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At least 829 records · Page 46Linked to original sources
PubMed1998

Molecular dynamics simulations of epidermal growth factor and transforming growth factor-alpha structures in water.

AMBER v. 4.1 force field in 1.5 ns NPT molecular dynamics simulations of murine epidermal growth factor (mEGF), human epidermal growth factor (hEGF), and human transforming growth factor-alpha (hTGF-alpha) structures with explicit TIP3P solvation were used to investigate differences in backbone stability, changes in secondary structure, interdomain flexibility, and weakly polar interactions. Backbone root mean square deviations of sections of each peptide show that the most stable regions in mEGF and hEGF are the A-, B-, and C-loops, whereas the most stable regions in hTGF-alpha are the A- and B-loops. The secondary structure in the B-loops of mEGF and hEGF differ significantly from the nuclear magnetic resonance (NMR) structures of mEGF and hEGF. The position and type of turns in the B-loop of mEGF and hEGF increase the interstrand distance of the antiparallel beta-sheets thereby disrupting their structure. The interdomain flexibility of simulated hTGF-alpha structure is greater than in either mEGF or hEGF. The phi, psi dihedrals of hTGF-alpha occupy two distinct populations of phase space corresponding to either a Ceq7 or an alpha-helical conformation. This change in dihedral angle is stabilized by Phe15 with Arg42 and Phe17 with Arg42 N-pi weakly polar interactions that are present only in hTGF-alpha but not in mEGF or hEGF.

Amino Acid Sequence↗
PubMed1998

Molecular dynamics simulation of cytochrome c3: studying the reduction processes using free energy calculations.

The tetraheme cytochrome c3 from Desulfovibrio vulgaris Hildenborough is studied using molecular dynamics simulation studies in explicit solvent. The high heme content of the protein, which has its core almost entirely made up of c-type heme, presents specific problems in the simulation. Instability in the structure is observed in long simulations above 1 ns, something that does not occur in a monoheme cytochrome, suggesting problems in heme parametrization. Given these stability problems, a partially restrained model, which avoids destruction of the structure, was created with the objective of performing free energy calculations of heme reduction, studies that require long simulations. With this model, the free energy of reduction of each individual heme was calculated. A correction in the long-range electrostatic interactions of charge groups belonging to the redox centers had to be made in order to make the system physically meaningful. Correlation is obtained between the calculated free energies and the experimental data for three of four hemes. However, the relative scale of the calculated energies is different from the scale of the experimental free energies. Reasons for this are discussed. In addition to the free energy calculations, this model allows the study of conformational changes upon reduction. Even if the precise details of the structural changes that take place in this system upon individual heme reduction are probably out of the reach of this study, it appears that these structural changes are small, similarly to what is observed for other redox proteins. This does not mean that their effect is minor, and one example is the conformational change observed in propionate D from heme I when heme II becomes reduced. A motion of this kind could be the basis of the experimentally observed cooperativity effects between heme reduction, namely positive cooperativity.

Biophysical Phenomena↗
PubMed2006

Molecular dynamics simulations of ligand dissociation from thyroid hormone receptors: evidence of the likeliest escape pathway and its implications for the design of novel ligands.

Steered molecular dynamics simulations of ligand dissociation from Thyroid hormone receptors indicate that dissociation is favored via rearrangements in a mobile part of the LBD comprising H3, the loop between H1 and H2, and nearby beta-sheets, contrary to current models in which the H12 is mostly involved. Dissociation is facilitated in this path by the interaction of the hydrophilic part of the ligand with external water molecules, suggesting strategies to enhance ligand binding affinity.

Computer Simulation↗
PubMed2000

Molecular dynamics simulations of protein-tyrosine phosphatase 1B. II. substrate-enzyme interactions and dynamics.

