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At least 649 records · Page 36Linked to original sources
PubMed2001

Effects of oxygenated sterol on phospholipid bilayer properties: a molecular dynamics simulation.

The properties of dipalmitoylphosphatidylcholine (DPPC):6-ketocholestanol bilayer at 50 mol% sterol were studied using the molecular dynamics simulation technique. Our simulations were performed at constant pressure and temperature on a nanosecond time scale. Data from this simulation were compared to the results of our previous simulations on DPPC and DPPC-cholesterol bilayers. We conclude that the differences in the properties of membranes with cholesterol and ketocholestanol are due to the difference in 6-ketocholestanol and cholesterol location in the bilayer. The presence of the keto group in ketocholestanol moves the sterol towards the polar region closer to interface with water. We predict that similar mechanisms would govern the properties of membranes with other oxygenated sterols, such as for example 7-ketocholesterol. Results of our simulations are in a good agreement with the data available from the experiment.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2001

Molecular dynamics simulations of the three dimensional model of plasmepsin II-peptidic inhibitor complexes.

Plasmodium falciparum is a major causative agent of malaria, a disease of worldwide importance. Inhibition of a hemoglobin degrading P. falciparum aspartic protease Plasmepsin II (Plm II) provides a viable strategy for antimalarial therapy. Linear peptidic inhibitors based on the 4(S)-amino-3(S)-hydroxy-5-phenylpentanoic acid at the P1-P1' positions are known which inhibit Plm II with improved selectivity over cathepsin D. A series of computations were performed in order to gain insight into the interactions of these inhibitors with Plm II. The docking and molecular dynamics simulations were performed on a model ligand/enzyme complex to optimize the variables involved in the generation of ligand/enzyme models. This protocol of docking and molecular dynamics (MD) simulation was then used to derive the ligand-enzyme complexes of the molecules used in the present study. Different modes of binding of pepstatin and the three linear inhibitors were studied. Molecular dynamics simulation was performed at 300K for 100ps with a time step of Ifs. The structural effects of ligand binding were analyzed on the basis of hydrogen bond interactions, interaction energies, hydrophobic contacts and RMS deviations in the resulting energy-minimized structures of the receptor-ligand complexes. The results indicate that hydrophobic and hydrogen bonding interactions are responsible for selective inhibition of Plm II and improved selectivity over cathepsin D. Hydrogen bonding interaction plays an important role for amino acid residues such as Asp-34, Asp-214, Thr-217, Ser-218, Val-78, Ser-79, Tyr-192 and Gly-216. The binding of the inhibitors to the enzyme, while producing no large distortions in the enzyme active site cleft, results in significant RMS deviations of the inhibitor, which represent the distortion of the inhibitor, effected by the proteinase. Thus, the information generated from this analysis should be useful for further work in the area of antimalarial research.

Aspartic Acid Endopeptidases↗
PubMed2001

Molecular dynamics simulations of stratum corneum lipid models: fatty acids and cholesterol.

We report the results of an investigation on stratum corneum lipids, which present the main barrier of the skin. Molecular dynamics simulations, thermal analysis and FTIR measurements were applied. The primary objective of this work was to study the effect of cholesterol on skin structure and dynamics. Two molecular models were constructed, a free fatty acid bilayer (stearic acid, palmitic acid) and a fatty acid/cholesterol mixture at a 1:1 molar ratio. Our simulations were performed at constant pressure and temperature on a nanosecond time scale. The resulting model structures were characterized by calculating surface areas per headgroup, conformational properties, atom densities and order parameters of the fatty acids. Analysis of the simulations indicates that the free fatty acid fraction of stratum corneum lipids stays in a highly ordered crystalline state at skin temperatures. The phase behavior is strongly influenced when cholesterol is added. Cholesterol smoothes the rigid phases of the fatty acids: the order of the hydrocarbon tails (mainly of the last eight bonds) is reduced, the area per molecule becomes larger, the fraction of trans dihedrals is lower and the hydrophobic thickness is reduced. The simulation results are in good agreement with our experimental data from FTIR analysis and NIR-FT Raman spectroscopy.

