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Results for “Molecular Dynamic simulation”

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At least 163 records · Page 9Linked to original sources

PubMed1994

Molecular dynamics simulations of trp apo- and holorepressors: domain structure and ligand-protein interaction.

Molecular dynamics simulations of the apo- and holo-forms of the trp-repressor protein were performed under extensively solvated conditions in order to elucidate their dynamic structures and ligand-protein interactions. The root mean square fluctuations calculated from the trajectories agreed with those calculated from X-ray temperature factors. Distance, distance fluctuation, and dynamic cross-correlation maps were drawn to provide information on the dynamic structures and communications among the domains. A three-domain format has been proposed for the crystal structure (Zhang et al., Nature 327:591-597, 1987); namely, helices A-C and F of both subunits make up a central core, and D and E of each subunit forms a DNA binding head. The results of the simulations were mostly consistent with the three-domain format. However, helix F was more flexible and freer than other parts of the central core. The turn DE, the helix-turn-helix DNA binding motif, was free from interactions and correlations with other domains in both forms of the repressor. A comparison of the simulations of the aporepressor and holorepressor showed that tryptophan binding made the DNA-binding helix D more flexible but helix F less flexible. Several amino acid residues in contact with the bound tryptophan were identified as making concerted motions with it. Interaction energies between the corepressor and the amino acid residues of the protein were analyzed; the results were mostly consistent with the mutational experiments.

Amino Acid Sequence↗

PubMed1997

Molecular dynamics simulation study of DNA dodecamer d(CGCGAATTCGCG) in solution: conformation and hydration.

A molecular dynamics simulation of the dodecamer duplex d(CGCGAATTCGCG) using the particle mesh Ewald sum assumed a B-conformation remarkably close to the observed X-ray structure. The Ewald summation method effectively eliminates the usual "cut-off" of long-range interactions and allowed us to evaluate the full effect of the electrostatic forces. This simulation showed remarkable agreement with the Dickerson X-ray structure in both average structure and B-factors; within the EcoRI site itself, the rms deviation between the average theoretical and observed structures was 1.1 A. The width of the minor groove fluctuated between a wide and narrow configuration with the latter corresponding closely to the X-ray structure. The simulation also suggested a strong sequence-dependent signature on the minor groove width in both wide and narrow conformers. Hydration shells in both the major and minor grooves were observed. The "spine of hydration" in the minor groove was clear. In the major groove the first hydration shell appears to be a ribbon-like structure that reproduces the principal features of observed X-ray structures; subtle variations of this hydration pattern suggest sequence dependencies. Sequence-dependent features were also examined for helical and other geometric parameters. The successful reproduction of many experimentally observed fine structural features shows that the Ewald summation significantly improves the fidelity of the calculations.

Crystallography, X-Ray↗

PubMed1993

Molecular dynamics simulations and rigid body (TLS) analysis of aspartate carbamoyltransferase: evidence for an uncoupled R state.

In the R form of ATCase complexed with the bisubstrate analogue, N-(phosphonacetyl)-L-aspartate, large temperature factors are reported for the allosteric domains of the regulatory chains. We studied the conformational flexibility of the holoenzyme with molecular dynamics simulations and rigid body (TLS) analysis. The results of the molecular dynamics simulations suggest that, although local atomic fluctuations account for the temperature factors of the catalytic and zinc domains, they do not account for the large temperature factors of the allosteric regions. However, the temperature factors of the allosteric domains can be satisfactorily analyzed using a rigid body model. The simulations and rigid body analysis support the idea that the allosteric regions are mechanically uncoupled from the rest of the enzyme in the PALA structure. Implications of this uncoupling for allosteric regulation are discussed.

Allosteric Site↗

PubMed1997

Molecular dynamics simulation in solvent of the estrogen receptor protein DNA binding domain in complex with a non-consensus estrogen response element DNA sequence.