Molecular dynamics simulations of protein tyrosine phosphatase 1B (PTP1B) complexed with the phosphorylated peptide substrate DADEpYL and the free substrate have been conducted to investigate 1) the physical forces involved in substrate-protein interactions, 2) the importance of enzyme and substrate flexibility for binding, 3) the electrostatic properties of the enzyme, and 4) the contribution from solvation. The simulations were performed for 1 ns, using explicit water molecules. The last 700 ps of the trajectories was used for analysis determining enthalpic and entropic contributions to substrate binding. Based on essential dynamics analysis of the PTP1B/DADEpYL trajectory, it is shown that internal motions in the binding pocket occur in a subspace of only a few degrees of freedom. In particular, relatively large flexibilities are observed along several eigenvectors in the segments: Arg(24)-Ser(28), Pro(38)-Arg(47), and Glu(115)-Gly(117). These motions are correlated to the C- and N-terminal motions of the substrate. Relatively small fluctuations are observed in the region of the consensus active site motif (H/V)CX(5)R(S/T) and in the region of the WPD loop, which contains the general acid for catalysis. Analysis of the individual enzyme-substrate interaction energies revealed that mainly electrostatic forces contribute to binding. Indeed, calculation of the electrostatic field of the enzyme reveals that only the field surrounding the binding pocket is positive, while the remaining protein surface is characterized by a predominantly negative electrostatic field. This positive electrostatic field attracts negatively charged substrates and could explain the experimentally observed preference of PTP1B for negatively charged substrates like the DADEpYL peptide.

Amino Acid Sequence↗
PubMed1995

Molecular dynamics simulation of E. coli ribonuclease H1 in solution: correlation with NMR and X-ray data and insights into biological function.

A 500 ps molecular dynamics simulation of Escherichia coli RNase H1 in the presence of explicit water molecules has been carried out to aid in the interpretation of NMR N-H backbone model free parameters and X-ray B-factor values of the free enzyme. Both experimental techniques have revealed unusual structural and dynamic features of the protein. Atomic fluctuations (B-factors) and re-orientational motions of the backbone heteronuclear bonds (order parameters) computed from the simulation are compared with results obtained from experiments. Qualitative agreement is obtained between the computed and X-ray B-factors, whereas the agreement between the computed and NMR generalized order parameters is as good as quantitative for most residues. Reasons for significant discrepancies, the physical basis and the plausible biological consequences of the observed protein dynamics are discussed.

Amino Acid Sequence↗
PubMed2002

Molecular dynamics simulation of 7, 8-dihydro-8-oxoguanine DNA.

To elucidate the effect of guanine lesion produced by the oxidative damage on DNA, 1 nanosecond molecular dynamics simulations of native and oxidized DNA were performed. The target DNA molecules are dodecamer duplex d(CGCGAATTCGCG)(2) and its derivative duplex d(C(1)G(2)C(3)(8-oxoG)(4)A(5)A(6)T(7)T(8)C(9)G(10)C(11)G(12).d(C(13)G(14)C(15)G(16)A(17)A(18)T(19)T(20)C(21)G(22)C(23)G(24), which has one oxidized guanine, 7, 8-dihydro-8-oxoguanine (8-oxoG), at the fourth position. The local structural change due to the lesion of 8-oxoG and the global dynamic structure of the 8-oxoG DNA were studied. It was found that the 8-oxoG DNA remained structurally stable during the simulation due to newly produced hydrogen bonds around the (8-oxoG)(4) residue. However, there were distinguishable differences in structural parameters and dynamic property in the 8-oxoG DNA. The conformation around the (8-oxoG)(4) residue departed from the usual conformation of native DNA and took an unique conformation of epsilon-zeta in B(II) conformation and chi in high anti orientation at the (8-oxoG)(4) residue, and adopted a very low helical twist angle at the C(3):G(22)-(8-oxoG)(4):C21) step. Further analysis by principal component analysis indicated that the formation of the hydrogen bonds around the (8-oxoG)(4) residue plays a role as a trigger for the conformational transition of the 8-oxoG DNA in the conformational space.

DNA↗
PubMed2004

Molecular dynamics simulations of the d(CCAACGTTGG)(2) decamer in crystal environment: comparison of atomic point-charge, extra-point, and polarizable force fields.

Molecular dynamics simulations of the DNA duplex d(CCAACGTTGG)(2) were used to study the relationship between DNA sequence and structure in a crystal environment. Three different force fields were used: a traditional description based on atomic point charges, a polarizable force field, and an "extra-point" force field (with additional charges on extranuclear sites). It is found that all the force fields reproduce fairly well the sequence-dependent features of the experimental structure. The polarizable force field, however, provides the most accurate representation of the crystal structure and the sequence-dependent effects observed in the experiment. These results point out to the need of the inclusion of polarization for accurate descriptions of DNA.

