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At least 109 records · Page 6Linked to original sources
PubMed2005

Conformational folding of xyloglucan side chains in aqueous solution from molecular dynamics simulation.

Molecular dynamics simulation was carried out on xyloglucan with explicit water molecules to investigate the folding mechanism of side chains onto a main chain in aqueous solution. The model xyloglucan was composed of 12 beta-D-glucopyranoses as a main chain substituted with six galactoses and three xyloses as side chains. Two conditions were set for the ribbon-like main chain; one is restricted to be 'flat' and the other is without restriction. The free main chain of xyloglucan has a 'twisted' conformation as the major one. Conformational folding of side chains onto the main chain was analyzed with dihedral angles at each glycosidic linkage. In a 5-ns calculation, the xyloglucan has a tendency to contract in both the restricted and the free systems, but the mode of contraction is different. Side chains tend to stick onto the flat surface of the main chain in the restricted system, while they do not tightly do so in the free one; instead the main chain takes a twisted and sometimes embowed conformation. This result indicates that the main chain has greater attractive forces to bind side chains when it is flat, while it loses the ability as it is twisted.

Carbohydrate Conformation↗
PubMed2004

Distribution of pentachlorophenol in phospholipid bilayers: a molecular dynamics study.

Molecular dynamics computer simulations of pentachlorophenol (PCP) in palmitoyl-oleoyl-phosphatidylethanolamine and palmitoyl-oleoyl-phosphatidylcholine lipid bilayers were carried out to investigate the distribution of PCP and the effects of PCP on the phospholipid bilayer structure. Starting from two extreme starting structures, including PCP molecules outside the lipid bilayer, the PCP distribution converges in simulations of up to 50 ns. PCP preferentially occupies the region between the carbonyl groups and the double bonds in the acyl chains of the lipid molecules in the bilayer. In the presence of PCP, the lipid chain order increases somewhat in both chains, and the average tilt angle of the lipid chains decreases. The increase in the lipid chain order in the presence of PCP was more pronounced in the palmitoyl-oleoyl-phosphatidylcholine bilayer compared to the palmitoyl-oleoyl-phosphatidylethanolamine bilayer. The number of trans conformations of lipid chain dihedrals does not change significantly. PCP aligns parallel to the alkyl chains of the lipid to optimize the packing in the dense ordered chain region of the bilayer. The hydroxyl group of PCP forms hydrogen bonds with both water and lipid oxygen atoms in the water/lipid interface region.

Computer Simulation↗
PubMed1997

Conformational analysis of six- and twelve-membered ring compounds by molecular dynamics.

A molecular dynamics (MD)-based conformational analysis has been performed on a number of cycloalkanes in order to demonstrate the reliability and generality of MD as a tool for conformational analysis. MD simulations on cyclohexane and a series of methyl-substituted cyclohexanes were performed at temperatures between 400 and 1200 K. Depending on the simulation temperature, different types of interconversions (twist-boat-twist-boat, twist-boat-chair and chair-chair) could be observed, and the MD simulations demonstrated the expected correlation between simulation temperature and ring inversion barriers. A series of methyl-substituted 1,3-dioxanes were investigated at 1000 K, and the number of chair-chair interconversions could be quantitatively correlated to the experimentally determined ring inversion barrier. Similarly, the distribution of sampled minimum-energy conformations correlated with the energy-derived Boltzmann distribution. The macrocyclic ring system cyclododecane was subjected to an MD simulation at 1000 K and 71 different conformations could be sampled. These conformations were compared with the results of previously reported conformational analyses using stochastic search methods, and the MD method provided 19 out of the 20 most stable conformations found in the MM2 force field. Finally, the general performance of the MD method for conformational analysis is discussed.

Calorimetry↗
PubMed2006

Similarity and difference in the unfolding of thermophilic and mesophilic cold shock proteins studied by molecular dynamics simulations.

Molecular dynamics simulations were performed to unfold a homologous pair of thermophilic and mesophilic cold shock proteins at high temperatures. The two proteins differ in just 11 of 66 residues and have very similar structures with a closed five-stranded antiparallel beta-barrel. A long flexible loop connects the N-terminal side of the barrel, formed by three strands (beta1-beta3), with the C-terminal side, formed by two strands (beta4-beta5). The two proteins were found to follow the same unfolding pathway, but with the thermophilic protein showing much slower unfolding. Unfolding started with the melting of C-terminal strands, leading to exposure of the hydrophobic core. Subsequent melting of beta3 and the beta-hairpin formed by the first two strands then resulted in unfolding of the whole protein. The slower unfolding of the thermophilic protein could be attributed to ion pair formation of Arg-3 with Glu-46, Glu-21, and the C-terminal. These ion pairs were also found to be important for the difference in folding stability between the pair of proteins. Thus electrostatic interactions appear to play similar roles in the difference in folding stability and kinetics between the pair of proteins.

