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At least 19 recordsLinked to original sources
PubMed1992

The conformational behaviour of complexes of alpha-cyclodextrin with p-chlorophenol and p-hydroxybenzoic acid in water as studied by molecular dynamics simulations.

Molecular dynamics simulations were performed to obtain information about the conformational behaviour and stabilization of alpha-cyclodextrin (alpha CD) complexes in water. Simulations of p-chlorophenol and p-hydroxybenzoic acid in alpha CD showed that the complex is a very flexible system. The guest compound rotates inside the cavity and partly moves in and out. alpha CD continuously adapts its conformation to the orientation of the guest compound (or vice versa): the hexagon of the glycosidic oxygen atoms is stretched parallel to the plane of the aromatic ring of the guest compound during 80% of the simulation. This suggests that Van der Waals interactions play an important role in the stabilization of the complex. Each intramolecular hydrogen bond between neighbouring glucose units is formed during 30-80% of the simulation. Hydrogen bonds between alpha CD and the guest compound, on the other hand, are rarely formed. Thus, intermolecular hydrogen bonding seems to play a minor role in the stabilization of alpha CD complexes.

Chlorophenols↗
PubMed1992

Cholesterol in model membranes. A molecular dynamics simulation.

Molecular dynamics simulations of a model membrane with inserted cholesterol molecules have been performed to study the perturbing influence of cholesterol. In the fluid phase of a lipid bilayer at 13 mol% concentration of cholesterol, local ordering of the hydrocarbon chains is induced. This perturbation decays with the distance from the cholesterol, and the effect extends 1.25 nm. It can be monitored in several ways, e.g., by an order parameter corresponding to deuterium nuclear magnetic resonance quadrupolar splittings, by the fraction of gauche bonds, or by the local bilayer thickness. At constant surface density, the local ordering is accompanied by disordering of the bulk phase, and, consequently, the net ordering effect is small. After compressing the system laterally in accordance with experimentally known surface areas, the bulk order parameters agree with those of a pure system, and the average order parameters are in accordance with experimental data. The necessity for this lateral compression is supported by calculated lateral pressures. At lower cholesterol concentration (3%), no direct perturbing effect is observed. A smaller lateral pressure than in a pure system indicates that the system with cholesterol is expected to have a smaller surface area, which would result in an increase of the order parameters, thus accounting for the experimental observations. The lack of spatial variation is, however, puzzling and may indicate a cooperative ordering effect.

Cholesterol↗
PubMed1991

Cooperative ligand reorientations in cytochrome c3: a molecular dynamics simulation.

Molecular dynamics simulations of a tetraheme cytochrome c3 were performed to investigate dynamic aspects of the motion of the axial heme iron ligands. It was found that persistent transitions between alternate axial imidazole orientations of the histidine incorporated in the CXXCH heme binding sequence occurred via correlated motions. The correlated motions involved virtually all of the atoms comprising the polypeptide backbone of the heme binding sequence as well as the histidine imidazole side-chain.

Amino Acid Sequence↗
PubMed1990

Using molecular dynamics simulations on crambin to evaluate the suitability of different continuum dielectric and hydrogen atom models for protein simulations.

Molecular dynamics simulations of enzymes with enough explicit waters of solvation to realistically account for solute-solvent interactions can burden the computational resources required to perform the simulation by more than two orders of magnitude. Since enzyme simulations even with an implicit solvation model can be imposing for a supercomputer, it is important to assess the suitability of different continuum dielectric models for protein simulations. A series of 100-picosecond molecular dynamics simulations were performed on the X-ray crystal structure of the protein crambin to examine how well computed structures, obtained using seven continuum dielectric and two hydrogen atom models, agreed with the X-ray structure. The best level of agreement between computed and experimental structures was obtained using a constant dielectric of 2 and the all-hydrogen model. Continuum dielectric models of 1, 1r, and 2r also led to computed structures in reasonably good agreement with the X-ray structure. In all cases, the all-hydrogen model gave better agreement than the united atom model, although, in one case, the difference was not significant. Dielectric models of 4, 80, and 4r with either hydrogen model yielded significantly poorer fits. It is especially noteworthy that the observed trends did not semiquantitatively converge until about 50 picoseconds into the simulations, suggesting that validation studies for protein calculations based on energy minimizations or short simulations should be viewed with caution.

Computer Simulation↗
PubMed1990

Dynamic properties of the first enzymatic reaction steps of porcine pancreatic elastase. How rigid is the active site of the native enzyme? Molecular dynamics simulation.

