, and Thr301, which therefore are expected to have a major impact on regioselectivity. In addition, modeling predicts that autoactivation of warfarin is sterically hindered. Our study demonstrates how the combination of mobile surface and rigid core leads to interesting properties: a broad substrate profile and simultaneously a high regioselectivity.

Aryl Hydrocarbon Hydroxylases↗

PubMed1991

Molecular dynamics simulation of trp-aporepressor in a solvent.

Molecular dynamics simulations of Escherichia coli trp-aporepressor were carried out in the absence and presence of explicit water molecules. The vacuum simulations resulted in significant deformation of the initial X-ray structure. A solvated simulation with a nonbonded cut-off radius of 9 A gave a better result, and the most satisfactory result was obtained when electrostatic interactions within a cut-off radius of 18 A were considered by a twin-range method. The trajectory from the last simulation was used to analyze the dynamical properties of the aporepressor. The root-mean-square fluctuations of the residues showed the rigidity of the central core and the flexibility of the DNA-binding sites, consistent with the X-ray temperature factors. The dynamical cross-correlation map indicated a significant negative correlation between the central core and the two DNA-binding sites, and thus reproduced the three-domain format (a central core and two DNA-binding heads) from a dynamical point of view. The core region showed weak, but many, intra- and inter-molecular correlations, while the helix-turn-helix DNA-binding motifs were free from correlations with other regions.

Apoproteins↗

PubMed2006

Crystallization of helical oligomers with chirality selection. I. A molecular dynamics simulation for bare helix.

Helical polymers often exhibit pronounced chirality recognition during crystallization. By molecular dynamics simulation, we have already shown that the helical polymers crystallize with or without marked chirality selection depending on structural details of the polymer molecules. We have there classified the helical polymers into two categories: the bare helices made of only backbone atoms which show rather tolerant chirality selection, and the general helices with large side groups showing strict chirality recognition. Polymer crystallization is in general largely hampered and retarded by slow dynamics of the entangled chains, and therefore short helical oligomers are very suitable models for studying the chiral crystallization. We here report on molecular simulations of crystallization in the bare helical oligomer molecules by the use of Monte Carlo and molecular dynamics simulations. First we confirm the low temperature chiral crystal phase and the reversible order-disorder transition. We also observe frequent inversions of the helical sense, and the helix reversal defects propagating along the chains. Then we investigate crystallization from the melt into the chiral crystal phase. We find that the crystallization rate depends very sensitively on the degree of undercooling. The crystallization is found to be the first order transition that conforms well to the traditional picture of crystal growth in small molecules. Even when the crystallization directly into the chiral crystal phase is conducted, marked chirality selections are not observed at the early stage of crystallization; the chains adhere to the crystal surfaces selecting their helical senses rather at random resulting in racemic crystallites. The isothermal crystallization for a sufficiently long time, however, yields lamellar crystals composed of well-developed chiral domains, the growth of which seems to be accomplished through the transition back into the ordered chiral crystal phase.

Journal Article↗

PubMed2006

Lattice boltzmann versus molecular dynamics simulation of nanoscale hydrodynamic flows.

A fluid flow in a simple dense liquid, passing an obstacle in a two-dimensional thin film geometry, is simulated by molecular dynamics (MD) computer simulation and compared to results of lattice Boltzmann (LB) simulations. By the appropriate mapping of length and time units from LB to MD, the velocity field as obtained from MD is quantitatively reproduced by LB. The implications of this finding for prospective LB-MD multiscale applications are discussed.

Computer Simulation↗

PubMed2003

Molecular dynamics simulations of the unfolding of beta(2)-microglobulin and its variants.