Body Temperature↗
PubMed2006

Diffraction-based density restraints for membrane and membrane-peptide molecular dynamics simulations.

We have recently shown that current molecular dynamics (MD) atomic force fields are not yet able to produce lipid bilayer structures that agree with experimentally-determined structures within experimental errors. Because of the many advantages offered by experimentally validated simulations, we have developed a novel restraint method for membrane MD simulations that uses experimental diffraction data. The restraints, introduced into the MD force field, act upon specified groups of atoms to restrain their mean positions and widths to values determined experimentally. The method was first tested using a simple liquid argon system, and then applied to a neat dioleoylphosphatidylcholine (DOPC) bilayer at 66% relative humidity and to the same bilayer containing the peptide melittin. Application of experiment-based restraints to the transbilayer double-bond and water distributions of neat DOPC bilayers led to distributions that agreed with the experimental values. Based upon the experimental structure, the restraints improved the simulated structure in some regions while introducing larger differences in others, as might be expected from imperfect force fields. For the DOPC-melittin system, the experimental transbilayer distribution of melittin was used as a restraint. The addition of the peptide caused perturbations of the simulated bilayer structure, but which were larger than observed experimentally. The melittin distribution of the simulation could be fit accurately to a Gaussian with parameters close to the observed ones, indicating that the restraints can be used to produce an ensemble of membrane-bound peptide conformations that are consistent with experiments. Such ensembles pave the way for understanding peptide-bilayer interactions at the atomic level.

Birefringence↗
PubMed2005

Molecular dynamics simulations of the influenza hemagglutinin fusion peptide in micelles and bilayers: conformational analysis of peptide and lipids.

Molecular dynamics simulations of the influenza hemagglutinin fusion peptide in two differently sized dodecylphosphocholine micelles and a palmitoyl oleoyl phosphatidylcholine bilayer were generated to analyze the influence of the environment. Four independent trajectories (5 ns each for the bilayer, and 2 ns each for the micelles) were generated for each system. The peptide lies at the surface of the micelles, while its N-terminal region inserts deeply in the bilayer. This leads to a substantial increase of the solvation and rigidity of the peptide in micelles as compared to the bilayer. The average structures, nevertheless, are similar in all three systems and agree reasonably with micelle-based NMR structures. When in the bilayer, the peptide increases the chain gauche population and area of adjacent lipids in the same binding leaflet, while it has the opposite effect for the nearby lipids of the other leaflet. These changes, which occur spontaneously to fill voids and defects, cause a decrease in the thickness of the membrane in the neighborhood of the peptide. They would be expected to promote positive curvature, as consistent with the formation of the convex bulge, or "nipple", in the initial stage of membrane fusion. An extension of the classical surfactant theory of Israelachvili based on shapes is proposed to introduce the concept of a "dynamically induced shape" of the membrane lipids by the peptide.

Computer Simulation↗
PubMed2004

Thermostability of protein studied by molecular dynamics simulation.

The thermostability of protein thermostable cathechol 2,3-dixoygenase (TC23O) has been studied by the parallel molecular dynamics simulations. By analysis of the exponent beta, which is related to the scattering spectrum and constant-pressure heat capacity Cp, we reveal the respective contribution of a specific residue 228 proline; a specific salt bridge, Lys188N-Glu291OE1; four ions; and a different water environment to the thermostability of TC23O. The dynamic transition temperature of the mutants, Pro228Ser and Glu291Gly of the TC23O, was decreased about 10 degrees C and 19 degrees C respectively. The displacement of the four ions had no significant effect on the thermostability of TC23O. Water affects the thermostability by influencing the changes of accessible conformation to a certain extent. All these results agree with the known experimental results.

Catechol 2,3-Dioxygenase↗
PubMed1986

Molecular dynamics simulation study of a two-dimensional fluid mixture system: a model for biological membranes.

