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At least 1,099 records · Page 61Linked to original sources
PubMed2004

Molecular dynamics simulation of amyloid beta dimer formation.

Recent experiments with amyloid beta (Abeta) peptide indicate that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Abeta dimer formation. 1), We use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations; and 2), we employ all-atom molecular mechanics simulations to estimate thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Abeta peptide model predicts 10 different planar beta-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Abeta(1-42) and Abeta(1-40) dimers. We find that 1), dimer conformations have higher free energies compared to their corresponding monomeric states; and 2), the free-energy difference between the Abeta(1-42) and the corresponding Abeta(1-40) dimer conformation is not significant. Our results suggest that Abeta oligomerization is not accompanied by the formation of thermodynamically stable planar beta-strand dimers.

Amyloid beta-Peptides↗
PubMed2006

Quantum mechanical and molecular dynamics simulations of ureases and Zn beta-lactamases.

Herein we briefly review theoretical contributions that have increased our understanding of the structure and function of metallo-beta-lactamases and ureases. Both are bimetallic metalloenzymes, with the former containing two zinc ions and the latter containing two nickel ions. We describe the use of several different methodologies, including quantum chemical calculations, molecular dynamic simulations, as well as mixed QM/MM approaches and how they have impacted our understanding of the structure and function of metallo-beta-lactamases and ureases.

Binding Sites↗
PubMed2003

Molecular dynamics simulation of hepatitis C virus IRES IIId domain: structural behavior, electrostatic and energetic analysis.

The dynamic behavior of the HCV IRES IIId domain is analyzed by means of a 2.6-ns molecular dynamics simulation, starting from an NMR structure. The simulation is carried out in explicit water with Na+ counterions, and particle-mesh Ewald summation is used for the electrostatic interactions. In this work, we analyze selected patterns of the helix that are crucial for IRES activity and that could be considered as targets for the intervention of inhibitors, such as the hexanucleotide terminal loop (more particularly its three consecutive guanines) and the loop-E motif. The simulation has allowed us to analyze the dynamics of the loop substructure and has revealed a behavior among the guanine bases that might explain the different role of the third guanine of the GGG triplet upon molecular recognition. The accessibility of the loop-E motif and the loop major and minor groove is also examined, as well as the effect of Na+ or Mg2+ counterion within the simulation. The electrostatic analysis reveals several ion pockets, not discussed in the experimental structure. The positions of these ions are useful for locating specific electrostatic recognition sites for potential inhibitor binding.

Amino Acid Motifs↗
PubMed2005

Distribution and effect of water content on molecular mobility in poly(vinylpyrrolidone) glasses: a molecular dynamics simulation.

PURPOSE: This work explores the distribution of water and its effects on molecular mobilities in poly(vinylpyrrolidone) (PVP) glasses using molecular dynamics (MD) simulation technology. METHODS: PVP glasses containing 0.5% and 10% w/w water and a small amount of ammonia and Phe-Asn-Gly were generated. Physical aging processes and associated structural and dynamic properties were monitored vs. time for periods up to 0.1 micros by MD simulation. RESULTS: Increasing water content from 0.5% to 10% w/w was found to reduce the Tg by about 90 K and increase the rates of volume and enthalpy relaxation. At 0.5% w/w, water molecules are mostly isolated and uniformly distributed while at 10% w/w, water distribution is markedly heterogeneous, with strands of water molecules occupying channels between the polymer chains. At 10% w/w, each water molecule has an average of 2.0 neighboring water molecules. The plasticization effects of water were revealed in diffusion coefficient increases of 3.7-, 7.3-, and 7.6-fold for water, ammonia, and the individual polyvinylpyrrolidone segments, respectively, and in shorter relaxation times (37- to 47-fold) for rotation of polymer segments with an elevation in water content from 0.5% to 10% w/w. Water diffusivity was found to linearly correlate with the number of neighboring water molecules. Rotation of the PVP segments is comprised of a fast wobble motion within a highly restrained cavity and a slow rotation over a wider angular space. Only the slow rotation was shown to be significantly affected by water content. CONCLUSIONS: Water distribution in the PVP glass is highly heterogeneous at 10% w/w water, reflecting the formation of water strands or small clusters rather than complete phase separation. Local enhancement of mobility with increasing water content has been demonstrated using MD simulations.