In this study, we examined the unfolding processes of native beta(2)-microglobulin and two related variants, one with an N-terminal hexapeptide deletion DeltaN6 and another with Lys57-Asp58 cleavage, by high-temperature molecular dynamics simulations. Three simulation models were used, molecular dynamics (MD) simulations with explicit water solvation, MD simulations with the CHARMM EEF1 force field and Langevin dynamics with the CHARMM EEF1 force field. Our simulations reproduce many of the experimentally observed structural changes. The most striking agreement is in the beta-strands to alpha-helix transition. In our simulations, strands beta(3), beta(4) and beta(5) consistently change to alpha-helix, whereas beta(8) changes to an alpha-helix only briefly. Through comparisons of the conformational behavior of the native, the DeltaN6 and the Lys-cut beta(2)-m, using the three simulation methods, we identified the consensus conformational changes that differentiate between the native beta(2)-m and its two variants. We found that the main effect of the removal of the N-terminal hexapeptide is to increase the separation between strands beta(2) and beta(6) and to facilitate the beta to alpha transition. On the other hand, the lysine cleavage only increases the flexibility of strand beta(5) and does not affect the interactions between strands beta(2) and beta(6). These conformational changes may relate to polymerization tendencies of these variants.

Amyloidosis↗

PubMed2003

Molecular dynamics simulations of simple fluids confined in realistic models of nanoporous carbons.

We present molecular dynamics simulations in the micro-canonical ensemble of a Lennard-Jones model of nitrogen confined in realistic models for saccharose-based carbons developed in our previous work. We calculate the velocity autocorrelation function and mean-squared displacement, and the self-diffusivities from the latter. We observe that the self-diffusivity increases with temperature and exhibits a maximum with loading or adsorbate density. To the best of our knowledge, a maximum in self-diffusivities has not been observed in molecular dynamics simulations of fluids confined in slit pores.

Computer Simulation↗

PubMed1990

Studies on somatostatin with time-resolved spectroscopy and molecular dynamics simulations.

Somatostatin was studied by time-resolved fluorescence spectroscopy and by molecular dynamics simulations. The results obtained indicate the existence of mainly one conformation in DMSO, and the existence of several conformations in other solvents. Molecular dynamics simulations showed that the most important region for activity (residue 7-9) is also the most flexible region in the peptide.

Computer Simulation↗

PubMed2003

Protocol for MM/PBSA molecular dynamics simulations of proteins.

Continuum solvent models have been employed in past years for understanding processes such as protein folding or biomolecular association. In the last decade, several attempts have been made to merge atomic detail molecular dynamics simulations with solvent continuum models. Among continuum models, the Poisson-Boltzmann solvent accessible surface area model is one of the oldest and most fundamental. Notwithstanding its wide usage for simulation of biomolecular electrostatic potential, the Poisson-Boltzmann equation has been very seldom used to obtain solvation forces for molecular dynamics simulation. We propose here a fast and reliable methodology to implement continuum forces in standard molecular mechanics and dynamics algorithms. Results for a totally unrestrained 1 ns molecular dynamics simulation of a small protein are quantitatively similar to results obtained by explicit solvent molecular dynamics simulations.

Computer Simulation↗

PubMed2005

Substrate distortion in the Michaelis complex of Bacillus 1,3-1,4-beta-glucanase. Insight from first principles molecular dynamics simulations.

The structure and dynamics of the enzyme-substrate complex of Bacillus 1,3-1,4-beta-glucanase, one of the most active glycoside hydrolases, is investigated by means of Car-Parrinello molecular dynamics simulations (CPMD) combined with force field molecular dynamics (QM/MM CPMD). It is found that the substrate sugar ring located at the -1 subsite adopts a distorted 1S3 skew-boat conformation upon binding to the enzyme. With respect to the undistorted 4C1 chair conformation, the 1S3 skew-boat conformation is characterized by: (a) an increase of charge at the anomeric carbon (C1), (b) an increase of the distance between C1 and the leaving group, and (c) a decrease of the intraring O5-C1 distance. Therefore, our results clearly show that the distorted conformation resembles both structurally and electronically the transition state of the reaction in which the substrate acquires oxocarbenium ion character, and the glycosidic bond is partially broken. Together with analysis of the substrate conformational dynamics, it is concluded that the main determinants of substrate distortion have a structural origin. To fit into the binding pocket, it is necessary that the aglycon leaving group is oriented toward the beta region, and the skew-boat conformation naturally fulfills this premise. Only when the aglycon is removed from the calculation the substrate recovers the all-chair conformation, in agreement with the recent determination of the enzyme product structure. The QM/MM protocol developed here is able to predict the conformational distortion of substrate binding in glycoside hydrolases because it accounts for polarization and charge reorganization at the -1 sugar ring. It thus provides a powerful tool to model E.S complexes for which experimental information is not yet available.