Two molecular dynamics simulations (100 and 50 ps) of native porcine pancreatic elastase i.e., without bound substrate and with the active site hydrated by a dome of water (630 molecules) have been performed. Dynamical properties of the catalytic tetrad have been examined. While relative conformations of the Asp 102, His 57, and Ser 214 are rather stable in time, the side chain of Ser 195 undergoes several conformational changes. No preferences are observed for the formation of a hydrogen bond between the O gamma-H group (Ser 195) and nitrogen N, (His 57). A cluster of ordered water molecules effectively competes with the H-O gamma group (Ser 195) and thereby prevents the formation of this H bond, which is generally agreed to be crucial for catalysis.

Animals↗
PubMed1989

Superoxide dismutase: fluctuations in the structure and solvation of the active site channel studied by molecular dynamics simulation.

The molecular dynamics (MD) simulation of superoxide dismutase (SOD) in water is carried out for a total of 23 ps. The simulation system is a 26 A sphere centered at the active site of SOD, including 1602 atoms from SOD and 1761 water molecules. There is no gross deviation from the x-ray structure for the average MD structure. The structure and potential fluctuations around the active site are examined. The results provide new insight to the interactions between SOD and its substrate superoxide.

Binding Sites↗
PubMedDate not supplied

Disaccharide conformational flexibility. II. Molecular dynamics simulations of sucrose.

Molecular dynamics simulations have been used to study the motions in vacuum of the disaccharide sucrose. Ensembles of trajectories were calculated for each of the five local minimum energy conformations identified in the adiabatic conformational energy mapping of this molecule. The model sucrose molecules were found to exhibit a variety of motions, although the global minimum energy conformation was found to be dynamically stable, and no transitions away from this structure were observed to occur spontaneously. In all but one of these vacuum trajectories, the intramolecular hydrogen bond between residues was maintained, in accord with recent nmr studies of this molecule in aqueous solution. Considerable flexibility of the furanoid ring was found in the trajectories. No "flips" to the opposite puckering for this ring were found in the simulations starting from the global minimum, although such a transition was observed for a trajectory initiated with one of the higher local minimum energy conformations. Overall, the observed structural fluctuations were consistent with the experimental picture of sucrose as a relatively rigid molecule.

Carbohydrate Conformation↗
PubMed1985

Atomic motions in phenylalanine transfer RNA probed by molecular dynamics simulations.

A 24 psec molecular dynamics simulation of tRNAPhe reveals a very stable model whose average structure is close to that of the crystallographic studies. The root mean square atomic motions correlate very well with the thermal factors from crystallography and are largely determined by packing forces. These motions are generally more anisotropic than those seen in a molecular dynamics simulation of a globular protein, and the anisotropic effects are also primarily a consequence of packing considerations. The development and examination of molecular dynamics models for macromolecules is an interesting basic research problem in biophysical chemistry, and it is now reasonably well advanced. The more exciting tasks of using these models to predict experimental properties and to examine biological function are just beginning.

Models, Molecular↗
PubMed1990

Molecular dynamics simulations in biology.

Molecular dynamics--the science of simulating the motions of a system of particles--applied to biological macromolecules gives the fluctuations in the relative positions of the atoms in a protein or in DNA as a function of time. Knowledge of these motions provides insights into biological phenomena such as the role of flexibility in ligand binding and the rapid solvation of the electron transfer state in photosynthesis. Molecular dynamics is also being used to determine protein structures from NMR, to refine protein X-ray crystal structures faster from poorer starting models, and to calculate the free energy changes resulting from mutations in proteins.

Chemical Phenomena↗
PubMed1992

Application of restrained minimization, simulated annealing and molecular dynamics simulations for the conformational analysis of oligosaccharides.

The purpose of the present study was to determine the confidence with which the small number of 1H NMR nuclear Overhauser effect (NOE) distance constraints measurable across glycosidic linkages in oligosaccharides could be used for solution conformational analysis. This was assessed by use of these constraints in restrained molecular mechanical minimization of the tetrasaccharide Gal beta 1----4(Fuc alpha 1----3)Glc-NAc beta 1----3Gal, a model compound of the Lewis-X antigenic determinant. This presents a particularly severe test case in view of extreme resonance overlap and a dearth of inter-residue distance constraints. It is concluded that these constraints, when used in conventional restrained minimization, result in the generation of 'virtual conformations' and local minima about glycosidic linkages. However, these restraints are nevertheless found to be useful in the initial stages of a conformational analysis strategy involving restrained minimization combined with dynamical simulated annealing to define more accurately the global minimum energy configuration, together with molecular dynamics simulation to explore conformational mobility about this minimum. Theoretical ROE values calculated over the time course of the MD simulation, using a formalism appropriate for the time scale of the internal motion, are compared with those obtained experimentally in the oligosaccharide.