We investigated protein/DNA interactions, using molecular dynamics simulations computed between a 10 Angstom water layer model of the estrogen receptor (ER) protein DNA binding domain (DBD) amino acids and DNA of a non-consensus estrogen response element (ERE) consisting of 29 nucleotide base pairs. This ERE nucleotide sequence occurs naturally upstream of the Xenopus laevis Vitelligenin A1 gene. The ER DBD is encoded by three exons. Namely, exons 2 and 3 which encode the two zinc binding motifs and a sequence of exon 4 which encodes a predicted alpha helix. We generated a computer model of the ER DBD using atomic coordinates derived from the average of 30 nuclear magnetic resonance (NMR) spectroscopy coordinate sets. Amino acids on the carboxyl end of the ER DBD were disordered in both X-ray crystallography and NMR determinations and no coordinates were reported. This disordered region includes 10 amino acids of a predicted alpha helix encoded in exon 4 at the exon 3/4 splice junction. These amino acids are known to be important in DNA binding and are also believed to function as a nuclear translocation signal sequence for the ER protein. We generated a computer model of the predicted alpha helix consisting of the 10 amino acids encoded in exon 4 and attached this helix to the carboxyl end of the ER DBD at the exon 3/4 splice junction site. We docked the ER DBD model within the DNA major groove halfsites of the 29 base pair non-consensus ERE and flanking nucleotides. We constructed a solvated model with the ER DBD/ERE complex surrounded by a ten Angstrom water layer and conducted molecular dynamics simulations. Hydrogen bonding interactions were monitored. In addition, van der Waals and electrostatic interaction energies were calculated. Amino acids of the ER DBD DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon-anticodon nucleotide base and backbone sites within the ERE DNA right major groove halfsite. Amino acids of the ER DBD exon 4 encoded predicted alpha helix formed direct and water mediated H-bonds with base and backbone sites of their cognate codon-anticodon nucleotides within the minor grooves flanking the ERE DNA major groove halfsites. These interactions together induced bending of the DNA into the protein.

Animals↗

PubMed1993

Molecular dynamics simulation of a phospholipase A2-substrate complex.

We have used knowledge of the three-dimensional structure of phospholipids and phospholipases A2 together with biochemical data, computer graphics modelling and a 48 ps molecular dynamics simulation to predict the structure of a phospholipase A2-substrate complex. There is remarkable similarity between this predicted structure of enzyme-substrate complex and the structure that can be deduced from the observed enzyme-inhibitor complex. Molecular dynamics simulation highlights the importance of the calcium-ion in substrate binding and the persistence of the His-48 to water-hydrogen bond is compatible with the proposed role of this water molecule as the nucleophile in catalysis.

Animals↗

PubMed2026

Molecular docking, molecular dynamics simulation, and enzyme inhibitory studies of vitamin K family members on aldose reductase.

Aldose reductase (AR) is a key enzyme in the polyol pathway and plays a major role in the progression of secondary complications of diabetes. Despite extensive efforts to develop natural and synthetic aldose reductase inhibitors (ARIs), most candidates have shown limited clinical efficacy, highlighting the need for more potent and selective inhibitors. In this study, we have systematically evaluated the inhibitory potential of vitamin K family members (vitamin K1, vitamin K2, and vitamin K3) using molecular docking, protein-ligand interaction analysis, molecular dynamics simulations, and enzyme kinetics. Docking analysis predicted that vitamin K2 has the highest binding affinity for AR. Subsequent molecular dynamics simulations revealed that both vitamin K1 and vitamin K2 formed stable complexes with the protein, exhibiting comparable RMSD (∼0.5 Å difference), similar RMSF profiles, and reduced radius of gyration, indicating compact and stable binding. Interaction analysis demonstrated that ligand binding is predominantly driven by hydrophobic interactions, with vitamin K2 forming a higher number of hydrophobic contacts, while vitamin K1 exhibited slightly more hydrogen bonding. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) results further supports stronger binding of vitamin K2 (-56 kcal/mol) compared to vitaminK1 (-51 kcal/mol). Consistent with these findings, enzyme kinetics showed a slightly lower Ki value for vitamin K2 than vitamin K1. In contrast, vitamin K3 failed to maintain stable binding and moved out of the active site during simulation. Overall, the study highlights that hydrophobic interaction-driven stabilization plays a key role in ligand binding, and identifies vitamin K1 and vitamin K2 as promising inhibitors against AR, with vitamin K2 exhibiting more favourable hydrophobic interactions and binding stability.

Aldose Reductase↗

PubMed1994

Molecular dynamics simulations of an enzyme surrounded by vacuum, water, or a hydrophobic solvent.