Amino Acid Sequence↗
PubMed1992

Cholesterol in model membranes. A molecular dynamics simulation.

Molecular dynamics simulations of a model membrane with inserted cholesterol molecules have been performed to study the perturbing influence of cholesterol. In the fluid phase of a lipid bilayer at 13 mol% concentration of cholesterol, local ordering of the hydrocarbon chains is induced. This perturbation decays with the distance from the cholesterol, and the effect extends 1.25 nm. It can be monitored in several ways, e.g., by an order parameter corresponding to deuterium nuclear magnetic resonance quadrupolar splittings, by the fraction of gauche bonds, or by the local bilayer thickness. At constant surface density, the local ordering is accompanied by disordering of the bulk phase, and, consequently, the net ordering effect is small. After compressing the system laterally in accordance with experimentally known surface areas, the bulk order parameters agree with those of a pure system, and the average order parameters are in accordance with experimental data. The necessity for this lateral compression is supported by calculated lateral pressures. At lower cholesterol concentration (3%), no direct perturbing effect is observed. A smaller lateral pressure than in a pure system indicates that the system with cholesterol is expected to have a smaller surface area, which would result in an increase of the order parameters, thus accounting for the experimental observations. The lack of spatial variation is, however, puzzling and may indicate a cooperative ordering effect.

Cholesterol↗
PubMed1997

Investigation of the proton release channel of bacteriorhodopsin in different intermediates of the photo cycle. A molecular dynamics study.

Molecular dynamics simulations on bacteriorhodopsin were performed starting from a conformation based on electron cryomicroscopy studies [Henderson, R., et al. (1990) J. Mol. Biol. 213, 899-929]. We examined the proton release channel in different intermediates of the bacteriorhodopsin photocycle. In the simulations of the ground state, two stable sets of conformations were observed differing in the distance of the guanidinium group of Arg82 to the Schiff base. The set of conformations in which Arg82 is located closer to the Schiff base has a lower potential energy and agrees better with experimental data than the other set. With both sets, we performed a series of simulations in which the chromophore was isomerized to different states using purposive and nonpurposive methods. The energetic consideration of the different states argues for the location of the guanidinium group of Arg82 close to the Schiff base. The results also show that no C13-C14, C14-C15 dicis conformation of the retinal occurs in the K/L-intermediate of the photocycle instead supporting the occurrence of C13-C14 cis in these intermediates. In a last series of simulations, we modeled the M-intermediate of the bacteriorhodopsin photocycle. Again, comparison to different experimental data indicates that Arg82 points toward the Schiff base. We conclude that the guanidinium group of Arg82 is located close to the Schiff base at a distance of approximately 4.5 A and stays there at least up to the M-intermediate of the photocycle.

Arginine↗
PubMed2005

Characterization of the denaturation of human alpha-lactalbumin in urea by molecular dynamics simulations.

Molecular dynamics (MD) simulations were used to characterize the non-cooperative denaturation of the molten globule A-state of human alpha-lactalbumin by urea. A solvent of explicit urea and water molecules was used, corresponding to a urea concentration of approximately 6M. Three simulations were performed at temperatures of 293K, 360K and 400K, with lengths of 2 ns, 8 ns and 8 ns respectively. The results of the simulations were compared with experimental data from NMR studies of human alpha-lactalbumin and related peptides. During the simulations, hydrogen bonds were formed from the protein to both urea and water molecules as intra-protein hydrogen bonds were lost. Urea was shown to compete efficiently with water as both a hydrogen bond donor and acceptor. Radial distribution functions of water and urea around hydrophobic side chain atoms showed a significant increase in urea molecules in the solvation shell as the side chains became exposed during denaturation. A considerable portion of the native-like secondary structure persisted throughout the simulations. However, in the simulations at 360K and 400K, there were substantial changes in the packing of aromatic and other hydrophobic side chains in the protein, and many native contacts were lost. The results suggest that during the non-cooperative denaturation of the molten globule, secondary structure elements are stabilized by non-specific, non-native interactions.

Circular Dichroism↗
PubMed1990

Binding of substrate CO2 to the active site of human carbonic anhydrase II: a molecular dynamics study.