Carbohydrate Conformation↗
PubMed1992

Characterization of "native" apomyoglobin by molecular dynamics simulation.

We have used molecular dynamics simulation methods to study the structure and fluctuations of "native" apomyoglobin in aqueous solution for a period of greater than 0.5 nanosecond. This work was motivated by the recent attempts of Hughson et al. to characterize the structure and motion of both this molecule and the less compact, acid stabilized I stage, using methods of pulsed H/2H exchange. The study of these systems provides new insights into protein folding intermediates and our simulation has yielded a detailed model for structure and fluctuations in apomyoglobin which complements the experimental studies. We find that local (short-time) fluctuations agree well with fluctuations observed for the holoprotein in aqueous solution, as well as results from the crystallographic B-factors. In addition, the structural features we observe for native apomyoglobin are very similar to the holoprotein, in basic agreement with the findings of Hughson et al. By examining larger-scale motions, developing only over timescales in excess of a 100 picoseconds, we are able to identify conformationally "labile" and "non-labile" regions within native apomyoglobin. These regions correspond extremely well to those identified in the nuclear magnetic resonance experiments as unstable and stable "folding subdomains" in the I state of apomyoglobin. Overall we find that helices A, B, E, G and H show the least amount of motion and helices C, D and F move substantially over the timescales examined. The major motions, and the primary difference between the holo and apo structures as we have observed them, are due to the shifting motion of helices C, D and F into the vacant heme cavity. We also find that motions at the interface of helical segments can be large, with one important exception being the chain segment connecting helices G and H. This segment of chain interacts with the conformationally "non-labile" helix A to form a relatively rigid subdomain composed of helices A, G and H. We believe that these findings provide direct support for the suggestion of Hughson et al. that helices A, G and H constitute a compact subdomain that remains in a native-like conformation as the protein begins to unfold in environments of decreasing pH.

Apoproteins↗
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↗
PubMed1992

Molecular dynamics simulations of the whey protein beta-lactoglobulin.

Molecular dynamics simulations have been used to model the motions and conformational behavior of the whey protein bovine beta-lactoglobulin. Simulations were performed for the protein by itself and complexed to a single retinol ligand located in a putative interior binding pocket. In the absence of the retinol ligand, the backbone loops around the opening of this interior pocket shifted inward to partially close off this cavity, similar to the shifts observed in previously reported molecular dynamics simulations of the uncomplexed form of the homologous retinol binding protein. The protein complexed with retinol does not exhibit the same conformational shifts. Conformational changes of this type could serve as a recognition signal allowing in vivo discrimination between the free and retinol complexed forms of the beta-lactoglobulin molecule. The unusual bending of the single alpha-helix observed in the simulations of retinol binding protein were not observed in the present calculations.

Animals↗
PubMed1991

Molecular dynamics simulation on a network of workstations using a machine-independent parallel programming language.

Molecular dynamics simulations investigate local and global motion in molecules. Several parallel computing approaches have been taken to attack the most computationally expensive phase of molecular simulations, the evaluation of long range interactions. This paper develops a straightforward but effective algorithm for molecular dynamics simulations using the machine-independent parallel programming language, Linda. The algorithm was run both on a shared memory parallel computer and on a network of high performance Unix workstations. Performance benchmarks were performed on both systems using two proteins. This algorithm offers a portable cost-effective alternative for molecular dynamics simulations. In view of the increasing numbers of networked workstations, this approach could help make molecular dynamics simulations more easily accessible to the research community.

Algorithms↗
PubMed1992

Molecular dynamics simulation on a network of workstations using a machine-independent parallel programming language.

Molecular dynamics simulations investigate local and global motion in molecules. Several parallel computing approaches have been taken to attack the most computationally expensive phase of molecular simulations, the evaluation of long range interactions. This paper reviews these approaches and develops a straightforward but effective algorithm using the machine-independent parallel programming language, Linda. The algorithm was run both on a shared memory parallel computer and on a network of high performance Unix workstations. Performance benchmarks were performed on both systems using two proteins. This algorithm offers a portable cost-effective alternative for molecular dynamics simulations. In view of the increasing numbers of networked workstations, this approach could help make molecular dynamics simulations more easily accessible to the research community.

Algorithms↗
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↗
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↗
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↗