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At least 1,747 records · Page 97Linked to original sources
PubMed1998

Conformational studies of human islet amyloid peptide using molecular dynamics and simulated annealing methods.

Molecular dynamics simulations and simulated annealing in vacuum, model aqueous solution, and simulated membrane were used to analyze the conformational preferences of a segment spanning 20-29 residues of human islet amyloid polypeptide, [referred to as IAPPH (20-29)]. Molecular dynamics simulations were conducted at 300 K on IAPPH (20-29). The minimum energy conformers obtained in model aqueous solution and vacuum exhibited similar structures. Even in the absence of any constraints on peptide bonds, trans conformation was preferred consistently by all the peptide bonds. Analysis of the minimum energy conformers indicated that IAPPH (20-29) showed a strong preference for turn structures in all the environments. These turn structures were stabilized by the formation of hydrogen bonds between the backbone amide and carbonyl groups. A good agreement was found between the results obtained from the molecular dynamics simulation and solid-state nmr experimental studies.

Amino Acid Sequence↗
PubMed2005

Molecular dynamics simulations of the cytolytic toxin Cyt1A in solution.

Cytolytic toxin Cyt1A from Bacillus thuringiensis var. israelensis is used as an environmentally friendly insecticide, but its mode of action has not been clearly established. One main obstacle seems to be the lack of the experimentally determined structure of the toxin. As a first step in computer simulations of Cyt1A, in this paper, a three-dimensional molecular structure of Cyt1A in solution was generated by homology modeling, potential energy minimization and molecular dynamics. Regions of the toxin molecule that manifest increased conformational flexibility--and thus are likely to participate in the initial membrane binding and conformational changes--were then identified. Finally, the simulated structure was used to study the effect of a single amino-acid mutation that is known to abrogate the toxicity of Cyt1A in vivo.

Amino Acid Sequence↗
PubMed2006

Molecular dynamics simulation of the cybotactic region in gas-expanded methanol-carbon dioxide and acetone-carbon dioxide mixtures.

Local solvation and transport effects in gas-expanded liquids (GXLs) are reported based on molecular simulation. GXLs were found to exhibit local density enhancements similar to those seen in supercritical fluids, although less dramatic. This approach was used as an alternative to a multiphase atomistic model for these mixtures by utilizing experimental results to describe the necessary fixed conditions for a locally (quasi-) stable molecular dynamics model of the (single) GXL phase. The local anisotropic pair correlation function, orientational correlation functions, and diffusion rates are reported for two systems: CO2-expanded methanol and CO2-expanded acetone at 298 K and pressures up to 6 MPa.

Acetone↗
PubMed1998

Conformational changes of neuromedin B and delta sleep-inducing peptide induced by their interaction with lipid membranes as revealed by spectroscopic techniques and molecular dynamics simulation.

Static and dynamic spectroscopic properties of the tryptophanil emission in conjunction with circular dichroism (CD) spectroscopy and molecular dynamics are used to investigate the interactions of the neuropeptide neuromedin B (NMB) and the membrane-permeable delta sleep-inducing peptide (DSIP) with the membrane lipid phase. Our data indicate that in solution both peptides exist in energetically equivalent conformations, whereas in the presence of the membrane specific conformational states are stabilized. By changing from the aqueous to the lipid phase, the static and the dynamic fluorescence properties of the NMB's tryptophan residue are clearly affected: the fluorescence steady-state spectrum as well as the resolved fluorescence decay-associated spectra (DAS) are shifted to the blue with a significant increase of the fluorescence intensity of the second lifetime component (tau 2-DAS). On the other hand, in the lipid environment the same parameters of DSIP are negligibly affected as compared to the aqueous buffer. The CD and molecular dynamics analyses are consistent with these results and indicate that, while NMB assumes a helix-like conformation with the tryptophan residue in the apolar surface, DSIP adopts a globule-like structure with the indole ring that is surface-exposed. As previously found for neuromedin C (Polverini, E., Neyroz, P., Fariselli, P., Casadio, R., and Masotti, L., Biochem. Biophys. Res. Commun. 214, 663-668, 1995), for NMB the stabilized "lipophilic" structure also may favor the correct peptide-receptor contact and recognition. For DSIP, the lipid-stabilized conformation does not support an amphiphilic structure-driven peptide-membrane interaction and suggests a hydrophobicity-driven diffusion across the bilayer.