Molecular dynamics has been used to study binding of substrate CO2 to the active site of human carbonic anhydrase II. Three potential CO2 binding sites have been located. The first is at the active-site hydrophobic pocket (the catalytically productive site), where CO2 is approximately 3.5 A from the zinc ion and interacts with His-94, His-119, Val-121, Val-143, Leu-198, Thr-199, the zinc ion, and the zinc-bound hydroxide ion. The second CO2 binding site is approximately 6 A from the zinc ion, where CO2 interacts with His-64, His-94, Leu-198, Thr-200, Pro-201, Pro-202, and some active-site water molecules. The third CO2 binding site is approximately 10 A from the zinc ion, is largely solvated by water molecules, and interacts with His-64, Asn-67, and Gln-92. At these three CO2 binding sites, the CO2 molecule is highly localized (the average Zn-CO2 distance fluctuation is approximately 1 A) and favors the linear binding orientation toward the zinc ion. This linear binding orientation of CO2 and its electrostatic interaction with the zinc ion direct diffusion of CO2 toward the zinc ion and facilitate the nucleophilic attack from O of the zinc-bound OH- to C of CO2 in the productive hydrophobic binding site. Finally, the two CO2 binding sites outside the hydrophobic binding pocket, which may represent two intermediate states along the CO2 binding pathway, could play important roles as a CO2 relay.

Amino Acid Sequence↗
PubMed2001

Exploration of partially unfolded states of human alpha-lactalbumin by molecular dynamics simulation.

Molecular dynamics simulations are used to probe the properties of non-native states of the protein human alpha-lactalbumin (human alpha-LA) with a detailed atomistic model in an implicit aqueous solvent environment. To sample the conformational space, a biasing force is introduced that increases the radius of gyration relative to the native state and generates a large number of low-energy conformers that differ in terms of their root-mean-square deviation, for a given radius of gyration. The resulting structures are relaxed by unbiased simulations and used as models of the molten globule and partly denatured states of human alpha-LA, based on measured radii of gyration obtained from nuclear magnetic resonance experiments. The ensembles of structures agree in their overall properties with experimental data available for the human alpha-LA molten globule and its more denatured states. In particular, the simulation results show that the native-like fold of the alpha-domain is preserved in the molten globule. Further, a considerable proportion of the antiparallel beta-strand in the beta-domain are present. This indicates that the lack of hydrogen exchange protection found experimentally for the beta-domain is due to rearrangement of the beta-sheet involving transient populations of non-native beta-structures. The simulations also provide details concerning the ensemble of structures that contribute as the molten globule unfolds and shows, in accord with experimental data, that unfolding is not cooperative; i.e. the various structural elements do not unfold simultaneously.

Binding Sites↗
PubMed1995

Structure and fluctuations of bacteriorhodopsin in the purple membrane: a molecular dynamics study.

Molecular dynamics simulations on bacteriorhodopsin were performed starting from the model structure described by Henderson et al. The simulations were gradually improved by first treating a monomer in vacuum and then adding further monomers, lipids, and water to finally simulate a unit cell of the hexagonal lattice of the purple membrane containing a trimer and lipids and water on both sides. During all simulations, the protein structure moved away from the model structure to reach a root-mean-square (r.m.s.) deviation of 2 to 3 A. In the simulations with the trimer, the structures of the three monomers differed by about the same amount and averaging over them led to an average structure with a considerably smaller r.m.s. deviation. The best average structure obtained had an r.m.s. deviation from the model structure of 1.3 A. Fluctuations of the protein, the lipids, and water were analyzed in detail. As expected, the membrane-spanning helices of the protein fluctuate less than the peripheral loops. Unexpected, however, was the finding that the fluctuations of the protein are asymmetric with respect to the midplane of the membrane. The fluctuations of the loops and the ends of the helices on the inner side of the membrane are much stronger than on the outer side. This asymmetry is also reflected by the fluctuations for the lipids, the lipids of the inner leaflet fluctuating more strongly than those of the outer leaflet. The asymmetry was observed only in the presence of water on both sides of the membrane. On the average, nine water molecules were found inside the protein, most of them undergoing exchange with external water.

Amino Acid Sequence↗
PubMed2003

Effects of a carane derivative local anesthetic on a phospholipid bilayer studied by molecular dynamics simulation.

