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At least 1,783 records · Page 99Linked to original sources
PubMed2004

Nuclear magnetic shielding and quadrupole coupling tensors in liquid water: a combined molecular dynamics simulation and quantum chemical study.

Nuclear magnetic resonance (NMR) shielding tensors for the oxygen and hydrogen nuclei, as well as nuclear quadrupole coupling tensors for the oxygen and deuterium nuclei of water in the liquid and gaseous state, are calculated using Hartree-Fock and density functional theory methods, for snapshots sampled from Car-Parrinello molecular dynamics trajectories. Clusters representing local liquid structures and instantaneous configurations of a single molecule representing low-density gas are fed into a quantum chemical program for the calculation of the NMR tensors. The average isotropic and anisotropic tensorial properties of 400 samples in both states, averaged using a common Eckart coordinate frame, are calculated from the data. We report results for the gas-to-liquid chemical shifts of (17)O and (1)H nuclei, as well as the corresponding change in the nuclear quadrupole couplings of (17)O and (2)H. Full thermally averaged shielding and quadrupole coupling tensors are reported for the gaseous and liquid-state water, for the first time in the case of liquid. Electron correlation effects, the difference of classical vs quantum mechanical rovibrational averaging, and different methods of averaging anisotropic properties are discussed.

Journal Article↗
PubMed1999

Transport coefficients for granular media from molecular dynamics simulations.

Under many conditions, macroscopic grains flow like a fluid; kinetic theory predicts continuum equations of motion for this granular fluid. In order to test the theory, we perform event-driven molecular simulations of a two-dimensional gas of inelastic hard disks, driven by contact with a heat bath. Even for strong dissipation, high densities, and small numbers of particles, we find that continuum theory describes the system well. With a bath that heats the gas homogeneously, strong velocity correlations produce a slightly smaller energy loss due to inelastic collisions than that predicted by kinetic theory. With an inhomogeneous heat bath, thermal or velocity gradients are induced. Determination of the resulting fluxes allows calculation of the thermal conductivity and shear viscosity, which are compared to the predictions of granular kinetic theory, and which can be used in continuum modeling of granular flows. The shear viscosity is close to the prediction of kinetic theory, while the thermal conductivity can be overestimated by a factor of 2; in each case, transport is lowered with increasing inelasticity.

Journal Article↗
PubMed1992

Substrate mobility in a deeply buried active site: analysis of norcamphor bound to cytochrome P-450cam as determined by a 201-psec molecular dynamics simulation.

While cytochrome P-450cam catalyzes the hydroxylation of camphor to 5-exo-hydroxycamphor with 100% stereospecificity, norcamphor is hydroxylated by this enzyme yielding 45% 5-exo-, 47% 6-exo-, and 8% 3-exo-hydroxynorcamphor (Atkins, W.M., Sligar, S.G., J. Am. Chem. Soc. 109:3754-3760, 1987). The present study describes a 201-psec molecular dynamics (MD) stimulation of norcamphorbound cytochrome P-450cam to elucidate the relationship between substrate conformational mobility and formation of alternative products. First, these data suggest that the product specificity is, at least partially, due to the mobility of the substrate within the active site. Second, the high mobility of norcamphor in the active site leads to an average increase in separation between the heme iron and the substrate of about 1.0 A; this increase in separation may be the cause of the uncoupling of electron transfer when norcamphor is the substrate. Third, the active site water located in the norcamphorbound crystal structure possesses mobility that correlates well with the spin-state equilibrium of this enzyme-substrate complex.

Binding Sites↗
PubMed2004

A molecular basis for the selectivity of thiadiazole urea inhibitors with stromelysin-1 and gelatinase-A from generalized born molecular dynamics simulations.

Matrix metalloproteinases (MMPs) represent a potentially important class of therapeutic targets for the treatment of diseases such as cancer. Selective inhibition of MMPs will be required given the high sequence identity across the family and the discovery that individual MMPs also regulate the natural angiogenesis inhibitor angiostatin. In this study, we have used computational methods to model the selectivity for six thiadiazole urea inhibitors with stromelysin-1 and gelatinase-A, two homologous MMPs that have been implicated in breast cancer. From continuum Generalized Born molecular dynamics (GB-MD) and MM-GBSA analysis, we estimated ligand free energies of binding using 200 snapshots obtained from a short 40 ps simulation of the relevant protein-ligand complex. The MM-GBSA free energies, computed from the continuum GB-MD trajectories, show strong correlation with the experimental affinities (r(2) = 0.74); prior studies have employed explicit water MD simulations. Including estimates for changes in solute entropy in the binding calculations slightly diminishes the overall correlation with experiment (r2 = 0.71). Notably, in every case, the simulation results correctly predict that a given ligand will bind selectively to stromelysin-1 over gelatinase-A which is gratifying given the high degree of structural homology between the two proteins. The increased selectivity for stromelysin-1 appears to be driven by (1) increased favorable van der Waals interactions, (2) increased favorable Coulombic interactions, and (3) decreased unfavorable total electrostatic energies (Coulombic plus desolvation).

