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At least 451 records · Page 25Linked to original sources
PubMed1994

Molecular dynamics simulations in solvent of the glucocorticoid receptor protein in complex with a glucocorticoid response element DNA sequence.

We investigated protein/DNA interactions, using molecular dynamics simulations computed in solvent, between the glucocorticoid receptor (GR) DNA binding domain (DBD) amino acids and DNA of a glucocorticoid receptor response element (GRE). We compared findings obtained from a fully solvated 80 Angstrom water droplet GR DBD/GRE model with those from a 10 Angstrom water layer GR DBD/GRE model. Hydrogen bonding interactions were monitored. In addition, van der Waals and electrostatic interaction energies were calculated. Molecular dynamics simulations from both models yielded similar findings; amino acids of the GR DBD DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon/anticodon nucleotide base sites within the GRE right major groove halfsite. Likewise GR DBD amino acids in a beta strand structure adjacent to the DNA recognition helix formed both direct and water mediated hydrogen bonds at cognate codon/anticodon nucleotide base and backbone sites. We also investigated protein/DNA interactions with a 10 Angstrom water layer model consisting of the same GR DBD as above but with a predicted alpha helix attached to the carboxyl terminus of the GR DBD docked at the same GRE as above with additional flanking nucleotides. In this model, the interactions between amino acids of the DNA recognition helix and beta strand and nucleotides within the GRE right major groove halfsite were at cognate codon/anticodon nucleotide sites as found in the two models above. In addition, amino acids within the predicted alpha helix located on the carboxyl terminus of the GR DBD interacted at codon/anticodon nucleotide sites on the DNA backbone of the GRE flanking nucleotides. These interactions together induced breakage of Watson-Crick nucleotide base pairing hydrogen bonds, resulting in bending of the DNA, strand elongation and unwinding events similar to those described for helicases.

Amino Acid Sequence↗
PubMed2005

Recognition of RNA by amide modified backbone nucleic acids: molecular dynamics simulations of DNA-RNA hybrids in aqueous solution.

Thermodynamic and structural properties of a chemically modified DNA-RNA hybrid in which a phosphodiester linkage is replaced by a neutral amide-3 linkage (3'-CH(2)-CONH-5') were investigated using UV melting experiments, molecular dynamics simulations in explicit water, and continuum solvent models. van't Hoff analysis of the experimental UV melting curves suggests that the significant increase of the thermodynamic stability of a 15-mer DNA-RNA with seven alternated amide-3 modifications (+11 degrees C) is mainly due to an increased binding enthalpy. To further evaluate the origin in the observed affinities differences, the electrostatic contribution to the binding free energy was calculated by solving the Poisson-Boltzmann equation numerically. The nonelectrostatic contribution was estimated as the product of a hydrophobic surface tension coefficient and the surface area that is buried upon double strand formation. Structures were taken from 10 ns molecular dynamics simulations computed in a consistent fashion using explicit solvent, counterions, and the particle-mesh Ewald procedure. The present preliminary thermodynamic study suggests that the favorable binding free energy of the amide-3 DNA single strand to the complementary RNA is equally driven by electrostatic and nonpolar contributions to the binding compared to their natural analogues. In addition, molecular dynamics simulations in explicit water were performed on an amide-3 DNA single strand and the corresponding natural DNA. Results from the conformations cluster analysis of the simulated amide-3 DNA single strand ensembles suggest that the 25% of the population sampled within 10 ns has a pre-organized conformation where the sugar C3' endo pucker is favored at the 3'-flanking nucleotides. These structural and thermodynamic features contribute to the understanding of the observed increased affinities of the amide-3 DNA-RNA hybrids at the microscopic level.

Amides↗
PubMed2005

Molecular dynamics simulations of the anchoring and tilting of the lung-surfactant peptide SP-B1-25 in palmitic acid monolayers.