Algorithms↗
PubMed2002

Helix motion in protein C12A-p8(MTCP1): comparison of molecular dynamics simulations and multifield NMR relaxation data.

The human p8(MTCP1) protein is constituted by an original disulfide bridged alpha-hairpin motif, and a third hydrophilic helix that appeared mobile and independent in NMR analysis. To get atomic scale description of the possible motions involved, a 12-ns molecular dynamics simulation of the C12A-p8(MTCP1) mutated protein and 10 400-ps simulations were performed in explicit water at 298 K. Analyses of the essential dynamics subspace and of the time-evolution of secondary structures indicate large displacements and internal motions of the third helix. Simulated order parameters, S,(2) are consistent to those obtained from (15)N-NMR relaxation data recorded at five different magnetic fields (proton resonance frequencies: 400, 500, 600, 700, and 800 MHz). The simulations show a fairly rigid alpha-hairpin motif with only very small local conformational changes, although the loop between helices undergoes significant correlated motions. The displacements and internal motions of the third helix can be essentially accounted for by alpha-helical to 3(10)-helical transitions near its N-terminus and by a hinge-bending motion near glycine 52. The loss of the alpha-helical conformation for a large part of the third helix during about 25% of the simulation time supports the possible occurrence of a slow motion as suggested by previous analyses of the (3)J(NH-H(alpha)) coupling constant values and of the proton-deuterium NH exchange kinetics.

Computer Simulation↗
PubMed2004

Changes in phosphatidylcholine headgroup tilt and water order induced by monovalent salts: molecular dynamics simulations.

The association between monovalent salts and neutral lipid bilayers is known to influence global bilayer structural properties such as headgroup conformational fluctuations and the dipole potential. The local influence of the ions, however, has been unknown due to limited structural resolution of experimental methods. Molecular dynamics simulations are used here to elucidate local structural rearrangements upon association of a series of monovalent Na(+) salts to a palmitoyl-oleoyl-phosphatidylcholine bilayer. We observe association of all ion types in the interfacial region. Larger anions, which are meant to rationalize data regarding a Hofmeister series of anions, bind more deeply within the bilayer than either Cl(-) or Na(+). Although the simulations are able to reproduce experimentally measured quantities, the analysis is focused on local properties currently invisible to experiments, which may be critical to biological systems. As such, for all ion types, including Cl(-), we show local ion-induced perturbations to headgroup tilt, the extent and direction of which is sensitive to ion charge and size. Additionally, we report salt-induced ordering of the water well beyond the interfacial region, which may be significant in terms of hydration repulsion between stacked bilayers.

Computer Simulation↗
PubMed1998

Dynamic exchange between stabilized conformations predicted for hyaluronan tetrasaccharides: comparison of molecular dynamics simulations with available NMR data.

Studies of the hyaluronan (HA) tetrasaccharides are important for understanding hydrogen-bonding in the HA polymer, as they are probably the smallest oligomers in which characteristics of the constituent monosaccharides and the polymer are simultaneously exhibited. Here we present extensive molecular dynamics simulations of the two tetrasaccharides of HA in dilute aqueous solution. These simulations have confirmed the existence of intramolecular hydrogen-bonds between the neighboring sugar residues of HA in solution, as proposed by Scott (1989). However, our simulations predict that these intramolecular hydrogen-bonds are not static as previously proposed, but are in constant dynamic exchange on the sub-nanosecond time-scale. This process results in discrete internal motion of the HA tetrasaccharides where they rapidly move between low energy conformations. Specific interactions between water and intramolecular hydrogen-bonds involving the hydroxymethyl group were found to result in differing conformations and dynamics for the two alternative tetrasaccharides of HA. This new observation suggests that this residue may play a key role in the entropy and stability of HA in solution, allowing it to stay soluble up to high concentration. The vicinal coupling constants3 J NHCH of the acetamido groups have been calculated from our aqueous simulations of HA. We found that high values of 3J NHCH approximately 8 Hz, as experimentally measured for HA, are consistent with mixtures of both trans and cis conformations, and thus3 J NHCH cannot be used to imply a purely trans conformation of the acetamido. The rapid exchange of intramolecular hydrogen-bonds indicates that although the structure is at any moment stabilized by these hydrogen-bonds, no one hydrogen-bond exists for an extended period of time. This could explain why NMR often fails to provide evidence for intramolecular hydrogen-bonds in HA and other aqueous carbohydrate structures.