We report on molecular dynamics simulations of a medium-sized protein, a lipase from Rhizomucor miehei, in vacuum, in water, and in a nonpolar solvent, methyl hexanoate. Depending on force field and solvent, the molecular dynamics structures obtained as averages over 150 ps had root-mean-square deviations in the range of 1.9 to 3.6 A from the crystal structure. The largest differences between the structures were in hydrogen bonding and exposed surface areas of the protein. The surface area increased in both solvents and became smaller in vacuum. The change of surface exposure varied greatly between different residues and occurred in accordance with the hydrophobicity of the residue and the nature of the solvent. The fluctuations of the atoms were largest in the external loops and agreed well with crystallographic temperature factors. Root-mean-square fluctuations were significantly smaller in the nonpolar solvents than they were in water, which is in accordance with the notion that proteins become more rigid in nonpolar solvents. In methyl hexanoate a partial opening of the lid covering the active site occurred, letting a methyl hexanoate molecule approach the active site.

Computer Simulation↗

PubMed1997

Transmembrane helix structure, dynamics, and interactions: multi-nanosecond molecular dynamics simulations.

To probe the fundamentals of membrane/protein interactions, all-atom multi-nanosecond molecular dynamics simulations were conducted on a single transmembrane poly(32)alanine helix in a fully solvated dimyristoyphosphatidylcholine (DMPC) bilayer. The central 12 residues, which interact only with the lipid hydrocarbon chains, maintained a very stable helical structure. Helical regions extended beyond these central 12 residues, but interactions with the lipid fatty-acyl ester linkages, the lipid headgroups, and water molecules made the helix less stable in this region. The C and N termini, exposed largely to water, existed as random coils. As a whole, the helix tilted substantially, from perpendicular to the bilayer plane (0 degree) to a 30 degrees tilt. The helix experienced a bend at its middle, and the two halves of the helix at times assumed substantially different tilts. Frequent hydrogen bonding, of up to 0.7 ns in duration, occurred between peptide and lipid molecules. This resulted in correlated translational diffusion between the helix and a few lipid molecules. Because of the large variation in lipid conformation, the lipid environment of the peptide was not well defined in terms of "annular" lipids and on average consisted of 18 lipid molecules. When compared with a "neat" bilayer without peptide, no significant difference was seen in the bilayer thickness, lipid conformations or diffusion, or headgroup orientation. However, the lipid hydrocarbon chain order parameters showed a significant decrease in order, especially in those methylene groups closest to the headgroup.

Computer Simulation↗

PubMed1998

Deducing polymeric structure from aqueous molecular dynamics simulations of oligosaccharides: predictions from simulations of hyaluronan tetrasaccharides compared with hydrodynamic and X-ray fibre diffraction data.

Molecular dynamics simulations of the two hyaluronan tetrasaccharides in water predict that over a period of 500 ps, their central linkages populate a single primary minima. Over the same period the peripheral linkages explore this minima, but also a secondary minima. Structures constructed using the primary minima were found to be extended left-handed helices of axial rise per disaccharide (h) 0.8 to 1.0 nm and 2.8 to 4.5 disaccharides per turn (n), in good agreement with n=3 and n=4 helices found by X-ray fibre diffraction studies. We have used the predicted average conformation from molecular dynamics to calculate the translational diffusion coefficients of the oligosaccharide series up to decasaccharide, and compared these with experimental measurements obtained using the method of capillary dispersion. Our calculated values are found to be in good agreement with experiment beyond the size of a tetrasaccharide. A partial digest of hyaluronan in the molecular mass range 10 to 100 kDa was fractionated by gel chromatography. Molecular weights were determined by in-line laser light-scattering measurements, and the translational diffusion coefficients of selected fractions were determined by dynamic laser light-scattering. A similar experiment was performed on hyaluronan with a molecular mass greater than 1MDa. The data suggest a change from rod-like to stiff coil behaviour beyond a molecular weight of 10 kDa. We have also examined the conformations available using the secondary minima, found at the peripheral linkages. In contrast to the extended structures previously described we have found left and right-handed helices with high values of n (5-10) and low values of h. Although there is no experimental evidence for these structures, they are of interest as, over short stretches, they would introduce folds, loops, and turns into the hyaluronan molecule. Such shapes may play an important role in the hydrodynamics of hyaluronan and its interaction with lipids and proteins.