We have performed molecular dynamics simulations of multiple copies of the lung-surfactant peptide SP-B1-25 in a palmitic acid (PA) monolayer. SP-B1-25 is a shorter version of lung-surfactant protein B, an important component of lung surfactant. Up to 30 ns simulations of 20 wt % SP-B1-25 in the PA monolayers were performed with different surface areas of PA, extents of PA ionization, and various initial configurations of the peptides. Starting with initial peptide orientation perpendicular to the monolayer, the predicted final tilt angles average 54 degrees approximately 62 degrees with respect to the monolayer normal, similar to those measured experimentally by Lee et al. (Biophysical Journal. 2001. Synchrotron x-ray study of lung surfactant-specific protein SP-B in lipid monolayers. 81:572-585). In their final conformations, hydrogen-bond analysis and amino acid mutation studies show that the peptides are anchored by hydrogen bond interactions between the cationic residues Arg-12 and Arg-17 and the hydrogen bond acceptors of the ionized PA headgroup, and the tilt angle is affected by the interactions of Tyr-7 and Gln-19 with the PA headgroup. Our work indicates that the factors controlling orientation of small peptides in lipid layers can now be uncovered through molecular dynamics simulations.

Adsorption↗
PubMed2005

An independent method for the analysis of protein folding kinetics from all-atom molecular dynamics simulations.

We propose a method for extracting useful kinetic information from all-atom molecular dynamics simulations of protein folding. By calculating the time correlation functions between the evolution of different structural properties during the course of the simulation we can determine the endpoint of the reaction and the mechanism by which it occurs. As a test of our method we use thermal denaturation simulations on a 76 residue protein, ubiquitin. The method we present should be used in combination with current techniques for analyzing molecular dynamics trajectories.

Computer Simulation↗
PubMed1999

Accelerated diffusion of Na(+) in a hydrophobic region revealed by molecular dynamics simulations of a synthetic ion channel.

To get insight into the significance of the hydrophobic lining on the ion permeation, we performed molecular dynamics simulations on a Na(+) permeation through a de novo synthetic hydrophobic channel. Electrophysiological study has suggested that the channel is formed from a tail-to-tail associated dimer of a cyclic octa-peptide coupled with hydrophobic acyl chains. The acyl chains line the channel pore while the cyclic peptide forms the channel entrance [Z. Qi, M. Sokabe, K. Donowaki, H. Ishida, Biophys. J. 76 (1999) 631]. Molecular dynamics simulation of water in the channel indicated that the inferred structure is physically reasonable [Z. Qi, M. Sokabe, Biophys. Chem. 71 (1998) 35]. In the present study, the potential energy profile of the Na(+) and the energy contributions from each component of the system at different positions along the channel axis were calculated. An energy well instead of a peak is located at the central hydrophobic cavity of the channel, due to its ability of accommodating at least five water molecules to hydrate the ion. Interestingly, the ion diffuses much faster in the hydrophobic acyl chain region, particularly in the central hydrophobic cavity, than it does in the peptide ring region and even surprisingly faster than that in the bulk phase. These results provide a physical basis for an idea that the hydrophobic lining of the K(+) channel [D.A. Doyle, J.M. Cabral, R.A. Pfuetzner, A. Kuo, J.M. Gulbis, S.L. Cohen, B.T. Chait, R. MacKinnon, Science 280 (1998) 69] plays an active role to facilitate the ion permeation through the channel pore.

Journal Article↗
PubMed1999

Study of the electrostatics treatment in molecular dynamics simulations.

This article considers the treatment of long-range interactions in molecular dynamics simulations. We investigate the effects of using different cutoff distances, constant versus distance-dependent dielectric, and different smoothing methods. In contrast to findings of earlier studies, we find that increasing the cutoff over 8 A does not significantly improve the accuracy (Arnold and Ornstein, Proteins 1994;18:19-33), and using a distance-dependent dielectric instead of a constant dielectric also does not improve accuracy (Guenot and Kollman, Protein Sci 1992;1:1185-1205). This might depend on differences in simulation protocols or force fields, or both, because we use the CHARMM22 force field with stochastic boundary conditions, whereas earlier studies used other protocols and energy functions. We also note that the stability of the simulations is highly dependent on the starting structure, showing that accurate molecular simulations not only depend on a realistic simulation protocol but also on correct initial conditions.

Algorithms↗
PubMed2005

Elucidating the vibrational spectra of hydrogen-bonded aggregates in solution: electronic structure calculations with implicit solvent and first-principles molecular dynamics simulations with explicit solvent for 1-hexanol in n-hexane.