The computer simulation technique of molecular dynamics was applied to a model two-dimensional fluid mixture system to examine the short-range ordering of lipid and protein molecules in biological membranes. The model system consists of small disks (lipids) and large disks (proteins) with a radius ratio of 6, constrained to move in a plane. The particles interact with pairwise additive repulsive short range potentials, so as to simulate hard disks. Periodic boundary conditions are assumed in order to minimize boundary effects. For values of the number density of the small disks and of the temperature appropriate for a lipid membrane, the fraction, f, of small disks 'next to' at least one large disk was computed by molecular dynamics. This was done as a function of concentration and for several definitions of 'next to'. The molecular dynamics results show that, at moderately low mole fractions of the large disks, the calculated values of f deviate noticeably from the linear relation which would be expected in the absence of protein-protein proximity effects. The results are discussed in terms of current models of lipid-protein ordering in biological membranes.

Computers↗
PubMed2006

Beta-sheet containment by flanking prolines: molecular dynamic simulations of the inhibition of beta-sheet elongation by proline residues in human prion protein.

Previous molecular dynamic simulations have reported elongation of the existing beta-sheet in prion proteins. Detailed examination has shown that these elongations do not extend beyond the proline residues flanking these beta-sheets. In addition, proline has also been suggested to possess a possible structural role in preserving protein interaction sites by preventing invasion of neighboring secondary structures. In this work, we have studied the possible structural role of the flanking proline residues by simulating mutant structures with alternate substitution of the proline residues with valine. Simulations showed a directional inhibition of elongation, with the elongation progressing in the direction of valine including evident inhibition of elongation by existing proline residues. This suggests that the flanking proline residues in prion proteins may have a containment role and would confine the beta-sheet within a specific length.

Amino Acid Sequence↗
PubMed2005

Structural differences between allelic variants of the ovine prion protein revealed by molecular dynamics simulations.

We have modeled ovine prion protein (residues 119-233) based on NMR structures of PrP from other mammalian species. Modeling of the C-terminal domain of ovine PrP predicts three helices: helix-1 (residues 147-155), flanked by two short beta-strands; helix-2 (residues 176-197), and helix-3 (residues 203-229). Molecular dynamics simulations on this model of ovine PrP have determined structural differences between allelic variants. At neutral pH, limited root mean-squared (RMS) fluctuations were seen in the region of helix-1; between beta-strand-2 and residue 171, and the loop connecting helix-2 and helix-3. At low pH, these RMS fluctuations increased and showed allelic variation. The extent of RMS fluctuation between beta-strand 2 and residue 171 was ARR > ARQ > VRQ. This order was reversed for the loop region connecting helix-2 and helix-3. Although all three variants have the potential to display an extended helix at the C-terminal region of helix-1, the major influence of the VRQ allele was to restrict the conformations of the Asn162 and Arg139 side-chains. Variations observed in the simulations in the vicinity of helix-1 correlated with reactivity of C-terminal specific anti-PrP monoclonal antibodies with peripheral blood cells from scrapie-susceptible and -resistant genotypes of sheep: cells from VRQ homozygous sheep showed uniform reactivity, while cells from ARQ and ARR homozygous sheep showed variable binding. Our data show that molecular dynamics simulations can be used to determine structural differences between allelic variants of ovine PrP. The binding of anti-PrP monoclonal antibodies to ovine blood cells may validate these structural predictions.

Animals↗
PubMed1992

Combined use of molecular dynamics simulations and NMR to explore peptide bond isomerization and multiple intramolecular hydrogen-bonding possibilities in a cyclic pentapeptide, cyclo(Gly-Pro-D-Phe-Gly-Val).