Carbohydrate Conformation↗
PubMed2004

A molecular dynamics simulation of the melting points and glass transition temperatures of myo- and neo-inositol.

The heat of sublimation, density, melting point, and glass transition temperature are calculated for myo- and neo-inositol, using the condensed-phase optimized molecular potentials for atomistic simulation studies (COMPASS) force field and molecular dynamics techniques. Our results show that the calculated heats of sublimation and density are very close to the experimental values for both compounds. Furthermore, our simulated melting temperatures for myo- and neo-inositol also compare very well to the experimentally obtained data. The glass transition temperatures for myo- and neo-inositol have been calculated to be ca. 494 K and ca. 518 K, respectively, and the shape of the volume versus temperature plots produced are typical for a glass transition. As a result, it is our view that the COMPASS force field suitably describes these two compounds in molecular simulations and that molecular dynamics techniques, combined with this force field, can be used to simulate the melt and glass transitions for such molecules.

Journal Article↗
PubMed2006

Characterization of the solvation dynamics of an ionic liquid via molecular dynamics simulation.

The solvation dynamics of ionic liquids have been the subject of intense experimental study but remain poorly understood. We present the results of molecular dynamics simulations of the solvation dynamics of the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate in response to photoexcitation of the fluorescent dye coumarin-153. We reproduce the time-resolved fluorescence Stokes shift using linear response theory, then use novel statistical techniques to analyze cation and anion contributions to the signal. We find that the solvation dynamics are dominated by collective ionic motion and characterize the time scale for various features of the collective response. Further, we use the Steele analysis [Mol. Phys. 61, 1031 (1987)] to characterize the contributions to the observed Stokes shift made by translational and rovibrational degrees of freedom. Our results indicate that in contrast to molecular liquids, the rovibrational response is trivial and the observed fluorescence response arises almost entirely from ionic translation. Our results resolve previously open questions in the literature about the nature of the rapid dynamics in room-temperature ionic liquids and offer insight into the physical principles governing ionic liquid behavior on longer time scales.

Journal Article↗
PubMed1998

Solution conformations and thermodynamics of structured peptides: molecular dynamics simulation with an implicit solvation model.

Calculations of the ensemble of solution conformations and thermodynamics of an analogue of the C-terminal helix of ribonuclease A (RN24) and of a synthetic, beta-hairpin forming peptide (BH8) are presented. For efficient sampling of conformation space, molecular dynamics simulations with an implicit solvent potential and umbrella sampling of the potential energy are performed. Starting from the fully extended chains, the simulations yield several folding and unfolding transitions between disordered (coil) conformations of the peptides and the "native" state (RN24, helix; BH8, hairpin); the simulations also lead to the occurrence of "misfolded" conformations (RN24, hairpin; BH8, helix). In agreement with experiment, the calculations predict 58% helix for RN24 at 275 K and an antiparallel-beta content of 38% at 275 K for BH8; the calculated probabilities for the misfolded species are 2% or smaller at all temperatures considered (250-1100 K). Good agreement is also shown between the calculated 3JHNalpha spin-spin coupling constants of RN24 and BH8 at 275 K, and those obtained from NMR experiments at the same temperature. From the calculated probabilities of helix (h), beta-hairpin (b), and coil (c), the free energy differences between the structured substates are DeltaGch=Gc-Gh approximately 1 kcal/mol and DeltaGbh>/=1.8 kcal/mol for RN24, and DeltaGcb approximately 0.7 kcal/mol and DeltaGhb>/=2.7 kcal/mol for BH8. The free energy difference between "correctly" folded and misfolded secondary structures are of interest for understanding the alpha to beta transition that is thought to play a role in amyloid fibril formation.