Carbohydrate Conformation↗

PubMed1996

The application of different solvation and electrostatic models in molecular dynamics simulations of ubiquitin: how well is the X-ray structure "maintained"?

We present molecular dynamics simulations on ubiquitin with explicit solvent molecules and investigate the influence of different force fields [Weiner et al. (J. Am. Chem. Soc. 106:765-784, 1984; J. Comput. Chem. 7:230-252, 1986) vs. Cornell et al. (J. Am. Chem. Soc. 117:5179-5197, 1995)], different treatments of the long-range electrostatic interaction (8 A cutoff vs. particle mesh Ewald), and different solvation models (periodic box vs. small shell of water molecules) on the structure and the dynamics of the protein. Structural data are monitored by atomic root mean square deviations (RMSDs) from the crystal structure, the radius of gyration, the solvent-accessible surface area, and the pattern of the backbone hydrogen bonds. The dynamic behavior is assessed by the atomic fluctuations and the order parameters of the N-H backbone vectors. With the Cornell et al. force field and a periodic box model, the simulated structures stay much closer to the experimental X-ray structure than with the older Weiner et al. force field. A further improvement of the simulation is found when the electrostatic interaction is evaluated with the particle mesh Ewald method; after 1.2 ns of simulation the backbone RMSD amounts to only 1.13 A. The analysis of the dynamic parameters shows that this good structural agreement is not due to a damping of internal motion in the protein. For a given length of simulation time, the shell models achieve an agreement between simulated and experimental structures that is comparable to the best models that employ a periodic box of solvent models. However, compared with the box models, the fluctuations of the protein atoms in the shell models are smaller, and only with simulation times as long as 2 ns do they become of comparable size to the experimental ones.

Computer Simulation↗

PubMed1987

Anisotropy and anharmonicity of atomic fluctuations in proteins: analysis of a molecular dynamics simulation.

Positional probability density functions (pdf) for the atomic fluctuations are determined from a molecular dynamics simulation for hen egg-white lysozyme. Most atoms are found to have motions that are highly anisotropic but only slightly anharmonic. The largest deviations from harmonic motion are in the direction of the largest rms fluctuations in the local principal axis frame. Backbone atoms tend to be more nearly harmonic than sidechain atoms. The atoms with the largest anharmonicities tend to have pdfs with multiple peaks, each of which is close to harmonic. Several model pdfs are evaluated on the basis of how well they fit probability densities from the dynamics simulations when parameterized in terms of the moments of the distribution. Gram-Charlier and Edgeworth perturbation expansions, which have been successful in describing the motions of small molecules in crystals, are shown to be inadequate for the distributions found in the dynamics of proteins. Multipeaked distribution functions are found to be more appropriate.

Animals↗

PubMed1998

Molecular Dynamic Simulations of Single, Interacting, and Sheared Double Layers.

This article presents the results of molecular dynamic simulations of double layers developing on a flat mineral surface in aqueous sodium chloride solution. This part depicts the simulation results compared to classical double layer theory. Ion distribution, solvent orientation, and potential curve were derived for this propose. Dynamical values were calculated in the steady state and used to assess the idea of two parts of a double layer, stagnant and mobile, separated by a shear plane. Copyright 1998 Academic Press.

Journal Article↗

PubMed1998

Molecular Dynamic Simulations of Single, Interacting, and Sheared Double Layers.

This article presents the results of molecular dynamic simulations of double layers developing on a flat mineral surface in aqueous sodium chloride solutions. The first part considered the configuration of the double layer in comparison to the classical point of view. This part investigates the influences of changed system properties on the double layer. For this purpose systems of different temperature, electrolyte concentration, and surface charge were simulated. The interaction of two overlapping double layers was investigated in comparison to that of single double layers. Nonequilibrium investigations using electrokinetic and rheological measurements provide findings regarding the microscopic behavior of a double layer under shear. Copyright 1998 Academic Press.

Journal Article↗

PubMed1996

Comment on a "fluctuation and cross correlation analysis of protein motions observed in nanosecond molecular dynamics simulations".