Circular Dichroism↗
PubMed1996

Internal mobility of the oligonucleotide duplexes d(TCGCG)2 and d(CGCGCG)2 in aqueous solution from molecular dynamics simulations.

In this paper we present longitudinal relaxation times, order parameters and effective correlation times for the base and sugar carbons in both strands of the oglionucleotide duplexes d(TCGCG)2 and d(CGCGCG)2, as calculated from 400 ps molecular dynamics trajectories in aqueous solution. The model-free approach (Lipari and Szabo, 1982) was used to determine the amplitudes and time scales of the internal motion. Comparisons were made with NMR relaxation measurements (Borer et al., 1994). The order parameters could acceptably be reproduced, and the effective correlation times were found to be lower than the experimental estimates. Reasonable T1 relaxation times were obtained in comparison with experiment for the nonterminal nucleosides. The T1 relaxation times were found to depend mainly on the order parameters and overall rotational correlation time.

Base Sequence↗
PubMed1997

A molecular dynamics simulation study of segment B1 of protein G.

The immunoglobulin binding protein, segment B1 of protein G, has been studied experimentally as a paradigm for protein folding. This protein consists of 56 residues, includes both beta sheet and alpha helix and contains neither disulfide bonds nor proline residues. We report an all-atom molecular dynamics study of the native manifold of the protein in explicit solvent. A 2-ns simulation starting from the nuclear magnetic resonance (NMR) structure and a 1-ns control simulation starting from the x-ray structure were performed. The difference between average structures calculated over the equilibrium portion of trajectories is smaller than the difference between their starting conformations. These simulation averages are structurally similar to the x-ray structure and differ in systematic ways from the NMR-determined structure. Partitioning of the fluctuations into fast (< 20 ps) and slow (> 20 ps) components indicates that the beta sheet displays greater long-time mobility than does the alpha helix. Clore and Gronenborn [J. Mol. Biol. 223:853-856, 1992] detected two long-residence water molecules by NMR in a solution structure of segment B1 of protein G. Both molecules were found in the fully exposed regions and were proposed to be stabilized by bifurcated hydrogen bonds to the protein backbone. One of these long-residence water molecules, found near an exposed loop region, is identified in both of our simulations, and is seen to be involved in the formation of a stable water-mediated hydrogen bond bridge. The second water molecule, located near the middle of the alpha helix, is not seen with an exceptional residence time in either as a result of the conformation being closer to the x-ray structure in this region of the protein.

Crystallography, X-Ray↗
PubMed2000

Molecular dynamics simulation of four-alpha-helix bundles that bind the anesthetic halothane.

The mutation of a single leucine residue (L38) to methionine (M) is known experimentally to significantly increase the affinity of the synthetic four-alpha-helix bundle (Aalpha(2))(2) for the anesthetic halothane. We present a molecular dynamics study of the mutant (Aalpha(2)-L38M)(2) peptide, which consists of a dimer of 62-residue U-shaped di-alpha-helical monomers assembled in an anti topology. A comparison between the simulation results and those obtained for the native (Aalpha(2))(2) peptide indicates that the overall secondary structure of the bundle is not affected by the mutation, but that the side chains within the monomers are better packed in the mutant structure. Unlike the native peptide, binding of a single halothane molecule to the hydrophobic core of (Aalpha(2)-L38M)(2) deforms the helical nature of one monomer in a region close to the mutation site. Increased exposure of the cysteine side chain to the hydrophobic core in the mutant structure leads to the enhancement of the attractive interaction between halothane and this specific residue. Since the mutated residues are located outside the hydrophobic core the observed increased affinity for halothane appears to be an indirect effect of the mutation.

Amino Acid Sequence↗
PubMed1992

Computer graphics presentations and analysis of hydrogen bonds from molecular dynamics simulation.

To obtain better insights into the dynamic nature of hydrogen bonding, computer graphics representations were introduced as an aid for the analysis of molecular dynamics trajectories. A schematic representation of hydrogen bonding patterns is generated to reflect the frequency and the type of hydrogen bonding occurring during the simulation period. Various trajectory plots for monitoring geometrical parameters and for analyzing three-center hydrogen bonding were also generated. The methods proposed are applicable to a variety of biopolymers. In this study, hydrogen bonding in the d(G)6.d(C)6 system was examined. For the nucleic acid fragments examined, three-center hydrogen bonds can be classified as in-plane and major or minor groove types. The in-plane three-center hydrogen bond represents a stable state in which both bonds simultaneously satisfy the relaxed hydrogen bonding criteria for a measurable period. On the other hand, groove three-center hydrogen bonds behave as a transient intermediate state in a flip-flop hydrogen bonding system.