Fourier transform infrared spectroscopy is a popular method for the experimental investigation of hydrogen-bonded aggregates, but linking spectral information to microscopic information on aggregate size distribution and aggregate architecture is an arduous task. Static electronic structure calculations with an implicit solvent model, Car-Parrinello molecular dynamics (CPMD) using the Becke-Lee-Yang-Parr (BLYP) exchange and correlation energy functionals and classical molecular dynamics simulations for the all-atom version of the optimized parameters for liquid simulations (OPLS-AA) force field were carried out for an ensemble of 1-hexanol aggregates solvated in n-hexane. The initial configurations for these calculations were size-selected from a distribution of aggregates obtained from a large-scale Monte Carlo simulation. The vibrational spectra computed from the static electronic structure calculations for monomers and dimers and from the CPMD simulations for aggregates up to pentamers demonstrate the extent of the contribution of dangling or nondonating hydroxyl groups found in linear and branched aggregates to the "monomeric" peak. Furthermore, the computed spectra show that there is no simple relationship between peak shift and aggregate size nor architecture, but the effect of hydrogen-bond cooperativity is shown to differentiate polymer-like (cooperative) and dimer-like (noncooperative) hydrogen bonds in the vibrational spectrum. In contrast to the static electronic structure calculations and the CPMD simulations, the classical molecular dynamics simulations greatly underestimate the vibrational peak shift due to hydrogen bonding.

Journal Article↗
PubMed1992

3 Nsec molecular dynamics simulation of the protein ubiquitin and comparison with X-ray crystal and solution NMR structures.

Mainly due to computational limitations, past protein molecular dynamics simulations have rarely been extended to 300 psec; we are not aware of any published results beyond 350 psec. The present work compares a 3000 psec simulation of the protein ubiquitin with the available x-ray crystallographic and solution NMR structures. Aside from experimental structure availability, ubiquitin was studied because of its relatively small size (76 amino acids) and lack of disulfide bridges. An implicit solvent model was used except for explicit treatment of waters of crystallization. We found that the simulated average structure retains most of the character of the starting x-ray crystal structure. In two highly surface accessible regions, the simulation was not in agreement with the x-ray structure. In addition, there are six backbone-backbone hydrogen bonds that are in conflict between the solution NMR and x-ray crystallographic structures; two are bonds that the NMR does not locate, and four are ones that the two methods disagree upon the donor. Concerning these six backbone-backbone hydrogen bonds, the present simulation agrees with the solution NMR structure in five out-of-the six cases, in that if a hydrogen bond is present in the x-ray structure and not in the NMR structure, the bond breaks within 700 psec. Of the two hydrogen bonds that are found in the NMR structure and not in the x-ray structure, one forms at 1400 psec and the other forms rarely. The present results suggest that relatively long molecular dynamics simulations, that use protein x-ray crystal coordinates for the starting structure and a computationally efficient solvent representation, may be used to gain an understanding of conformational and dynamic differences between the solid-crystal and dilute-solution states.

Computer Simulation↗
PubMed1992

Combined use of homo- and heteronuclear coupling constants as restraints in molecular dynamics simulations.

A penalty function for scalar coupling constants has been applied in molecular dynamics simulations as an experimental constraint. The function is based on the difference between the coupling constant calculated from the dihedral angle and the experimentally measured coupling constant. The method is illustrated on a model cyclic pentapeptide for which 3JHN-H alpha and 3JHN-C beta, both about the phi backbone dihedral angle, have been measured. The function is efficient in producing structures consistent with the scalar couplings, but removed from the conformation observed in solution. This arises from the lack of J restraints for the psi dihedral angle. Simulations with both nuclear Overhauser effect (NOE) and J-coupling restraints illustrates small but significant differences from simulations using only NOEs.

Amino Acid Sequence↗
PubMed1987

Molecular dynamics simulations of "loop closing" in the enzyme triose phosphate isomerase.

We present molecular dynamics simulations on the active site region of dimeric triose phosphate isomerase (TIM) using the co-ordinates of native chicken muscle TIM as a starting point and performing simulations with no substrate, with dihydroxyacetone phosphate (DHAP), the natural substrate, and with dihydroxyacetone sulfate (DHAS), a substrate analog. Whereas most of the protein moves less than 1 A during the simulation, some residues in the active site loop move more than 8 A during the 10.5 picoseconds of dynamics for each of the simulations. Most interestingly, the nature of the loop motion depends on the substrate, with the largest motion found in the presence of DHAP, and only in the presence of DHAP does the loop move to "close off" the active site pocket. The final structure found for the DHAP-chicken TIM complex is qualitatively similar to that described by Alber et al. for DHAP-yeast TIM. Simulations on the monomeric protein gives insight into why the molecule is active only as a dimer.