Molecular dynamics (MD) simulations of two hydrated palmitoyloleoylphosphatidylcholine (POPC) bilayers each containing eight carane derivative (KP-23) local anesthetic (LA) molecules in neutral (POPC-LA) or protonated (POPC-LAH) forms were carried out to investigate the effect of KP-23 and its protonation on the bilayer. 3-ns trajectories were used for analyses. A pure POPC bilayer was employed as a reference system. In both POPC-LA and POPC-LAH systems a few KP-23 molecules intercalated into the bilayer and moved near the bilayer/water interface. They were located on the hydrophobic core side of the interface in the POPC-LA bilayer, but on the water phase side in the POPC-LAH bilayer. The order of the POPC chains was higher in the POPC-LA bilayer than in the pure POPC bilayer and was lower in the POPC-LAH bilayer. Interactions between polar groups of KP-23 and POPC or water were responsible for a lower hydration of POPC headgroups in POPC bilayers containing KP-23 than in the pure POPC bilayer. KP-23 molecules were found to form aggregates both in POPC-LA and POPC-LAH bilayers. Due to higher amphiphilicity of LAH, the LAH aggregate was more micelle-like and larger than the LA one. The results demonstrate the rapid timescales of the initial processes that take place at and near the bilayer interface as well as details of the atomic level interactions between local anesthetic and the lipid matrix of a cell membrane.

Anesthetics, Local↗
PubMed1998

Lipid properties and the orientation of aromatic residues in OmpF, influenza M2, and alamethicin systems: molecular dynamics simulations.

Molecular dynamics simulations allow a direct study of the structure and dynamics of membrane proteins and lipids. We describe the behavior of aromatic residues and lipid properties in POPE and POPC bilayer models with the Escherichia coli OmpF trimer, single alamethicin and Influenza M2 helices, 4-helix M2 bundles, and two alamethicin 6-helix channel models. The total simulation time is over 24 ns, of systems containing solvent, protein, and between 104 and 318 lipids. Various types of adjustment between lipids and proteins occur, depending on the size of the protein and the degree of hydrophobic mismatch between lipid and protein. Single helices cause little measurable effect on nearby lipids whereas the 4-helix bundles, 6-helix channel models, and OmpF cause a significant lowering of order parameters in nearby lipid chains, an increased difference between odd and even chain dihedrals in the magnitude of the trans dihedral fractions and dihedral transition rates, and in most cases a decreased gauche population and a decrease in bilayer thickness. An increased tilt of the lipid chains near the proteins can account for most of the observed decrease in order parameters. The orientation of tryptophans and tyrosines on the outside of the proteins is determined by packing at the protein exterior and non-specific hydrogen bonding with lipids and solvent. The tyrosines in the broad bands that delimit the hydrophobic exterior of OmpF show little change in orientation over one nanosecond. Their rings are oriented predominantly perpendicular to the bilayer plane, with the hydroxyl group pointing toward the lipid-water interface. Phenylalanines in OmpF, alamethicin, and Influenza M2 are more mobile and assume a variety of orientations.

Alamethicin↗
PubMed1998

Interaction of human SRY protein with DNA: a molecular dynamics study.

Molecular dynamics simulations have been conducted to study the interaction of human sex-determining region Y (hSRY) protein with DNA. For this purpose, simulations of the hSRY high mobility group (HMG) domain (hSRY-HMG) with and without its DNA target site, a DNA octamer, and the DNA octamer alone have been carried out, employing the NMR solution structure of hSRY-HMG-DNA complex as a starting model. Analyses of the simulation results demonstrated that the interaction between hSRY and DNA was hydrophobic, just a few hydrogen bonds and only one water molecule as hydrogen-bonding bridge were observed at the protein-DNA interface. These two hydrophobic cores in the hSRY-HMG domain were the physical basis of hSRY-HMG-DNA specific interaction. They not only maintained the stability of the complex, but also primarily caused the DNA deformation. The salt bridges formed between the positive-charged residues of hSRY and phosphate groups of DNA made the phosphate electroneutral, which was advantageous for the deformation of DNA and the formation of a stable complex. We predicted the structure of hSRY-HMG domain in the free state and found that both hSRY and DNA changed their conformations to achieve greater complementarity of geometries and properties during the binding process; that is, the protein increased the angle between its long and short arms to accommodate the DNA, and the DNA became bent severely to adapt to the protein, although the conformational change of DNA was more severe than that of the hSRY-HMG domain. The sequence specificity and the role of residue Met9 are also discussed.

Amino Acid Sequence↗
PubMed2005

Stability and fluctuations of amide hydrogen bonds in a bacterial cytochrome c: a molecular dynamics study.

