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At least 1,189 records · Page 66Linked to original sources
PubMed2006

Protein under pressure: molecular dynamics simulation of the arc repressor.

Experimental nuclear magnetic resonance results for the Arc Repressor have shown that this dimeric protein dissociates into a molten globule at high pressure. This structural change is accompanied by a modification of the hydrogen-bonding pattern of the intermolecular beta-sheet: it changes its character from intermolecular to intramolecular with respect to the two monomers. Molecular dynamics simulations of the Arc Repressor, as a monomer and a dimer, at elevated pressure have been performed with the aim to study this hypothesis and to identify the major structural and dynamical changes of the protein under such conditions. The monomer appears less stable than the dimer. However, the complete dissociation has not been seen because of the long timescale needed to observe this phenomenon. In fact, the protein structure altered very little when increasing the pressure. It became slightly compressed and the dynamics of the side-chains and the unfolding process slowed down. Increasing both, temperature and pressure, a tendency of conversion of intermolecular into intramolecular hydrogen bonds in the beta-sheet region has been detected, supporting the mentioned hypothesis. Also, the onset of denaturation of the separated chains was observed.

Amino Acid Sequence↗
PubMed2002

Effect of a neutralized phosphate backbone on the minor groove of B-DNA: molecular dynamics simulation studies.

Alternative models have been presented to provide explanations for the sequence-dependent variation of the DNA minor groove width. In a structural model groove narrowing in A-tracts results from direct, short-range interactions among DNA bases. In an electrostatic model, the narrow minor groove of A-tracts is proposed to respond to sequence-dependent localization of water and cations. Molecular dynamics simulations on partially methylphosphonate substituted helical chains of d(TATAGGCCTATA) and d(CGCGAATTCGCG) duplexes have been carried out to help evaluate the effects of neutralizing DNA phosphate groups on the minor groove width. The results show that the time-average minor groove width of the GGCC duplex becomes significantly more narrow on neutralizing the phosphate backbone with methylphosphonates. The minor groove of the AATT sequence is normally narrow and the methylphosphonate substitutions have a smaller but measurable affect on this sequence. These results and models provide a system that can be tested by experiment and they support the hypothesis that the electrostatic environment around the minor groove affects the groove width in a sequence-dependent dynamic and time-average manner.

Base Sequence↗
PubMed2003

Molecular dynamics simulation of protein folding by essential dynamics sampling: folding landscape of horse heart cytochrome c.

A new method for simulating the folding process of a protein is reported. The method is based on the essential dynamics sampling technique. In essential dynamics sampling, a usual molecular dynamics simulation is performed, but only those steps, not increasing the distance from a target structure, are accepted. The distance is calculated in a configurational subspace defined by a set of generalized coordinates obtained by an essential dynamics analysis of an equilibrated trajectory. The method was applied to the folding process of horse heart cytochrome c, a protein with approximately 3000 degrees of freedom. Starting from structures, with a root-mean-square deviation of approximately 20 A from the crystal structure, the correct folding was obtained, by utilizing only 106 generalized degrees of freedom, chosen among those accounting for the backbone carbon atoms motions, hence not containing any information on the side chains. The folding pathways found are in agreement with experimental data on the same molecule.

Algorithms↗
PubMed1998

Conformations of nicked and gapped DNA structures by NMR and molecular dynamic simulations in water.

We have analyzed and compared the molecular structures and dynamics of DNA duplexes containing a nick or a gap of one nucleotide where the base in front of the gap is a guanine. The continuous strand has the sequence 5'(CAGAGTCXCTGGCTC) where the residue X is absent for the nick, 14-mer, and where it is a G residue for the gap. Duplexes were formed with the two corresponding 7-mers. Neither of these is phosphorylated adjacent at the nick site, but it is a good model for a single strand break. For the nick structure, the quantitative NMR data show that the global conformation is very close to canonical B-form DNA, but it displays enhanced local flexibility. For the gap structure, we observe only one species in which the extra G is well stacked into the helix. The two half-helices around this residue also show a B-form conformation. As with the nick duplex, the adjacent G imino protons show enhanced exchange with solvent. The gap does not close completely. Using distance constraints, MD calculations show that the nick conformation is very close to a duplex with no lesion but is indeed more flexible in the central part. The gapped structure shows two families of conformations. One is close to B-DNA, the other is significantly kinked at the gap which reduces the size of the cavity. We observe a spine of hydration within the cavities, similar, but of different geometry in the two cases.