Acetone↗
PubMed1995

A sampling problem in molecular dynamics simulations of macromolecules.

Correlations in low-frequency atomic displacements predicted by molecular dynamics simulations on the order of 1 ns are undersampled for the time scales currently accessible by the technique. This is shown with three different representations of the fluctuations in a macromolecule: the reciprocal space of crystallography using diffuse x-ray scattering data, real three-dimensional Cartesian space using covariance matrices of the atomic displacements, and the 3N-dimensional configuration space of the protein using dimensionally reduced projections to visualize the extent to which phase space is sampled.

Computer Simulation↗
PubMed2001

Conformational investigation of a cyclic enterobacterial common antigen employing NMR spectroscopy and molecular dynamics simulations.

The three-dimensional structure of a cyclic enterobacterial common antigen (ECA) having four trisaccharide repeating units has been investigated by NMR spectroscopy and molecular dynamics simulations. Three different NMR parameters were determined: (a) (1)H,(1)H cross-relaxation rates from NOE experiments were used for determination of proton-proton distances; (b) trans-glycosidic (3)J(C,H) scalar coupling constants analyzed via a Karplus-type relationship provided information on torsion angles; and (c) (1)H,(13)C one-bond dipolar couplings obtained in a dilute liquid-crystalline medium were interpreted in terms of the orientational order and molecular conformations. The molecular dynamics simulations of the dodecasaccharide were performed with explicit water and counterions, which are important factors that strongly influence molecular conformation. Subsequently, the results from computer simulation were used to generate a three-dimensional structure of the cyclic ECA which is consistent with the experimental NMR parameters.

Antigens, Bacterial↗
PubMed1999

An alamethicin channel in a lipid bilayer: molecular dynamics simulations.

We present the results of 2-ns molecular dynamics (MD) simulations of a hexameric bundle of Alm helices in a 1-palmitoyl-2-oleoylphosphatidylcholine bilayer. These simulations explore the dynamic properties of a model of a helix bundle channel in a complete phospholipid bilayer in an aqueous environment. We explore the stability and conformational dynamics of the bundle in a phospholipid bilayer. We also investigate the effect on bundle stability of the ionization state of the ring of Glu18 side chains. If all of the Glu18 side chains are ionised, the bundle is unstable; if none of the Glu18 side chains are ionized, the bundle is stable. pKA calculations suggest that either zero or one ionized Glu18 is present at neutral pH, correlating with the stable form of the helix bundle. The structural and dynamic properties of water in this model channel were examined. As in earlier in vacuo simulations (Breed et al., 1996 .Biophys. J. 70:1643-1661), the dipole moments of water molecules within the pore were aligned antiparallel to the helix dipoles. This contributes to the stability of the helix bundle.

Alamethicin↗
PubMed1987

Molecular dynamics simulations of cyclosporin A: the crystal structure and dynamic modelling of a structure in apolar solution based on NMR data.

The conformation of the immunosuppressive drug cyclosporin A (CPA), both in apolar solution and in crystalline state, has been studied by computer simulation techniques. Three molecular dynamics (MD) simulations have been performed: one modelling the crystal structure and two modelling the structure in apolar solution, using a restrained MD approach in which data from nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy are taken into account. The simulation of the crystalline state (MDC) concerns a system of 4 unit cells containing 16 cyclosporin A molecules and 22 water molecules, which is simulated using crystalline periodic boundary conditions. The simulations modelling the apolar solvent conformation (MDS) concern one isolated cyclosporin A molecule. In these simulations an extra term in the interatomic potential function is used, which forces the molecule to satisfy a set of 57 atom-atom distance constraints originating from nuclear Overhauser effects (NOEs) obtained from NMR spectroscopy and one distance constraint deduced from IR spectroscopy. From a comparison of the results of the crystal simulation to those of the X-ray experiment in terms of structure, atomic fluctuations, hydrogen bond pattern, etc., it is concluded that the force field that is used yields an adequate representation of crystalline cyclosporin A. Secondly, it is shown that the dynamic modelling technique that is used to obtain a structure in a polar solution from NMR distance information works well. Starting from initial conformations which have a root mean square difference of 0.14 nm both distance restrained MD simulations converge to the same final solution structure. A comparison of the crystal structure of cyclosporin A and the one in apolar solution shows that there are significant differences. The overall difference in atomic positions is 0.09 nm for the C alpha atoms and 0.17 nm for all atoms. In apolar solution, the molecule is slightly more bent and the side chains of 1 MeBmt and 10 MeLeu adopt a different conformation.