Molecular dynamics (MD) simulations on a bacterial cytochrome c were performed to investigate the lifetime and fluctuations of backbone hydrogen bonds and to correlate these data with protection factors for hydrogen exchange measured by NMR spectroscopy (Bartalesi et al. in Biochemistry, 42:10923-10930, 2003). The MD simulations provide a consistent pattern in that long lifetimes of hydrogen bonds go along with small amplitude fluctuations. In agreement with experiments, differences in stability were found with a rather flexible N-terminal segment as compared with a more rigid C-terminal part. Protection factors of backbone hydrogen exchange correlate strongly with the number of contacts but also with hydrogen-bond occupancy, hydrogen-bond survival times, as well as the inverse of fluctuations of backbone atoms and hydrogen-bond lengths derived from MD simulation data. We observed a conformational transition in the C-terminal loop, and significant motion in the N-terminal loop, which can be interpreted as being the structural units involved in the onset of the protein unfolding process in agreement with experimental evidence on mitochondrial cytochrome c.

Amides↗
PubMed1991

Real-time interactive frequency filtering of molecular dynamics trajectories.

Molecular dynamics simulations of atomic motion in protein and nucleic acid molecules must be done on a femtosecond time-scale. Much of this rapid motion is unimportant for the slower changes that are most relevant to biological function (conformational changes, substrate binding, protein folding). The high-frequency motion makes simulations computationally expensive. More importantly, the high frequencies obscure visualization of the relevant dynamics processes. Sessions, Dauber-Osguthorpe and Osguthorpe presented a method for removing high-frequency motions from atomic co-ordinates of trajectories generated by simulation. While that study used fast Fourier methods and emphasized the use of filtering for analysis of trajectories, this communication describes a new method that makes it much easier to use frequency filtering in programs that display trajectories as a sequence of moving images. Tests of the method on systems extending from pure water to proteins and nucleic acid molecules in vacuo and in solution have demonstrated its general utility. Impressed with the power and simplicity of the new method, we wish to present it in sufficient detail to allow others to implement it themselves.

Fourier Analysis↗
PubMed2006

An investigation of the ionic and solvation patterns of dsDNG versus dsDNA by use of molecular dynamics simulations.

Molecular dynamics has been employed to analyze the counterion and water atmospheres around the deoxynucleic guanidine (DNG) duplex G(12)-C(12). These features are compared to those of DNA G(12)-C(12). The chloride counterions of cationic DNG demonstrate fewer penetrations and only fleeting residence times in the minor groove, as opposed to the multi-nanosecond visits seen by sodium ions in DNA minor grooves. The 10 ns simulations also show the differences in hydration patterns between the DNG and DNA duplexes.

Cations, Monovalent↗
PubMed2004

Effect of methylation on the stability and solvation free energy of amylose and cellulose fragments: a molecular dynamics study.

Molecular dynamics (MD) simulations were used to study the stability and solvation of amylose and cellulose fragments. The recently developed gromos carbohydrate force field was further tested by simulating maltose, cellobiose, and maltoheptaose. The MD simulations reproduced fairly well the favorable conformations of disaccharides defined by the torsional angles related with the glycosidic bond and the radius gyration of maltoheptaose. The effects of methylation at different hydroxyl groups on the stability of amylose and cellulose fragments were investigated. The methylations of O-2 and O-3 reduce the stability of a single helix more than methylation at O-6, while the latter reduces the stability of a double helix more. Solvation free-energy differences between the unsubstituted amylose and cellulose fragments and the methylated species were studied using the single-step perturbation method. It was found that methylation at O-2 has the biggest effect, in agreement with experiment.

Algorithms↗
PubMed2000

Mesoscopic undulations and thickness fluctuations in lipid bilayers from molecular dynamics simulations.

Molecular dynamics simulations of fully hydrated Dipalmitoylphosphatidylcholine bilayers, extending temporal and spatial scales by almost one order of magnitude, are presented. The present work reaches system sizes of 1024 lipids and times 10-60 ns. The simulations uncover significant dynamics and fluctuations on scales of several nanoseconds, and enable direct observation and spectral decomposition of both undulatory and thickness fluctuation modes. Although the former modes are strongly damped, the latter exhibit signs of oscillatory behavior. From this, it has been possible to calculate mesoscopic continuum properties in good agreement with experimental values. A bending modulus of 4 x 10(-20) J, bilayer area compressibility of 250-300 mN/m, and mode relaxation times in the nanosecond range are obtained. The theory of undulatory motions is revised and further extended to cover thickness fluctuations. Finally, it is proposed that thickness fluctuations is the explanation to the observed system-size dependence of equilibrium-projected area per lipid.

1,2-Dipalmitoylphosphatidylcholine↗