The conformational behavior of a model cyclic pentapeptide--cyclo(Gly-L-Pro-D-Phe-Gly-L-Val)--has been explored through the combined use of in vacuo molecular dynamics simulations and a range of nmr experiments (preceding paper). The molecular dynamics analysis suggests that, despite the conformational constraints imposed by formation of the pentapeptide cycle, this pentapeptide undergoes conformational transitions between various hydrogen-bonded conformations, characterized by low energy barriers. An inverse gamma turn with Pro in position i + 1 and a gamma turn with D-Phe in position i + 1 are two alternatives occurring frequently. Like other DLDDL cyclic pentapeptides, cyclo(Gly-Pro-D-Phe-Gly-Val) is also stabilized by an inverse gamma-turn structure with the beta-branched Val residue in position i + 1, and this hydrogen bond is retained in the different conformational families. The gamma-turn around D-Phe3 and the inverse gamma turn around Val5 are consistent with the nmr observations. 3JNH-CH alpha coupling constants of the all-trans forms were calculated from one of the molecular dynamics trajectories and are comparable to nmr experimental data, suggesting that the conformational states visited during the simulation are representative of the conformational distribution in solution. In addition to the equilibrium among various hydrogen-bonded all-trans conformers, the observation in nmr spectra of two sets of resonances for all peptide protons indicated a slow conformational interconversion of the Gly-Pro peptide bond between trans and cis isomers. The activation energy between these two conformers was determined experimentally by magnetization transfer and was calculated by high temperature constrained molecular dynamics simulation. Both methods yield a free energy of activation of ca. 20 kcal/mol. Furthermore, the free energy of activation is dependent on the direction of rotation of the Gly-Pro peptide bond.

Amino Acid Sequence↗
PubMed1995

Constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal phase dipalmitoylphosphatidylcholine bilayer.

We report a constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal (L alpha) phase bilayer of dipalmitoylphosphatidylcholine at 50 degrees C and 28 water molecules/lipid. We have shown that the bilayer is stable throughout the 1550-ps simulation and have demonstrated convergence of the system dimensions. Several important aspects of the bilayer structure have been investigated and compared favorably with experimental results. For example, the average positions of specific carbon atoms along the bilayer normal agree well with neutron diffraction data, and the electron density profile is in accord with x-ray diffraction results. The hydrocarbon chain deuterium order parameters agree reasonably well with NMR results for the middles of the chains, but the simulation predicts too much order at the chain ends. In spite of the deviations in the order parameters, the hydrocarbon chain packing density appears to be essentially correct, inasmuch as the area/lipid and bilayer thickness are in agreement with the most refined experimental estimates. The deuterium order parameters for the glycerol and choline groups, as well as the phosphorus chemical shift anisotropy, are in qualitative agreement with those extracted from NMR measurements.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2006

Structural insights into the effect of isonucleosides on B-DNA duplexes using molecular-dynamics simulations.

Some structural insights into the conformations of the isonucleosides containing duplexes have been provided. Unrestrained molecular-dynamics simulations on 18-mer duplexes with isonucleosides incorporated at the 3'-end or in the center of one strand have been carried out with explicit solvent under periodic boundary conditions using the AMBER force field and the particle mesh Ewald method. The Watson-Crick hydrogen-bonding patterns of the duplexes studied remained intact throughout the simulation. For the modified duplexes, the changes observed in the inter-base pair parameters and backbone torsional angles were primarily localized at the isonucleoside-inserted area. All five structures studied remained in the B-form family. The decreased stacking abilities indicated by the large changes in inter-base pair parameters and the large changes in backbones made the modified duplexes show a minor thermal destabilization in comparison with native DNA. The MM_PBSA method for estimating binding free energies on two complementary strands was used. The results showed that the binding free energies of isonucleoside-incorporated DNA duplexes were lower than the native DNA duplex, which is in good agreement with experimental observations.

Computer Simulation↗
PubMed2005

Molecular dynamics simulations for selection of kinetic hydrate inhibitors.

Natural gas hydrates are ice-like structures composed of water and gas molecules that have long been a problem in petroleum industry. Heavy cost of alcohol and glycol injection has spurred an interest in called 'kinetic inhibitors' able to slow down the hydrate formation rather than prevent it. Since it is not possible to compare directly the macroscopic effects of different inhibitors on the kinetics of hydrate formation in computer experiments, a scheme capable of culling the list of candidates for experimental testing was proposed earlier [B. Kvamme, G. Huseby, O.K. Førrisdahl, Molecular dynamics simulations of PVP kinetic inhibitor in liquid water and hydrate/liquid water systems, Mol. Phys. 90 (1997) 979-991]. Molecular dynamics simulations were implemented to test several kinetic inhibitors in a multiphase water-hydrate system with rigid hydrate interface. In addition, a long-scale run was implemented for a system where the hydrate was free to melt and reform. Our conclusion that PVCap will outperform PVP as a kinetic hydrate inhibitor is supported by experimental data. We demonstrate that numerical experiments can be a valuable tool for selecting kinetic inhibitors as well as provide insight into mechanisms of kinetic inhibition and hydrate melting and reformation.