Base Composition↗
PubMed1997

Molecular dynamics simulations of Leu-enkephalin in water and DMSO.

The structure of Leu-enkephalin (L-Enk) and Met-enkephalin (M-Enk) have frequently been studied, in particular by nuclear magnetic resonance spectroscopy. After more than 20 years of research, it was concluded that enkephalins have no preferred structure in aqueous solution, but that they may have in other solvents. We have performed molecular dynamics simulations of zwitterionic L-Enk in water, and zwitterionic as well as neutral L-Enk dimethyl sulfoxide (DMSO). In water the peptide is very flexible, although there seems to be a preference for compact conformations. In DMSO, the peptide forms a clear salt bridge in the zwitterionic form, but has no preferred conformation in the neutral form. This difference in conformation may provide an explanation for measurements in DMSO in which multiple conformations were found to exist. In this paper we introduce a new formulation for a dihedral angle autocorrelation function, and apply it to study side-chain dynamics in L-Enk. We find that the side-chain dynamics of the large Tyr and Phe residues cannot be adequately sampled in 2.0-ns simulations, while this does seem to be possible for the smaller Leu side chain.

Dimethyl Sulfoxide↗
PubMed2001

Statics and dynamics of ethane molecules in AlPO(4)-5: a molecular dynamics simulation study.

From an experimental perspective, there has been disagreement among researchers on whether ethane would display single-file or normal diffusive behavior in the channels of AlPO(4)-5. Pulsed field gradient nuclear magnetic resonance measurements implied single-file diffusion, while quasielastic neutron scattering showed normal diffusion. In this paper we present the results of extensive classical molecular dynamics simulations of the diffusion of ethane molecules adsorbed in AlPO(4)-5. Our aim is to provide microscopic details of the static and dynamic properties of the adsorbed molecules in order to verify whether the conditions for the single-file regime can be achieved in a nondefective AlPO(4)-5 crystal structure.

Journal Article↗
PubMed2002

Dislocation processes in the deformation of nanocrystalline aluminium by molecular-dynamics simulation.

The mechanical behaviour of nanocrystalline materials (that is, polycrystals with a grain size of less than 100 nm) remains controversial. Although it is commonly accepted that the intrinsic deformation behaviour of these materials arises from the interplay between dislocation and grain-boundary processes, little is known about the specific deformation mechanisms. Here we use large-scale molecular-dynamics simulations to elucidate this intricate interplay during room-temperature plastic deformation of model nanocrystalline Al microstructures. We demonstrate that, in contrast to coarse-grained Al, mechanical twinning may play an important role in the deformation behaviour of nanocrystalline Al. Our results illustrate that this type of simulation has now advanced to a level where it provides a powerful new tool for elucidating and quantifying--in a degree of detail not possible experimentally--the atomic-level mechanisms controlling the complex dislocation and grain-boundary processes in heavily deformed materials with a submicrometre grain size.

Journal Article↗
PubMed2004

Conformation of prion protein repeat peptides probed by FRET measurements and molecular dynamics simulations.

We report the combined use of steady-state fluorescence resonance energy transfer (FRET) experiments and molecular dynamics (MD) simulations to investigate conformational distributions of the prion protein (PrP) repeat system. FRET was used for the first time to probe the distance, as a function of temperature and pH, between a donor Trp residue and an acceptor dansyl group attached to the N-terminus in seven model peptides containing one to three repeats of the second decarepeat of PrP from marsupial possum (PHPGGSNWGQ)nG, and one and two human PrP consensus octarepeats (PHGGGWGQ)nG. In multirepeat peptides, single-Trp mutants were made by replacing other Trp(s) with Phe. As previous work has shown PrP repeats do not adopt a single preferred stable conformation, the FRET values are averages reflecting heterogeneity in the donor-acceptor distances. The T-dependence of the conformational distributions, and derived average dansyl-Trp distances, were obtained directly from MD simulation of the marsupial dansyl-PHPGGSNWGQG peptide. The results show excellent agreement between the FRET and MD T-dependent distances, and demonstrate the remarkable sensitivity and reproducibility of the FRET method in this first-time use for a set of disordered peptides. Based on the results, we propose a model involving cation-pi or pi-pi His-Trp interactions to explain the T- (5-85 degrees C) and pH- (6.0, 7.2) dependencies on distance, with HW i, i + 4 or WH i, i + 4 separations in sequence being more stable than HW i, i + 6 or WH i, i + 6 separations. The model has peptides adopting loosely folded conformations, with dansyl-Trp distances very much less than estimates for fully extended conformations, for example, approximately 16 vs. 33, approximately 21 vs. 69, and approximately 22 vs. 106 A for 1-3 decarepeats, and approximately 14 vs. 25 and approximately 19 vs. 54 A for 1-2 octarepeats, respectively. The study demonstrates the usefulness of combining FRET with MD, a combination reported only once previously. Initial "mapping" of the conformational distribution of flexible peptides by simulation can assist in designing and interpreting experiments using steady-state intensity methods, and indicating how time-resolved or anisotropy methods might be used.