Amino Acid Sequence↗
PubMed1999

What determines the van der Waals coefficient beta in the LIE (linear interaction energy) method to estimate binding free energies using molecular dynamics simulations?

Recently a semiempirical method has been proposed by Aqvist et al. to calculate absolute and relative binding free energies. In this method, the absolute binding free energy of a ligand is estimated as deltaGbind = alpha + beta , where Vel(bound) and Vvdw(bound) are the electrostatic and van der Waals interaction energies between the ligand and the solvated protein from an molecular dynamics (MD) trajectory with ligand bound to protein and Vel(free) and Vel(free) and Vvdw(free) are the electrostatic and van der Waals interaction energies between the ligand and the water from an MD trajectory with the ligand in water. A set of values, alpha = 0.5 and beta = 0.16, was found to give results in good agreement with experimental data. Later, however, different optimal values of beta were found in studies of compounds binding to P450cam and avidin. The present work investigates how the optimal value of beta depends on the nature of binding sites for different protein-ligand interactions. By examining seven ligands interacting with five proteins, we have discovered a linear correlation between the value of beta and the weighted non-polar desolvation ratio (WNDR), with a correlation coefficient of 0.96. We have also examined the ability of this correlation to predict optimal values of beta for different ligands binding to a single protein. We studied twelve neutral compounds bound to avidin. In this case, the WNDR approach gave a better estimate of the absolute binding free energies than results obtained using the fixed value of beta found for biotin-avidin. In terms of reproducing the relative binding free energy to biotin, the fixed-beta value gave better results for compounds similar to biotin, but for compounds less similar to biotin, the WNDR approach led to better relative binding free energies.

Algorithms↗
PubMed2003

Molecular dynamics simulation of dark-adapted rhodopsin in an explicit membrane bilayer: coupling between local retinal and larger scale conformational change.

The light-driven photocycle of rhodopsin begins the photoreceptor cascade that underlies visual response. In a sequence of events, the retinal covalently attached to the rhodopsin protein undergoes a conformational change that communicates local changes to a global conformational change throughout the whole protein. In turn, the large-scale protein change then activates G-proteins and signal amplification throughout the cell. The nature of this change, involving a coupling between a local process and larger changes throughout the protein, may be important for many membrane proteins. In addition, functional work has shown that this coupling occurs with different efficiency in different lipid settings. To begin to understand the nature of the efficiency of this coupling in different lipid settings, we present a molecular dynamics study of rhodopsin in an explicit dioleoyl-phosphatidylcholine bilayer. Our system was simulated for 40 ns and provides insights into the very early events of the visual cascade, before the full transition and activation have occurred. In particular, we see an event near 10 ns that begins with a change in hydrogen bonding near the retinal and that leads through a series of coupled changes to a shift in helical tilt. This type of event, though rare on the molecular dynamics time-scale, could be an important clue to the types of coupling that occur between local and large-scale conformational change in many membrane proteins.

Animals↗
PubMed2006

Revisiting the hexane-water interface via molecular dynamics simulations using nonadditive alkane-water potentials.