Long range positive correlations in the internal atomic motions have been observed in molecular dynamics simulations of the bovine pancreatic trypsin inhibitor. Since the results depend on the removal of overall translation and rotation (which is not unique), some care is required. It is pointed out that original use of all of the C atoms as a frame of reference is more appropriate than the selection of a particular subset. The former comes closest to reflecting the zero rotation condition in a normal mode analysis, which also shows the existence of long range correlations.

Animals↗

PubMed1998

Molecular dynamics simulations of peptide fragments from hen lysozyme: insight into non-native protein conformations.

Molecular dynamics simulations of four peptides taken from the hen lysozyme sequence have been used to generate models for non-native protein conformations. Comparisons between the different peptides and with experimental data for denatured lysozyme and peptide fragments provides insight into the characteristics of the conformational ensembles populated in these non-native states and the dependence of their structural features on the amino acid sequence. For the denatured conformers populated local contacts dominate in determining the properties observed in the trajectories, all four peptides showing similar characteristics. These include a significant increase in the number of main-chain O(i)-NH(i+2) hydrogen bonds and hydrogen bonds involving side-chain groups, this increase compensating to a large extent for the loss of hydrogen bonds involved in helical or beta-sheet secondary structure in the native fold, and the generation of a population of collapsed states with local clusterings of hydrophobic groups. The hydrophobic clusters enable at least partial burial of many side-chains exposed by the loss of tertiary contacts on denaturation and provide models that may explain the experimentally observed protection of amides from hydrogen exchange and the existence of residual secondary structure in non-native species of lysozyme. The results suggest that this approach has an important role to play in aiding the interpretation of experimental data for conformationally disordered non-native states of proteins.

Animals↗

PubMed1998

Large-scale molecular dynamics simulations of dislocation intersection in copper

The results of massively parallel three-dimensional molecular dynamics simulations of the perpendicular intersection of extended dislocations in copper are reported. The intersection process, which involves three of the four possible 111 glide planes in the face-centered cubic lattice, begins with junction formation, followed by unzipping, partial dislocation bowing, cutting, and, finally, unit jog formation. The investigation provides insights into this complex atomistic process, which is currently not accessible to experimental investigation.

Journal Article↗

PubMed1995

Estimation of binding free energies for HIV proteinase inhibitors by molecular dynamics simulations.

Absolute binding free energies for three inhibitors of HIV-1 proteinase were estimated from molecular dynamics simulations by a recently reported linear approximation procedure. The results were in fairly good agreement with experimental binding data. Two of the inhibitors were very similar and, for comparison, their relative free energies of binding were also calculated by free energy perturbation methods, giving virtually the same result. Effects of cut-off radii and charge states of the protein model were examined. The effects of pH on binding of one of the inhibitors were predicted.

Computer Simulation↗

PubMed1995

Molecular dynamics simulations indicate that F87W,T185F-cytochrome P450cam may reductively dehalogenate 1,1,1-trichloroethane.

Cytochrome P450cam is capable of reductively dehalogenating several chlorinated alkanes at low, but measurable, rates. In previous investigations of structure-function relationships in this enzyme using molecular dynamics simulations, we noticed that 1,1,1-trichloroethane (TCA) exhibits a very high degree of mobility in the active site due to its smaller molecular volume relative to the native substrate, camphor(1,2). Several amino acid sidechains lining the active site also exhibit significant dynamic fluctuations, possibly as a result of poor steric complementary to TCA. Guided by these results, we modeled double (F87W, T185F) and triple (F87W, T185F, V295I) mutants of P450cam, which provide additional bulk in the active site and increase the frequency of heme-substrate collision. Molecular dynamics simulations (300 ps on each protein) indicate that these mutants do not significantly perturb the three-dimensional fold of the enzyme, or local structure in the region of the active site. Both mutants bind the substrate more stably near the heme than the wild-type. Interestingly, however, the bulkier triple mutant seems to actually inhibit heme-substrate interactions relative to the double mutant. Over the final 200 ps of simulation, TCA is within 1 A of nonbonded contact with the heme 25% more often in the double mutant versus the wild-type. The triple mutant, on the other hand, binds TCA within 1 A of the heme only 15% as often as the wild-type. These results indicate that the double mutant may reductively dehalogenate TCA, a property not observed for the native protein. Implications for other experimentally measurable parameters are discussed.

Binding Sites↗