Computer Simulation↗
PubMed2004

Molecular dynamics simulation on devitrification: isothermal devitrification and thermodynamics of PbF2 glasses.

The vitrification and devitrification features of lead fluoride are investigated by means of molecular dynamic simulations. The influence of heating rate on the devitrification temperature as well as the dependence of the glass properties on its thermal history, i.e., the cooling rate employed, is identified. As expected, different glasses are obtained when the cooling rates differ. Diffusion coefficient analysis during heating of glass and crystal, indicates that the presence of defects on the glassy matrix favors the transition processes from the ionic to a superionic state, with high mobility of fluorine atoms, responsible for the high anionic conduction of lead fluoride. Nonisothermal and isothermal devitrification processes are simulated in glasses obtained at different cooling rates and structural organizations occurring during the heat treatments are clearly observed. When a fast cooling rate is employed during the glass formation, the devitrification of a single crystal (limited by the cell dimensions) is observed, while the glass obtained with slower cooling rate, allowing relaxations and organization of various regions on the glass bulk during the cooling process, devitrifies in more than one crystalline plane.

Journal Article↗
PubMed2005

A molecular dynamics simulation of the electrical conductivity behaviors of highly concentrated liquid ammoniates NaIalphaNH(3): comparison with experimental measurements.

In this paper, we present a molecular dynamics simulation study devoted to the calculation of the electrical conductivities of highly concentrated liquid electrolytes as a function of their dilution. As an illustration, we give the first such study of the ammoniate NaIalphaNH(3). The theoretical results are presented together with experimental data obtained at 293 K, and show that the calculated conductivities are in agreement with the experimental values in the whole salt dilution range provided that correlations between the species in the solution are taken into account. Indeed, the usual Nernst-Einstein relation is a crude approximation to calculate accurately the conductivities in such high concentrated electrolytes.

Journal Article↗
PubMed2004

Statistical properties of two particle systems in a rectangular box: molecular dynamics simulations.

Statistical properties of two particle systems, in which the interaction potentials include the soft repulsion/attraction within a hard rectangular box, are studied using molecular dynamics simulations. The pore size and the potential dependence of van der Waals instability arising from the packing mechanism are investigated. The van der Waals instability strongly depends both on the soft repulsion and on the position of soft attraction in these model systems. An addition of the soft repulsion to the hard-core system gives rise to the van der Waals instability near the position where two particles tend to face each other on the diagonal line of the rectangular box. For the hard-sphere system with the soft repulsion/attractions, the soft attraction significantly enhances the van der Waals instability, whereas, for the square-well spheres with the soft repulsion, the soft attraction reduces the van der Waals instability.

Chemistry↗
PubMed2002

Towards an understanding of complex biological membranes from atomistic molecular dynamics simulations.

Computer simulation has emerged as a powerful tool for studying the structural and functional properties of complex biological membranes. In the last few years, the use of recently developed simulation methodologies and current generation force fields has permitted novel applications of molecular dynamics simulations, which have enhanced our understanding of the different physical processes governing biomembrane structure and dynamics. This review focuses on frontier areas of research with important biomedical applications. We have paid special attention to polyunsaturated lipids, membrane proteins and ion channels, surfactant additives in membranes, and lipid-DNA gene transfer complexes.

Animals↗
PubMed2006

Investigation of interaction between enolase and phosphoglycerate mutase using molecular dynamics simulation.

Two glycolytic enzymes, phosphoglycerate mutase (PGM) and enolase from Saccharomyces cerevisiae have been chosen to detect complex formation between active centers (a/c), using molecular dynamics simulation. Enzymes have been separated by 10 A distance and placed in a water box of size 173 x 173 x 173 A. Three different orientations where a/c of PGM and enolase were positioned toward each other have been used for investigation. The two initial 3-phosphoglycerate substrates at near active centers of initial structure of PGM have been replaced with final 2-phosphoglycerate products. 150mM of NaCl have been added to the system to observe binding activity in the near physiological conditions. Analysis of interaction energies and conformation changes for 3ns simulation indicates that PGM and enolase do show binding affinity between their near active regions. Moreover the similarity between final conformations of the first two orientations with the initial conformation of the third orientation suggests that complex formation between a/c of enzymes is not confined only by discussed orientations. Clear interaction of enolase with C-terminal tail of PGM has been recorded. These results suggest that substrate direct transfer mechanism may exist between enzymes.