We present results addressing properties of a polarizable force field for hexane based on the fluctuating charge (FQ) formalism and developed in conjunction with the Chemistry at Harvard Molecular Mechanics (CHARMM) potential function. Properties of bulk neat hexane, its liquid-vapor interface, and its interface with a polarizable water model (TIP4P-FQ) are discussed. The FQ model is compared to a recently modified alkane model, C27r, also based on the CHARMM potential energy function. With respect to bulk properties, both models predict bulk density within 1%; the FQ model predicts the liquid vaporization enthalpy within 2%, while the C27r force field underestimates the property by roughly 20% (and in this sense reflects the quality of the C27r force field across the spectrum of linear and branched alkanes). The FQ hexane model realistically captures the dielectric properties of the bulk in terms of a dielectric constant of 1.94, in excellent agreement with experimental values in the range of 1.9-2.02. This behavior is also in conformity with a recent polarizable alkane model based on Drude oscillators. Furthermore, the bulk dielectric is essentially captured in the infinite frequency, or optical, dielectric contribution. The FQ model is in this respect a more realistic force field for modeling lipid bilayer interiors for which most current state-of-the-art force fields do not accurately capture the dielectric environment. The molecular polarizability of the FQ model is 11.79 A3, in good agreement with the range of experimental and ab initio values. In contrast to FQ models of polar solvents such as alcohols and water, there was no need to scale gas-phase polarizabilities in order to avoid polarization catastrophes in the pure bulk. In terms of the liquid-vapor and liquid-liquid interfaces, the FQ model displays a rich orientational structure of alkane and water in the respective interfacial systems, in general conforming with earlier simulation studies of such interfaces. The FQ force field shows a marked deviation in the interfacial dipole potentials computed from the charge densities averaged over simulation trajectories. At the liquid-vapor interface, the FQ model predicts a potential drop of -178.71 mV in contrast to the C27r estimate of -433.80 mV. For the hexane-water interface, the FQ force field predicts a dipole potential drop of -379.40 mV in contrast to the C27r value of -105.42 mV. Although the surface dipole potential predicted by the FQ model is roughly 3.5 times that predicted by the C27r potential, it is consistent with reported experimental potentials across solvated lipid bilayers in the range of 400-600 mV.

Alkanes↗
PubMed2006

Spontaneous formation of annular structures observed in molecular dynamics simulations of polyglutamine peptides.

Annular structures have been observed experimentally in aggregates of polyglutamine-containing proteins and other proteins associated with diseases of the brain. Here we report the observation of annular structures in molecular-level simulations of large systems of model polyglutamine peptides. A system of 24 polyglutamine chains 16 residues long at a concentration of 5 mM spontaneously formed large beta sheets which curved to form tube-like annular structures that resemble beta barrels. This work was accomplished by extending the PRIME model to polyglutamine. PRIME is an off-lattice, unbiased, intermediate-resolution protein model based on an amino acid representation of between three and seven united atoms depending on the residue being modeled. Our results are interesting not only because of the recent discovery of tubular protofibrils in experiments on aggregation of mutant huntingtin fragments containing expanded polyglutamine tracts but also because Perutz predicted that polyglutamine forms water filled nanotubes.

Brain Diseases↗
PubMed2005

Ab initio molecular dynamics simulation of a water-hydrogen fluoride equimolar mixture.

Hydrogen fluoride and water can be mixed in any proportion. The resulting solutions have unique acidic properties. In particular, hydrogen fluoride undergoes a weak-to-strong acidity transition with increasing concentration of HF To supplement the knowledge already obtained on dilute or moderately concentrated solutions and gas-phase aggregates, an equimolar mixture is studied here by Car-Parrinello molecular dynamics. The natures of the ions and of the complexes formed in the equimolar liquid were determined. Specifically, H3O+, H5O2+, FH-OH2, and HF2- were spontaneously obtained while only hydronium and fluoride ions pre-exist in the equimolar crystal. The behaviour of the proton in the equimolar liquid was compared with mixtures of other proportions simulated previously in an attempt to relate proton dynamics to acidity. In the same way, the behaviour of HF2- was also examined. In this case, proton localization and transfer appeared to be driven by the fluctuating environment of the solvated ion.

Journal Article↗
PubMed2005

Molecular dynamics simulation of room-temperature ionic liquid mixture of [bmim][BF4] and acetonitrile by a refined force field.

1-Butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]) is one of the promising room-temperature ionic liquids. To test the refined force field for [bmim][BF4] proposed in our previously work (J. Phys. Chem. B, 2004, 108, 12978-12989), thermodynamic properties of mixtures of [bmim][BF4](1)+ acetonitrile (2) are presented by using molecular dynamics over the whole concentration range. The calculated densities are in good agreement with the experimental data with deviations less than 2%, indicating the force field is applicable to the mixtures. In addition, the diffusion constants, viscosities, heats of vaporization, cohesive energy densities and excess properties of the mixtures are reported. The microscopic structures are discussed in detail, corresponding to the thermodynamic properties.

Acetonitriles↗
PubMed2004

Molecular dynamics simulations of spontaneous fibril formation by random-coil peptides.