Bacillus↗

PubMed1991

Molecular dynamics simulation of Lewis blood groups and related oligosaccharides.

Molecular dynamics simulations without explicit inclusion of solvent molecules have been performed to study the motions of Lewisa and Lewisb blood group oligosaccharides, and two blood group A tetrasaccharides having type I and type II core chains. The blood group H trisaccharide has also been studied and compared with the blood group A type II core chain. The potential energy surface developed by Rasmussen and co-workers was used with the molecular mechanics code CHARMM. The lowest energy minima of the component disaccharide fragments were obtained from conformational energy mapping. The lowest energy minima of these disaccharide fragments were used to build the tri- and tetrasaccharides that were further minimized before the actual heating/equilibration and dynamics simulations. The trajectories of the disaccharide fragments, e.g., Fuc alpha- (1----4)GlcNAc, Gal beta-(1----4)GlcNAc, etc., show transitions among various minima. However, the oligosaccharides were found to be dynamically stable and no transitions to other minimum energy conformations were observed in the time series of the glycosidic dihedral angles even during trajectories as long as 300 ps. The stable conformations of the glycosidic linkages in the oligosaccharides are not necessarily the same as the minimum energy conformation of the corresponding isolated disaccharides. The average fluctuations of the glycosidic angles in the oligosaccharides were well within the range of +/- 15 degrees. The results of these trajectory calculations were consistent with the relatively rigid single-conformation models derived for these oligosaccharides from 1H-nmr data.

Carbohydrate Conformation↗

PubMed2006

Hydration, swelling, interlayer structure, and hydrogen bonding in organolayered double hydroxides: insights from molecular dynamics simulation of citrate-intercalated hydrotalcite.

Molecular dynamics (MD) simulation of the Mg/Al (3:1) layered double hydroxide (LDH), hydrotalcite (HT), containing citrate, C6H5O7(3-), as the charge balancing interlayer anion provides new molecular scale insight into the interlayer structure, hydrogen bonding, and energetics of the hydration and consequent swelling of LDH compounds containing organic and biomolecules. Citrate-HT exhibits affinity for water up to very high hydration levels, in contrast to the preferred low hydration states of most LDHs intercalated with small, inorganic anions. This result is consistent with the recent experimental observation of the delamination of lactate-HT. The high water affinity is rationalized in terms of the preference of citrate ion for hydrogen bonds (H-bonds) donated from water molecules rather than from the hydroxyl groups of the metal hydroxide layer and the need to develop an integrated interlayer H-bond network among the citrate ions, water, and -OH groups of the hydroxide layers. The changes in the orientation of citrate molecules with progressive hydration are also intimately related to its preference to accept hydrogen bonds from water.

Journal Article↗

PubMed2005

Molecular dynamics simulations of grafted polyelectrolytes on two apposing walls.

Molecular dynamics simulations of polyelectrolytes grafted to two apposing surfaces were performed. Bead-spring polymer models are used to treat flexible chains [e.g., sodium poly(styrene sulfonate)] and stiff chains (double-stranded DNA). The counterions are explicitly treated. The effect of the surface density of the grafted polymer, the chain length, and the gap width on the structure and the pressure were studied. Results are compared to experimental measurements and to simulations of polyelectrolyte brushes on a single surface. The density profiles exhibit a maximum not found in single surface data. The maximum is due to the brushes shrinking to avoid interpenetration.

Computer Simulation↗

PubMed1999

Molecular dynamics simulation of DPPC bilayer in DMSO.