Amino Acid Sequence↗
PubMed2005

Elongation of ordered peptide aggregate of an amyloidogenic hexapeptide NFGAIL observed in molecular dynamics simulations with explicit solvent.

The mechanisms by which amyloidogenic peptides and proteins form soluble toxic oligomers remain elusive. We have studied the formation of partially ordered tetramers and well-ordered octamers of an amyloidogenic hexapeptide NFGAIL (residues 22-27 of the human islet amyloid polypeptide) in our previous work. Continuing the effort, we here probe the beta-sheet elongation process by a combined total of 2.0 micros molecular dynamics simulations with explicit solvent. In a set of 10 simulations with the peptides restrained to the extended conformation, we observed that the main growth mode was elongation along the beta-sheet hydrogen bonds through primarily a two-stage process. Driven by hydrophobic forces, the peptides initially attached to the surface of the ordered oligomer, moved quickly to the beta-sheet edges, and formed stable beta-sheet hydrogen bonds. Addition of peptides to the existing oligomer notably improved the order of the peptide aggregate in which labile outer layer beta-sheets were stabilized, which provides good templates for further elongation. These simulations suggested that elongation along the beta-sheet hydrogen bonds occurs at the intermediate stage when low-weight oligomers start to form. We did not observe significant preference toward either parallel or antiparallel beta-sheets at the elongation stage for this peptide. In another set of 10 unrestrained simulations, the dominant growth mode was disordered aggregation. Taken together, these results offered a glimpse at the molecular events leading to the formation of ordered and disordered low-weight oligomers.

Amyloid↗
PubMed2000

Replica-exchange molecular dynamics simulation for supercooled liquids

We investigate to what extend the replica-exchange Monte Carlo method is able to equilibrate a simple liquid in its supercooled state. We find that this method does indeed allow us to generate accurately the canonical distribution function even at low temperatures and that its efficiency is about 10-100 times higher than the usual canonical molecular dynamics simulation.

Journal Article↗
PubMed2004

Structural insights by molecular dynamics simulations into specificity of the major human AP endonuclease toward the benzene-derived DNA adduct, pBQ-C.

The benzetheno exocyclic adduct of the cytosine (C) base (pBQ-C) is a product of reaction between DNA and a stable metabolite of the human carcinogen benzene, p-benzoquinone (pBQ). We reported previously that the pBQ-C-containing duplex is a substrate for the human AP endonuclease (APE1), an enzyme that cleaves an apurinic/apyrimidinic (AP) site from double stranded DNA. In this work, using molecular dynamics simulation (MD), we provided a structural explanation for the recognition of the pBQ-C adduct by APE1. Molecular modeling of the DNA duplex containing pBQ-C revealed significant displacement of this adduct toward the major groove with pronounced kinking of the DNA at the lesion site, which could serve as a structural element recognized by the APE1 enzyme. Using 3 ns MD it was shown that the position of the pBQ-C adduct is stabilized by two hydrogen bonds formed between the adduct and the active site amino acids Asp 189 and Ala 175. The pBQ-C/APE1 complex, generated by MD, has a similar hydrogen bond network between target phosphodiester bond at the pBQ-C site and key amino acids at the active site, as in the crystallographically determined APE1 complexed with an AP site-containing DNA duplex. The position of the adduct at the enzyme active site, together with the hydrogen bond network, suggests a similar reaction mechanism for phosphodiester bond cleavage of oligonucleotide containing pBQ-C as reported for the AP site.