Computer Simulation↗
PubMed1995

Molecular dynamics simulations of the glucocorticoid receptor DNA-binding domain in complex with DNA and free in solution.

Molecular dynamics simulations have been performed on the glucocorticoid receptor DNA binding domain (GR DBD) in aqueous solution as a dimer in complex with DNA and as a free monomer. In the simulated complex, we find a slightly increased bending of the DNA helix axis compared with the crystal structure in the spacer region of DNA between the two half-sites that are recognized by GR DBD. The bend is mainly caused by an increased number of interactions between DNA and the N-terminal extended region of the sequence specifically bound monomer. The recognition helices of GR DBD are pulled further into the DNA major groove leading to a weakening of the intrahelical hydrogen bonds in the middle of the helices. Many ordered water molecules with long residence times are found at the intermolecular interfaces of the complex. The hydrogen-bonding networks (including water bridges) on either side of the DNA major groove involve residues that are highly conserved within the family of nuclear receptors. Very similar hydrogen-bonding networks are found in the estrogen receptor (ER) DBD in complex with DNA, which suggests that this is a common feature for proper positioning of the recognition helix in ER DBD and GR DBD.

Amino Acid Sequence↗
PubMed1995

Incorporation of surface tension into molecular dynamics simulation of an interface: a fluid phase lipid bilayer membrane.

In this paper we report on the molecular dynamics simulation of a fluid phase hydrated dimyristoylphosphatidylcholine bilayer. The initial configuration of the lipid was the x-ray crystal structure. A distinctive feature of this simulation is that, upon heating the system, the fluid phase emerged from parameters, initial conditions, and boundary conditions determined independently of the collective properties of the fluid phase. The initial conditions did not include chain disorder characteristic of the fluid phase. The partial charges on the lipids were determined by ab initio self-consistent field calculations and required no adjustment to produce a fluid phase. The boundary conditions were constant pressure and temperature. Thus the membrane was not explicitly required to assume an area/phospholipid molecule thought to be characteristic of the fluid phase, as is the case in constant volume simulations. Normal to the membrane plane, the pressure was 1 atmosphere, corresponding to the normal laboratory situation. Parallel to the membrane plane a negative pressure of -100 atmospheres was applied, derived from the measured surface tension of a monolayer at an air-water interface. The measured features of the computed membrane are generally in close agreement with experiment. Our results confirm the concept that, for appropriately matched temperature and surface pressure, a monolayer is a close approximation to one-half of a bilayer. Our results suggest that the surface area per phospholipid molecule for fluid phosphatidylcholine bilayer membranes is smaller than has generally been assumed in computational studies at constant volume. Our results confirm that the basis of the measured dipole potential is primarily water orientations and also suggest the presence of potential barriers for the movement of positive charges across the water-headgroup interfacial region of the phospholipid.

Crystallography, X-Ray↗
PubMed2001

The diluted aqueous solvation of carbohydrates as inferred from molecular dynamics simulations and NMR spectroscopy.