Amino Acid Sequence↗
PubMed2004

Molecular dynamics simulation study on the phase behavior of the Gay-Berne model with a terminal dipole and a flexible tail.

To study the effect of the alkyl tail and the terminal dipole on the stability of the liquid crystalline phase of mesogens, we have carried out molecular dynamics simulations for 1CB(4-methyl-4'-cyanobiphenyl) and 5CB(4-n-pentyl-4'-cyanobiphenyl) by using a coarse-grained model. In the coarse-grained model, a 5CB molecule is divided into the rigid part of 1CB moiety, which is represented by an ellipsoid, and the remaining flexible part which is represented by a chain of united atoms. The nonbonded potential between coarse-grained segments is represented by the generalized Gay-Berne (GB) potential and the potential parameters are determined by directly comparing the GB potential with the atomistic potentials averaged over the rotation of the mesogen around its axis. In addition, a dipole moment is placed at one end of the ellipsoid opposite to the flexible tail. The ordered state obtained in the polar 5CB model was assigned as the nematic phase, and the experimental static and dynamical properties were reproduced well by using this coarse-grained model. Both the dipole-dipole interactions and the thermal fluctuation of the flexible tail increase the positional disorder in the director direction, and stabilize the nematic phase. Thus, the nematic phase in the polar 5CB is induced by a cooperative effect of the flexible tail and the terminal dipole. It is noted that a local bilayer structure with head-to-head association is formed in the nematic phase, as experimentally observed by x-ray diffraction measurements.

Journal Article↗
PubMed2006

Side-chain interactions determine amyloid formation by model polyglutamine peptides in molecular dynamics simulations.

The pathological manifestation of nine hereditary neurodegenerative diseases is the presence within the brain of aggregates of disease-specific proteins that contain polyglutamine tracts longer than a critical length. To improve our understanding of the processes by which polyglutamine-containing proteins misfold and aggregate, we have conducted molecular dynamics simulations of the aggregation of model polyglutamine peptides. 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. The effects of hydrophobicity on the system are studied by varying the strength of the hydrophobic interaction from 12.5% to 5% of the hydrogen-bonding interaction strength. In our simulations, we observe the spontaneous formation of aggregates and annular structures that are made up of beta-sheets starting from random configurations of random coils. This result was interesting because tubular protofibrils were recently found in experiments on polyglutamine aggregation and because of Perutz's prediction that polyglutamine would form water-filled nanotubes.

Amino Acid Sequence↗
PubMed2001

Molecular dynamics simulation of carboxy-myoglobin embedded in a trehalose-water matrix.

We report on a molecular dynamics (MD) simulation of carboxy-myoglobin (MbCO) embedded in a water-trehalose system. The mean square fluctuations of protein atoms, calculated at different temperatures in the 100-300 K range, are compared with those from a previous MD simulation on an H2O-solvated MbCO and with experimental data from Mössbauer spectroscopy and incoherent elastic neutron scattering on trehalose-coated MbCO. The results show that, for almost all the atomic classes, the amplitude of the nonharmonic motions stemming from the interconversion among the protein's conformational substates is reduced with respect to the H2O-solvated system, and their onset is shifted toward higher temperature. Moreover, our simulation shows that, at 300 K, the heme performs confined diffusive motions as a whole, leaving the underlying harmonic vibrations unaltered.