Binding Sites↗
PubMed2006

Molecular dynamic simulations of the N-terminal receiver domain of NtrC reveal intrinsic conformational flexibility in the inactive state.

The N-terminal receiver domain of NtrC is the molecular switch in the two-component signal transduction. It is the first protein where structures of both the active (phosphyroylated) and inactive (unphosphyroylated) states are determined experimentally. Phosphorylation of the NtrC at the active site induces large structural change. NMR experiments suggested that the wild type unphosphorylated NtrC adopts both the active and the inactive conformations and the phosphorylation stabilizes the active conformations. We applied free (unconstrained) molecular dynamic (MD) simulation to examine the intrinsic flexibilities and stabilities of the NtrC receiver domain in both the active and inactive conformations. Molecular dynamic simulations showed that the inactive state of NtrC receiver domain is more flexible than the active state. There were large movements in helix 4 and loop beta3-alpha3 which coincide with major structural differences between the inactive and active states. We observed large root-mean-square deviations from the initial starting structure and the large root-mean-square fluctuations during MD simulation for the inactive state. We then investigated the activation pathway with Targeted MD simulation. We show that the intrinsic flexibility in the loop beta3-alpha3 plays an important role in triggering the conformational change. Phosphorylation at the active site may serve to stabilize the conformational change. These results together suggest that the unphosphorylated NtrC receiver domain could be involved in a conformational equilibrium between two different states.

Binding Sites↗
PubMed1999

Alamethicin helices in a bilayer and in solution: molecular dynamics simulations.

Alamethicin is an alpha-helical channel-forming peptide, which inserts into lipid bilayers in a voltage-dependent, asymmetrical fashion. Nanosecond molecular dynamics simulations have been used to compare alamethicin conformation and dynamics in three different environments: 1) in water; 2) in methanol; and 3) inserted into a lipid (palmitoyl-oleoyl-phosphatidylcholine) bilayer to form a transmembrane helix. In the bilayer and in methanol, there was little change (Calpha RMSD approximately 0.2 nm over 2 ns and 1 ns) from the initial helical conformation of the peptide. In water there were substantial changes (Calpha RMSD approximately 0.4 nm over 1 ns), especially in the C-terminal segment of the peptide, which lost its alpha-helical conformation. In the bilayer and in methanol, the alamethicin molecule underwent hinge-bending motion about its central Gly-X-X-Pro sequence motif. Analysis of H-bonding interactions revealed that the polar C-terminal side chains of alamethicin provided an "anchor" to the bilayer/water interface via formation of multiple H-bonds that persisted throughout the simulation. This explains why the preferred mode of helix insertion into the bilayer is N-terminal, which is believed to underlie the asymmetry of voltage activation of alamethicin channels.

Alamethicin↗
PubMed2004

Applied field nonequilibrium molecular dynamics simulations of ion exit from a beta-barrel model of the L-type calcium channel.

We present results of applied field nonequilibrium molecular dynamics simulations (AF NEMD) of a minimal beta-barrel model channel intended to represent an L-type calcium channel that suggests a possible relationship between glutamate side chain conformational changes and ion flux in calcium channels. The beta-barrel is used to provide a scaffolding for glutamate side chains and a confinement for electrolyte of dimensions similar to the expected channel structure. It was preloaded with ions to explore relative rates of ion exit for different occupancy configurations. Our simulations with an asymmetrical flexible selectivity filter represented by four glutamate side chains (EEEE), one of which differs in initial dihedrals from the other three, indicate a plausible mechanism for the observed anomalous mole fraction effect seen in calcium channels. Apparent rates of electric field-induced exit from channels preloaded with three Na+ ions are much higher than for channels with one Ca2+ followed by two Na+ ions, consistent with the common notion that Ca2+ block of Na+ current is due to competition between the Ca2+ and Na+ ions for the negatively charged (EEEE) locus. In our model, the Ca2+ ion ligates simultaneously to the four negatively charged glutamate side chains and sterically blocks the permeation pathway. Ca2+-relief of Ca2+-block is suggested by a much higher rate of exit for channels preloaded with three Ca2+ ions than for channels with two Ca2+ ions.

Algorithms↗
PubMed2006

How can a beta-sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin-1 in micelles.