The purpose of this paper is to review our understanding of the dilute hydration (aqueous solvation) behaviour of disaccharide compounds. To this end we discuss and scrutinize the results that have been obtained for the three model disaccharides: maltose, sucrose and trehalose from experimental NMR studies and from theoretical molecular dynamics studies in explicit aqueous solutions. The focus is on the description of molecular hydration features that will influence macroscopic entities such as diffusion and relaxation: residence times of hydration waters, hydration numbers and hydration densities. The principles of molecular dynamics simulation are briefly outlined while a detailed presentation is given of the key features that characterise hydration: the solvation of the glycosidic linkage, the radial hydration of the solute, the water density anisotropy around the solute, the residential behaviour of water molecules in the periphery of the solute, and rotational and translational diffusion coefficients. With respect to the use of NMR in characterising the structure and dynamics of the hydration, the hydrodynamic theory of rotational and translational diffusion of biomolecules as well as the use of pulse field gradient spin echo experiments are briefly presented. The NMR-defined rotational diffusion coefficients (D(r)) and the experimentally determined translational diffusion (D(t)) coefficients are reported for 4% (w/w) solutions of sucrose, trehalose and maltose. These results are compared with theoretical data obtained from molecular dynamics simulations of sucrose, trehalose and maltose under identical conditions (concentration, temperature, etc.). With our present level of knowledge we can propose that although carbohydrates share a number of hydration characteristics, evidence is accumulating in support of the notion that it is not the amount or overall hydration but rather the detailed individual carbohydrate-water interaction that is likely to determine carbohydrate structure and functionality.

Carbohydrate Conformation↗
PubMed2006

Molecular dynamics simulations of a cyclic-beta-(1-->2) glucan containing an alpha-(1-->6) linkage as a 'molecular alleviator' for the macrocyclic conformational strain.

The conformational preferences of a cyclic osmoregulated periplasmic glucan of Ralstonia solanacearum (OPGR), which is composed of 13 glucose units and linked entirely via beta-(1-->2) linkages excluding one alpha-(1-->6) linkage, were characterized by molecular dynamics simulations. Of the three force fields modified for carbohydrates that were applied to select a suitable one for the cyclic glucan, the carbohydrate solution force field (CSFF) was found to most accurately simulate the cyclic molecule. To determine the conformational characteristics of OPGR, we investigated the glycosidic dihedral angle distribution, fluctuation, and the potential energy of the glucan and constructed hypothetical cyclic (CYS13) and linear (LINEAR) glucans. All beta-(1-->2)-glycosidic linkages of OPGR adopted stable conformations, and the dihedral angles fluctuated in this energy region with some flexibility. However, despite the inherent flexibility of the alpha-(1-->6) linkage, the dihedral angles have no transition and are more rigid than that in a linear glucan. CYS13, which consists of only beta-(1-->2) linkages, is somewhat less flexible than other glycans, and one of its linkages adopts a higher energy conformation. In addition, the root-mean-square fluctuation of this linkage is lower than that of other linkages. Furthermore, the potential energy of glucans increases in the order of LINEAR, OPGR, and CYS13. These results provide evidence of the existence of conformational constraints in the cyclic glucan. The alpha-(1-->6)-glycosidic linkage can relieve this constraint more efficiently than the beta-(1-->2) linkage. The conformation of OPGR can reconcile the tendency for individual glycosidic bonds to adopt energetically favorable conformations with the requirement for closure of the macrocyclic ring by losing the inherent flexibility of the alpha-(1-->6)-glycosidic linkage.

Carbohydrate Conformation↗
PubMedDate not supplied

Membrane-bound ARF1 peptide: interpretation of neutron diffraction data by molecular dynamics simulation methods.

Adenosine diphosphate ribosylation factor-1 (ARF1) is activated by cell membrane binding of a self-folding N-terminal domain. We have previously presented four possible conformations of the membrane bound, human ARF1 N-terminal peptide in planar lipid bilayers of DOPC and DOPG (7:3 molar ratio), determined from lamellar neutron diffraction and circular dichroism data. In this paper we analyse the four possible conformations by molecular dynamics simulations. The aim of these simulations was to use MD to distinguish which of the four possible membrane bound structures was the most likely. The most likely conformation was determined according to the following criteria: (a) location of label positions on the peptide in relation to the bilayer, (b) lowest mean square displacement from the initial structure, (c) lowest system energy, (d) most peptide-lipid headgroup hydrogen bonding, (e) analysis of phi/psi angles of the peptide. These findings demonstrate the application of molecular dynamics simulations to explore neutron diffraction data.

ADP-Ribosylation Factor 1↗