Computer Graphics↗
PubMed1996

The STATIS method: characterization of conformational states of flexible molecules from molecular dynamics simulations in solution.

STATIS, a data analysis method used when data can be expressed as matrices, seems particularly well suited to characterize the internal molecular motions and conformational states extracted from MD trajectories. We first outline this method and the "adapted STATIS" method. Applications are presented for 18-crown-6 (simulated for 2 nsec in acetonitrile solution) and for the (L30)2Cu+ catenate (stimulated for 150 psec in chloroform). STATIS should be valuable for the classification of molecular conformations and simplified visualization of MD trajectories.

Acetonitriles↗
PubMed2002

Glassy behavior of a homopolymer from molecular dynamics simulations.

We study at- and out-of-equilibrium dynamics of a single homopolymer chain at low temperature using molecular dynamics. The main quantities of interest are the average root mean square displacement of the monomers below the theta point, and the structure factor, as a function of time. The observation of these quantities show a close resemblance to those measured in structural glasses and suggest that the polymer chain in its low temperature phase is in a glassy phase, with its dynamics dominated by traps. In equilibrium, at low temperature, we observe the trapping of the monomers and a slowing down of the overall motion of the polymer as well as nonexponential relaxation of the structure factor. Out of equilibrium, at low temperatures, we compute the two-time quantities and observe breaking of ergodicity in a range of waiting times, with the onset of aging.

Biophysics↗
PubMed2005

Car-Parrinello molecular dynamics simulation of Fe 3+ (aq).

The optimized geometry and energetic properties of Fe(D2O)n 3+ clusters, with n = 4 and 6, have been studied with density-functional theory calculations and the BLYP functional, and the hydration of a single Fe 3+ ion in a periodic box with 32 water molecules at room temperature has been studied with Car-Parrinello molecular dynamics and the same functional. We have compared the results from the CPMD simulation with classical MD simulations, using a flexible SPC-based water model and the same number of water molecules, to evaluate the relative strengths and weaknesses of the two MD methods. The classical MD simulations and the CPMD simulations both give Fe-water distances in good agreement with experiment, but for the intramolecular vibrations, the classical MD yields considerably better absolute frequencies and ion-induced frequency shifts. On the other hand, the CPMD method performs considerably better than the classical MD in describing the intramolecular geometry of the water molecule in the first hydration shell and the average first shell...second shell hydrogen-bond distance. Differences between the two methods are also found with respect to the second-shell water orientations. The effect of the small box size (32 vs 512 water molecules) was evaluated by comparing results from classical simulations using different box sizes; non-negligible effects are found for the ion-water distance and the tilt angles of the water molecules in the second hydration shell and for the O-D stretching vibrational frequencies of the water molecules in the first hydration shell.

Journal Article↗
PubMed1999

On the convergence of the conformational coordinates basis set obtained by the essential dynamics analysis of proteins' molecular dynamics simulations.

In this article we present a quantitative evaluation of the convergence of the conformational coordinates of proteins, obtained by the Essential Dynamics method. Using a detailed analysis of long molecular dynamics trajectories in combination with a statistical assessment of the significance of the measured convergence, we obtained that simulations of a few hundreds of picoseconds are in general sufficient to provide a stable and statistically reliable definition of the essential and near constraints subspaces, at least within the nanoseconds time range. Proteins 1999;36:419-424.

Algorithms↗
PubMed1998

Molecular dynamics simulation of a hydrated diphytanol phosphatidylcholine lipid bilayer containing an alpha-helical bundle of four transmembrane domains of the influenza A virus M2 protein.

An alpha-helical bundle composed of four transmembrane portions of the M2 protein from the Influenza A virus has been studied in a hydrated diphytanol phosphatidylcholine bilayer using molecular dynamics (MD) calculations. Experimentally, the sequence utilized is known to aggregate as a four-helix bundle and act as a pH-gated proton-selective ion channel, which is blocked by the drug amantadine hydrochloride. In the presented simulation, the ion channel was initially set up as a parallel four-helix bundle. The all-atom simulation consisted of almost 16,000 atoms, described classically, using a forcefield from the CHARMM22 database. Bilayers with and without the bundle were shown to be stable throughout the nanosecond timescale of the MD simulation. Structural and dynamical properties of the bilayer both with and without the transmembrane protein are reported.