Animals↗
PubMed2000

Ion-beam thinning. An atomistic view by molecular dynamics simulations

The purpose of this study is to offer a view of ion beam thinning at atomistic level. Therefore, a computer simulation of the type molecular dynamics is used to study the evolution of a stepped silicon surface undergoing ion bombardment. According to the methods used in radiation damage studies, the effect of the impinging beam is described by constructing a large ensemble of trajectories of displaced silicon atoms. The effects of the beam parameters, such as energy and angle, as well as the ones arising from the surface topography, are obtained from the properties of this ensemble. The results of the simulations are discussed in the light of the mesoscopic models of surface evolution.

Journal Article↗
PubMed2006

Mutations in alpha-helical solvent-exposed sites of eglin c have long-range effects: evidence from molecular dynamics simulations.

Eglin c is a small protease inhibitor whose structural and thermodynamic properties have been well studied. Previous thermodynamic measurements on mutants at solvent-accessible positions in the protein's helix have shown the unexpected result that the data could be best fit by the inclusion of residue- and position-specific parameters to the model. To explore the origins of this surprising result, long molecular dynamics simulations in explicit solvent have been performed. These simulations indicate specific long-range interactions between the solvent-exposed residues in the eglin c alpha-helix and binding loop, an unexpected observation for such a small protein. The residues involved in the interaction are on opposite sides of the protein, about 25 A apart. Simulations of alanine substitutions at the solvent-exposed helix positions, arginine 22, glutamic acid 23, threonine 26, and leucine 27, show both small and large perturbations of eglin c dynamics. Two mutations exhibit large impacts on the long-range helix-loop interactions. Previous stability measurements (Yi et al., Biochemistry 2003;42:7594-7603) had indicated that an alanine substitution at position 27 was less stabilizing than at other solvent-exposed positions in the helix. The L27A mutation effects observed in these simulations suggest that the position-dependent loss of stability measured in wet bench experiments is derived from changes in dynamics that involve long-range interactions; thus, these simulations support the hypothesis that solvent-exposed positions in helices are not always equivalent.

Computational Biology↗
PubMed2004

Characterization of the microscopic surface structure of the octadecylsilica stationary phase using a molecular-dynamics simulation.

The influence of the mobile-phase composition and temperature on the surface structure of the octadecylsilica (ODS) stationary-phase was investigated by applying a molecular-dynamics (MD) simulation. The molecular model to which the MD simulation was applied consisted of three parts: an amorphous silica base, dimethyloctadecylsilyl ligands and mobile-phase solvents. More detailed information on the effect of the mobile-phase composition was obtained by constructing larger molecular models than those used in our previous study. The thickness of the hydrocarbon layer of the stationary phase could be estimated based on the distance between the carbon atom located at the terminal end of the ODS ligand and the silica gel surface. The structural information obtained by the calculation showed good consistency with the experimentally observed values. The gauche fraction in the ODS ligand conformation could be also estimated to obtain a more detailed ligand conformation for each molecular model. It was found that as the temperature increased, the ligand conformation collapsed more. This trend was the same as the experimentally observed trends obtained by NMR, FT-IR, and Raman spectroscopic techniques.

Computer Simulation↗
PubMed2006

Molecular-dynamics simulation of a ceramide bilayer.

Ceramide is the simplest lipid in the biologically important class of glycosphingolipids. Ceramide is an important signaling molecule and a major component of the strateum corneum layer in the skin. In order to begin to understand the biophysical properties of ceramide, we have carried out a molecular-dynamics simulation of a hydrated 16:0 ceramide lipid bilayer at 368 K (5 degrees above the main phase transition). In this paper we describe the simulation and present the resulting properties of the bilayer. We compare the properties of the simulated ceramide bilayer to an earlier simulation of 18:0 sphingomyelin, and we discuss the results as they relate to experimental data for ceramide and other sphingolipids. The most significant differences arise at the lipid/water interface, where the lack of a large ceramide polar group leads to a different electron density and a different electrostatic potential but, surprisingly, not a different overall "dipole potential," when ceramide is compared to sphingomyelin.

Ceramides↗