Base Sequence↗
PubMed1999

Molecular dynamics simulations of the hyperthermophilic protein sac7d from Sulfolobus acidocaldarius: contribution of salt bridges to thermostability.

Hyperthermophilic proteins often possess an increased number of surface salt bridges compared with their mesophilic homologues. However, salt bridges are generally thought to be of minor importance in protein stability at room temperature. In an effort to understand why this may no longer be true at elevated temperatures, we performed molecular dynamics simulations of the hyperthermophilic protein Sac7d at 300 K, 360 K, and 550 K. The three trajectories are stable on the nanosecond timescale, as evidenced by the analysis of several time-resolved properties. The simulations at 300 K and (to a lesser extent) 360 K are also compatible with nuclear Overhauser effect-derived distances. Raising the temperature from 300 K to 360 K results in a less favourable protein-solvent interaction energy, and a more favourable intraprotein interaction energy. Both effects are almost exclusively electrostatic in nature and dominated by contributions due to charged side-chains. The reduced solvation is due to a loss of spatial and orientational structure of water around charged side-chains, which is a consequence of the increased thermal motion in the solvent. The favourable change in the intraprotein Coulombic interaction energy is essentially due to the tightening of salt bridges. Assuming that charged side-chains are on average more distant from one another in the unfolded state than in the folded state, it follows that salt bridges may contribute to protein stability at elevated temperatures because (i) the solvation free energy of charged side-chains is more adversely affected in the unfolded state than in the folded state by an increase in temperature, and (ii) due to the tightening of salt bridges, unfolding implies a larger unfavourable increase in the intraprotein Coulombic energy at higher temperature. Possible causes for the unexpected stability of the protein at 550 K are also discussed.

Archaeal Proteins↗
PubMed2003

Interdomain dynamics and ligand binding: molecular dynamics simulations of glutamine binding protein.

Periplasmic binding proteins from Gram-negative bacteria possess a common architecture, comprised of two domains linked by a hinge region, a fold which they share with the neurotransmitter-binding domains of ionotropic glutamate receptors (GluRs). Glutamine-binding protein (GlnBP) is one such protein, whose crystal structure has been solved in both open and closed forms. Multi-nanosecond molecular dynamics simulations have been used to explore motions about the hinge region and how they are altered by ligand binding. Glutamine binding is seen to significantly reduce inter-domain motions about the hinge region. Essential dynamics analysis of inter-domain motion revealed the presence of both hinge-bending and twisting motions, as has been reported for a related sugar-binding protein. Significantly, the influence of the ligand on GlnBP dynamics is similar to that previously observed in simulations of rat glutamate receptor (GluR2) ligand-binding domain. The essential dynamics analysis of GlnBP also revealed a third class of motion which suggests a mechanism for signal transmission in GluRs.

Binding Sites↗
PubMed2006

Impact of the mutation A21G (Flemish variant) on Alzheimer's beta-amyloid dimers by molecular dynamics simulations.

Soluble oligomers of the amyloid beta-protein (Abeta) are linked to Alzheimer's disease. Irrespective of the nature of the nucleus before fibril growth, dimers are essential species in Abeta assembly, but their transient character has precluded, thus far, high-resolution structure determination. We have investigated the effects of the point mutation A21G on Abeta dimers by performing high temperature all-atom molecular dynamics simulations of Abeta(40), Abeta(42), and their Flemish variants (A21G) starting from their fibrillar conformations. Abeta dimers are found in equilibrium between various topologies, and the absence of common structural features shared by the four species makes problematic the design of a unique inhibitor for blocking dimers. We also show that the impact of the point mutation A21G on Abeta structure and dynamics varies from Abeta(40) to Abeta(42). Finally, we provide a possible structural explanation for the reduced aggregation rate of Abeta fibrils containing the Flemish disease-causing mutation.

Amyloid beta-Peptides↗
PubMed2006

Drug resistance of HIV-1 protease against JE-2147: I47V mutation investigated by molecular dynamics simulation.