Computer Simulation↗
PubMed2005

Energy landscape of amyloidogenic peptide oligomerization by parallel-tempering molecular dynamics simulation: significant role of Asn ladder.

Recent evidence suggests that amyloidogenic oligomers may be the toxic species in cell cultures. Thus, it is crucial to understand their structure and oligomerization mechanism in atomistic detail. By employing tens of fast central processing units and an advanced phase-space sampling algorithm, parallel-tempering molecular dynamics, we have explored the energy landscape of amyloidogenic peptide oligomerization in explicit water. A pentapeptide, DFNKF, derived from human calcitonin and its mutant, DFAKF, was simulated with a total simulation time of approximately 500 ns. The detailed oligomerization process of a DFNKF parallel beta-sheet formation at 300 K has been characterized. The assembly of a parallel beta-sheet from the amorphous state mainly occurs via a "bottleneck" channel where the interstrand Asn-Asn stacking is the major interaction. The interactions of Asn-Asn stacking include both backbone and side-chain hydrogen bonds. The Asn-Asn interactions work like "glue" by sticking the DFNKF strands together and assist the "on-pathway" oligomerization. The Asn-Asn stacking observed here is similar to the Asn ladder commonly found in globular beta-helix proteins. A control run shows that when Asn is mutated to Ala, the stability and population of the DFAKF parallel beta-sheet is decreased. Furthermore, our in vitro mutagenesis experiments show that the ability of DFAKF peptides to form amyloid fibrils is significantly reduced, in agreement with the simulations. Knowledge of the energy landscape of oligomerization may provide hints for rational drug design, preventing amyloid-associated diseases.

Algorithms↗
PubMed2004

Accurate detection of protein:ligand binding sites using molecular dynamics simulations.

Accurate prediction of location of cavities and surface grooves in proteins is important, as these are potential sites for ligand binding. Several currently available programs for cavity detection are unable to detect cavities near the surface or surface grooves. In the present study, an optimized molecular dynamics based procedure is described for detection and quantification of interior cavities as well as surface pockets. This is based on the observation that the mobility of water in such pockets is significantly lower than that of bulk water. The algorithm efficiently detects surface grooves that are sites of protein-ligand and protein-protein interaction. The algorithm was also used to substantially improve the performance of an automated docking procedure for docking monomers of nonobligate protein-protein complexes. In addition, it was applied to predict key residues involved in the binding of the E. coli toxin CcdB with its inhibitor. Predictions were subsequently validated by mutagenesis experiments.

Algorithms↗
PubMed2003

Molecular dynamics simulation of surfactin molecules at the water-hexane interface.

The dynamics of surfactin, a lipopeptide surfactant from Bacillus subtilis, has been studied by molecular dynamics at different interfacial concentrations in a water-hexane medium reproducing a hydrophilic/hydrophobic biphasic system. The shapes and orientations of surfactin molecules, as hydrogen bonds and Ramachandran angles, have been recorded to investigate the environment effect on the molecular structure. We demonstrate that the peptidic backbone can exhibit a large flexibility and that conformational motions and structural fluctuations depend strongly on the interfacial concentration. Moreover, we have measured the surface activity of this biosurfactant by computing the interfacial tension and lateral and rotational diffusion coefficients.

Algorithms↗
PubMed2001

Structural determinants of MscL gating studied by molecular dynamics simulations.

The mechanosensitive channel of large conductance (MscL) in prokaryotes plays a crucial role in exocytosis as well as in the response to osmotic downshock. The channel can be gated by tension in the membrane bilayer. The determination of functionally important residues in MscL, patch-clamp studies of pressure-conductance relationships, and the recently elucidated crystal structure of MscL from Mycobacterium tuberculosis have guided the search for the mechanism of MscL gating. Here, we present a molecular dynamics study of the MscL protein embedded in a fully hydrated POPC bilayer. Simulations totaling 3 ns in length were carried out under conditions of constant temperature and pressure using periodic boundary conditions and full electrostatics. The protein remained in the closed state corresponding to the crystal structure, as evidenced by its impermeability to water. Analysis of equilibrium fluctuations showed that the protein was least mobile in the narrowest part of the channel. The gating process was investigated through simulations of the bare protein under conditions of constant surface tension. Under a range of conditions, the transmembrane helices flattened as the pore widened. Implications for the gating mechanism in light of these and experimental results are discussed.

Computer Simulation↗