Assembly of normally soluble proteins into amyloid fibrils is a cause or associated symptom of numerous human disorders, including Alzheimer's and the prion diseases. We report molecular-level simulation of spontaneous fibril formation. Systems containing 12-96 model polyalanine peptides form fibrils at temperatures greater than a critical temperature that decreases with peptide concentration and exceeds the peptide's folding temperature, consistent with experimental findings. Formation of small amorphous aggregates precedes ordered nucleus formation and subsequent rapid fibril growth through addition of beta-sheets laterally and monomeric peptides at fibril ends. The fibril's structure is similar to that observed experimentally.

Amyloid↗
PubMed2004

Molecular dynamics simulations of bovine lactoferricin: turning a helix into a sheet.

Bovine lactoferricin is a 25-residue peptide that is excised through pepsin cleavage in the stomach from the intact 80 kDa bovine milk protein lactoferrin. This basic peptide contains a single disulfide crosslink and is considerably more active as an antimicrobial peptide than the intact protein. It has been suggested that the dramatic difference in potency is related to a change in the secondary and tertiary structure of this peptide, moving from a mixed alpha-helical beta-strand region in the protein to an amphipathic twisted antiparallel beta-sheet in the peptide. Here we have used equilibrium and restrained molecular dynamics calculations to compare the stability of the solution structure of the isolated peptide with that excised from the intact protein. Simulations were performed for fully solvated peptides in the absence and presence of 250 mM salt. Our results show that the peptide as released from the protein is relatively unstable, particularly in the absence of salt. However, even though the simulations extended over 60 nsecs, no interconversion could be observed between the crystal and solution structures, unless a relatively small directional force was exerted on the peptide. A pathway for the structural transition from a helical to a sheet structure was identified in this fashion.

Animals↗
PubMed2005

One gene, two diseases and three conformations: molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures.

Fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD) are associated to the same mutation at codon 178 but differentiate into clinicopathologically distinct diseases determined by this mutation and a naturally occurring methionine-valine polymorphism at codon 129 of the prion protein gene. It has been suggested that the clinical and pathological difference between FFI and CJD is caused by different conformations of the prion protein. Using molecular dynamics (MD), we investigated the effect of the mutation at codon 178 and the polymorphism at codon 129 on prion protein dynamics and conformation at normal and elevated temperatures. Four model structures were examined with a focus on their dynamics and conformational changes. The results showed differences in stability and dynamics between polymorphic variants. Methionine variants demonstrated a higher stability than valine variants. Elongation of existing beta-sheets and formation of new beta-sheets was found to occur more readily in valine polymorphic variants. We also discovered the inhibitory effect of proline residue on existing beta-sheet elongation.

Computer Simulation↗
PubMed2004

On the stability of different experimental dimeric structures of the SL1 sequence from the genomic RNA of HIV-1 in solution: a molecular dynamics simulation and electrophoresis study.

SL1 is a stem-loop RNA sequence from the genome of HIV-1 thought to be the initiation site for the dimerization of the retroviral genomic RNA. The aim of this study is to check the stability in solution of different experimental dimeric structures available in the literature. Two kinds of dimer have been evidenced: an extended duplex looking like a double helix with two internal bulges and a kissing complex in which the monomers with a stem/loop conformation are linked by intermolecular loop-loop interactions. Two divergent experimental structures of the kissing complex from the Lai isolate are reported in the literature, one obtained from NMR (Mujeeb et al., Nature Structural Biology, 1998, Vol. 5, pp. 432-436) and the other one from x-ray crystallography (Ennifar et al., Nature Structural Biology, 2001, Vol. 8, pp. 1064-1068). A crystallographic structure of the Mal isolate was also reported (Ennifar et al., Nature Structure Biology, 2001, Vol. 8, pp. 1064-1068). Concerning the extended duplex, a NMR structure is available for Lai (Girard et al., Journal of Biomolecular Structure and Dynamics, 1999, Vol. 16, pp. 1145-1157) and a crystallographic structure for Mal (Ennifar et al., Structure, 1999, Vol. 7, pp. 1439-1449). Using a molecular dynamics technique, all these experimental structures have been simulated in solution with explicit water and counterions. We show that both extended duplex structures are stable. On the contrary, the crystallographic structures of the Lai and Mal kissing complexes are rapidly destabilized in aqueous environment. Finally, the NMR structure of the Lai loop-loop kissing complex remains globally stable over a 20 ns MD simulation, although large rearrangements occur at the level of the stem/loop junctions that are flexible, as shown from free energy calculations. These results are compared to electrophoresis experiments on dimer formation.

Computer Simulation↗