Anti-retroviral therapies for acquired immunodeficiency syndrome (AIDS) patients are at risk because of drug resistance that has been identified with a number of currently marketed drugs. HIV-1 protease (HIV-pr), a well-validated AIDS therapeutic target, undergoes various mutations leading to resistance such existing drugs. However, the molecular basis of drug resistance of HIV-pr is still not fully understood. JE-2147, an experimental inhibitor of HIV-pr, shows a resistance profile different from that of known drugs. Noteworthy, it is less susceptible to several common mutations, but it is still susceptible to a few mutations, including I47V which appears to be specific for JE-2147. In this work, the molecular details of the effect of I47V mutation is investigated using molecular dynamics simulation. Four simulations of apo and complexed proteins in their wild type (WT) and mutant forms have been performed. It is found that the mobility of the side chain of mutant Val47 in chain B of HIV-pr about the inhibitor increases significantly relative to WT Ile47 in chain B. This is due to loss of optimized packing of the inhibitor to the residue 47 in chain B of the mutant when compared with WT enzyme. There also are subtle differences in motion involving residues in the flap region, which are more prominent in the apo form.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Atomistic modeling of crystal-to-amorphous transition and associated kinetics in the Ni-Nb system by molecular dynamics simulations.

With the aid of ab initio calculations, an n-body potential of the Ni-Nb system is constructed under the Finnis-Sinclair formalism and the constructed potential is capable of not only reproducing some static physical properties but also revealing the atomistic mechanism of crystal-to-amorphous transition and associated kinetics. With application of the constructed potential, molecular dynamics simulations using the solid solution models reveal that the physical origin of crystal-to-amorphous transition is the crystalline lattice collapsing while the solute atoms are exceeding the critical solid solubilities, which are determined to be 19 atom % Ni and 13 atom % Nb for the Nb- and Ni-based solid solutions, respectively. It follows that an intrinsic glass-forming ability of the Ni-Nb system is within 19-87 atom % Ni, which matches well with that observed in ion beam mixing/solid-state reaction experiments. Simulations using the Nb/Ni/Nb (Ni/Nb/Ni) sandwich models indicate that the amorphous layer at the interfaces grows in a layer-by-layer mode and that, upon dissolving solute atoms, the Ni lattice approaches and exceeds its critical solid solubility faster than the Nb lattice, revealing an asymmetric behavior in growth kinetics. Moreover, an energy diagram is obtained by computing the energetic sequence of the Ni(x)Nb(100)(-)(x) alloy in fcc, bcc, and amorphous structures, respectively, over the entire composition range, and the diagram could serve as a guide for predicting the metastable alloy formation in the Ni-Nb system.

Journal Article↗
PubMed2005

Molecular dynamics simulations of matrix deposition. III. Site structure analysis for porphycene in argon and xenon.

Porphycene (1) and porphyrin (2), two constitutional isomers, reveal completely different electronic spectral patterns in argon and xenon matrices. For the former the spectra recorded in the two solidified gases resemble each other, whereas for the latter they are completely different. This difference can be rationalized by molecular-dynamics simulations of the structure of the microenvironment carried out for the two chromophores embedded in argon and xenon hosts. For 1, the structure of the main substitutional site is the same for Ar and Xe and consists of a hexagonal cavity obtained by removing seven host atoms from the [111] crystallographic plane. An analogous structure is obtained for 2 in xenon. However, in argon the porphyrin chromophore environment is shared between several different sites, with the number of replaced host atoms ranging from seven to ten. These results demonstrate that a relatively minor structural alternation may lead to major changes in the spectral pattern of molecules embedded in rare-gas cryogenic matrices.

Journal Article↗
PubMed2005

Thermal vitrification in suspensions of soft colloids: molecular dynamics simulations and comparison with experiments.

Dense suspensions of multiarm star polymers are known to develop liquidlike microstructure, which has been attributed to the similarities between high functionality stars and colloidal particles interacting via soft, long ranged potentials. Recent experimental studies reported a counterintuitive solidification of suspensions with f=128 , upon increase of the temperature in marginal solvents. We present our results from molecular dynamics simulations of dense suspensions of multiarm star polymers. Star polymers are modeled as "soft spheres" interacting via a theoretically developed potential of mean field. Our results show a transition towards a "glassy" state at a temperature very close to the one reported experimentally. The features of the transition are consistent with those of ideal glass transitions, as described by ideal mode coupling theory. Furthermore, our findings illustrate the road to vitrification for these soft-colloidal suspensions. Higher temperatures result in arm expansion that causes jamming and more than compensates for faster short time, temperature induced kinetics.

Journal Article↗