Computer Simulation↗
PubMed2001

Dynamical properties of a hydrated lipid bilayer from a multinanosecond molecular dynamics simulation.

A fully hydrated dimiristoylphosphatidylcholine (DMPC) bilayer has been studied by a molecular dynamics simulation. The system, which consisted of 64 DMPC molecules and 1792 water molecules, was run in the NVE ensemble at a temperature of 333 K for a total of 10 ns. The resulting trajectory was used to analyze structural and dynamical quantities. The electron density, bilayer spacing, and order parameters (S(CD)), based on the AMBER forcefield and SPCE water model are in good agreement with previous calculations and experimental data. The simulation reveals evidence for two types of lateral diffusive behavior: cage hopping and that of a two-dimensional liquid. The lateral diffusion coefficient is 8 x 10(-8) cm(2)/s. We characterize the rotational motion, and find that the lipid tail rotation (D(rot_tail) = -0.04 rad(2)/ns) is slower then the head group rotation (D(rot_hg) = 2.2 rad(2)/ns), which is slower than the overall in plane (D(rot) = 3.2 rad(2)/ns) for the lipid molecule.

Computer Simulation↗
PubMed2001

Molecular-dynamics simulation for liquid chromatographic interactions: effect of mobile phase composition.

A molecular-dynamics simulation method has been applied to investigate the influence of the mobile-phase composition on the retention of solutes in HPLC. The distribution profiles of the distance between two atoms in ODS ligands were constructed to characterize the conformation of ODS ligand molecules. The distinct difference of ODS conformation is observed by comparing molecular models consisting of solvent molecules at each solvent composition. The distribution profiles of the distance between the mobile-phase solvent molecules and ODS ligand molecules were also constructed to characterize the distribution of the solvent molecules at each composition. In all distribution profiles, the difference in the distribution due to a change in the solvent compositions was very clearly found, and the facts seem to be very reasonable. The distribution profiles of the distance between the solute, n-propylbenzene, and the terminal carbon atom in the ODS ligand, and between the solute and the silicon atom in the ODS ligand have been also constructed to see the distribution of the solutes in the separation system. The calculated solute distribution in the ODS-methanol/water system is very consistent with the actual chromatographic retention behaviors.

Journal Article↗
PubMed2005

Electric field induced switching behaviors of monolayer-modified silicon surfaces: surface designs and molecular dynamics simulations.

Electric field induced switching behaviors of a series of low-density omega-carboxyalkyl modified H-Si(111) and the mixed omega-carboxyalkyl/alkyl covered H-Si(111) have been simulated by using molecular dynamics (MD) simulation techniques. The external electric fields may drive surface-confined molecules to reversibly change conformations between the all-trans (switching "on") and the mixed trans-gauche (switching "off") states. Such surfaces switch wettabilities between the hydrophilic state and the moderately hydrophobic state. It has been found in broad ranges of intensities of applied electric fields, -2.0 x 10(9) V/m < or = E(down) < or = 0 and 1.8 x 10(9) V/m < or = E(up) < or = 7.3 x 10(9) V/m, both the low-density (11.1%-33.3%) omega-carboxyalkyl and the mixed omega-carboxyalkyl/alkyl (in mole fraction of 0.4 < or = N(carboxyalkyl) : N(alkyl) < or = 3.0) monolayers covering H-Si(111) exhibit conformational switching in the aqueous medium. The critical intensity of the electric field, E(up) = 1.8 x 10(9) V/m, which is required to trigger the switches is observed by our MD simulations and further rationalized by a thermodynamical model. Some important factors in the control of switching performances, such as the steric hindrances, the formation of the electric double layer at the monolayer/electrolyte solution interface, the hydration effects of carboxylate anions, the components of surrounding electrolyte solutions, as well as the rigidity of surface-confined chains are elucidated. The lower ionic strength and additions of acetonitrile molecules in the surrounding aqueous solution can reduce the value of critical intensity of the electric field and hence facilitate the realization of switching. Some practical considerations in construction and optimum design of switching surfaces are also suggested.

Journal Article↗