We performed molecular dynamics simulations on dipalmitoylphosphatidylcholine (DPPC)/dimethylsulfoxide (DMSO) system that has the same lipid:solvent weight ratio as in our previous simulation done on DPPC/water. We did not observe a large change in the size of DPPC membrane when the solvent was changed from water to DMSO. Also, we did not observe that a large number of DMSO molecules is permeating into the membrane, as it was suggested to explain the observed change in the bilayer repeat period. We found that the surface potential reverses its sign when water is replaced by DMSO. Based on the results from our simulations, we propose that the repulsion force acting between membranes is reduced when DMSO is added to solvent water and therefore membrane surfaces approach closer to each other and the extra solvent is removed into excess solution.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2006

Molecular dynamics simulations of LysRS: an asymmetric state.

We report molecular dynamics simulations of the Escherichia coli Lysyl-tRNA synthetase LysU isoform carried out as a benchmark for mutant simulations in in silico protein engineering efforts. Unlike previous studies of aminoacyl-tRNA synthetases, LysU is modelled in its full dimeric form with explicit solvent. While developing a suitable simulation protocol, we observed an asymmetry that persists despite improvements to the model. This prediction has directly led to experiments that establish a functional asymmetry in nucleotide binding by LysU. The development of a simulation protocol and validation of the model are presented here. The observed asymmetry is described and the role of protein flexibility in developing the asymmetry is discussed.

Adenosine Triphosphate↗

PubMed2000

Tryptophanyl fluorescence lifetime distribution of hyperthermophilic beta-glycosidase from molecular dynamics simulation: a comparison with the experimental data.

A molecular dynamics simulation approach has been utilized to understand the unusual fluorescence emission decay observed for beta-glycosidase from the hyperthermophilic bacterium Solfolobus sulfotaricus (Sbeta gly), a tetrameric enzyme containing 17 tryptophanyl residues for each subunit. The tryptophanyl emission decay of Sbeta gly results from a bimodal distribution of fluorescence lifetimes with a short-lived component centered at 2.5 ns and a long-lived one at 7.4 ns (Bismuto E, Nucci R, Rossi M, Irace G, 1999, Proteins 27:71-79). From the examination of the trajectories of the side chains capable of causing intramolecular quenching for each tryptophan microenvironment and using a modified Stern-Volmer model for the emission quenching processes, we calculated the fluorescence lifetime for each tryptophanyl residue of Sbeta gly at two different temperatures, i.e., 300 and 365 K. The highest temperature was chosen because in this condition Sbeta gly evidences a maximum in its catalytic activity and is stable for a very long time. The calculated lifetime distributions overlap those experimentally determined. Moreover, the majority of trytptophanyl residues having longer lifetimes correspond to those originally identified by inspection of the crystallographic structure. The tryptophanyl lifetimes appear to be a complex function of several variables, such as microenvironment viscosity, solvent accessibility, the chemical structure of quencher side chains, and side-chain dynamics. The lifetime calculation by MD simulation can be used to validate a predicted structure by comparing the theoretical data with the experimental fluorescence decay results.

Fluorescence↗

PubMed2000

Effect of the reaction field electrostatic term on the molecular dynamics simulation of the activation domain of procarboxypeptidase B.

Molecular dynamics simulations of the activation domain of porcine procarboxypeptidase B (ADBp) were performed in order to examine the effects of the inclusion of a reaction field (RF) term into the calculation of electrostatics forces for highly charged proteins. Two simulations were performed with the GROMOS96 package, studying the influence of counterions on the final results. Comparison with previous results without the inclusion of the RF term (Martí-Renom, M.A., Mas,J.M., Oliva,B., Querol,E. and Avilés,F.X., Protein Engng, 1998, 11, 101-110) shows that the structure is well maintained when the RF term is included. Moreover, the analysis of the trajectories shows that simulations of solvated highly-charged proteins are sensitive to the presence of counterions, the secondary structures being more stable when their charges are neutralized.

Amino Acid Sequence↗