In this work, the naturally occurring beta-hairpin antimicrobial peptide protegrin-1 (PG-1) is studied by molecular dynamics simulation in all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These simulations provide a high-resolution picture of the interactions between the peptide and simple models of bacterial and mammalian membranes. Both micelles show significant disruption, as is expected for a peptide that is both active against bacteria and toxic to host cells. There is, however, clear differentiation between the behavior in SDS versus DPC, which suggests different mechanisms of interaction for PG-1 with mammalian and bacterial membranes. Specifically, the equilibrium orientation of the peptide relative to SDS is a mirror image of its position relative to DPC. In both systems, the arginine residues of PG-1 strongly interact with the head groups of the micelles. In DPC, the peptide prefers a location closer to the core of the micelle with Phe12, Val14, and Val16 imbedded in the core and the other side of the hairpin, which includes Leu5 and Tyr7, located closer to the surface of the micelle. In SDS, the peptide prefers a location at the micelle-water interface. The peptide position is reversed, with Leu5 and Cys6 imbedded furthest in the micelle core and Phe12, Val14, and Val16 on the surface of the micelle. We discuss the implications of these results with respect to activity and toxicity.

Amino Acid Sequence↗
PubMed1995

Molecular dynamics simulation of the solution structures of Ha-ras-p21 GDP and GTP complexes: flexibility, possible hinges, and levers of the conformational transition.

Unconstrained molecular dynamics simulations of the GDP and GTP complexes of Ha-ras p21 protein are performed in aqueous environment for 500 ps, using the GROMOS force field. The solvated structures are mutually compared as well as to the X-ray structures [Tong, L. A., de Vos, A. M., Milburn, M. V., & Kim, S. H. (1991) J. Mol. Biol. 217, 503-516; Pai, E. F., Krengel, U., Petsko, G. A., Goody, R. S., Kabsh, W., & Wittinghofer, A. (1990) EMBO J. 9, 2351-2359]. The simulations show areas of flexibility, with deviations from the original structures. The parts that show differences between the two solvated forms are those from residues 12 to 17, 25 to 38, 41 to 51, 57 to 73, 99 to 112, and 120 to 152, coincident with areas of flexibility. Some of these areas also show differences between the X-ray structures and are part of loops on the surface of the protein. Many of the residues in the ends of these loops undergo dihedral transitions during the solvation process. Of all the dihedral transitions observed, 62% occur around the ends of these loops. This suggests that the ends of the areas from 12 to 17, 25 to 38, and 57 to 73 are the hinge points of the conformational transition between the GTP and the GDP forms. The study of the nucleotide interactions in the solution forms shows that residues 29, 30, and 35 establish contacts with the gamma-phosphate and the sugar ring of the GTP and thus these contacts could be proposed as the possible levers of the conformational transition that accompanies GTP hydrolysis.

Amino Acid Sequence↗
PubMed2004

Development of softcore potential functions for overcoming steric barriers in molecular dynamics simulations.

In this work, we describe the development of softcore potential functions that permit occasional "tunneling" through the regions of conformational space during molecular dynamics (MD) simulations, which would otherwise be sterically prohibited. The modification consists of a truncation of the nonbonded interaction before the steeply repulsive region encountered at short interatomic distances. This modification affects both Lennard-Jones and Coulomb parts of the nonbonded potential. Critical to success is the choice of appropriate pairwise switching distances at which this modification should be made. In the present work, these are calculated based on potential of mean force functions extracted from model system molecular dynamics simulations. We believe that these functions describe the dynamic short-range interactions much better than mean force potentials derived from an ensemble of static structures (e.g. protein data bank (PDB)). Once a set of mean force potentials is obtained, a single empirical parameter, effective barrier height, is employed to determine switching distances for all pairwise atomic interactions. Changing this single parameter allows adjustment of the "softness" of the whole system. We tested the applicability of the new softcore potentials in a loop structure optimization study. The H1 loop in the antibody 17/9 was selected as our test case because substantial repacking of loop residues in the dense protein environment is necessary for successful relaxation of random initial conformations. Softcore simulations converted to correct loop conformations, in contrast to standard simulations which never sampled this structure even after 10 ns. The resulting root mean square deviation (RMSD) values (below 1.3 A for all heavy atoms of the loop) demonstrate the usefulness of the approach based on mean force derived softcore functions.

Amino Acids↗