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At least 73 records · Page 4Linked to original sources
PubMed2002

Evidence of turn and salt bridge contributions to beta-hairpin stability: MD simulations of C-terminal fragment from the B1 domain of protein G.

We ran and analyzed a total of eighteen, 10 ns molecular dynamics simulations of two C-terminal beta-hairpins from the B1 domain of Protein G: twelve runs for the last 16 residues and six runs for the last 15 residues, G41-E56 and E42-E56, respectively. Based on their CalphaRMS deviation from the starting structure and the pattern of stabilizing interactions (hydrogen bonds, hydrophobic contacts, and salt bridges), we were able to classify the twelve runs on G41-E56 into one of three general states of the beta-hairpin ensemble: 'Stable', 'Unstable', and 'Unfolded'. Comparing the specific interactions between these states, we find that on average the stable beta-hairpin buries 287 A(2) of hydrophobic surface area, makes 13 hydrogen bonds, and forms 3 salt-bridges. We find that the hydrophobic core prefers to make some specific contacts; however, this core does not require optimal packing. Side-chain hydrogen bonds stabilize the beta-hairpin turn with strong stabilizing interactions primarily due to the carboxyl of D46 with contributions from T49 hydroxyl. Buoyed by the strength of the hydrophobic core, other hydrogen bonds, primarily main-chain, guide the beta-hairpin into registration by forming a loose network of interactions, making an approximately constant number of hydrogen bonds from a pool of possible candidates. In simulations on E42-E56, where the salt bridge closing the termini is not favored, we observe that all the simulations show no 'Stable' behavior, but are 'Unstable' or 'Unfolded'. We can estimate that the salt-bridge between the termini provides approximately 1.3 kcal/mol. Altogether, the results suggest that the beta-hairpin folds beginning at the turn, followed by hydrophobic collapse, and then hydrogen bond formation. Salt bridges help to stabilize the folded conformations by inhibiting unfolded states.

Hydrogen Bonding↗
PubMed2002

Ligand binding affinities from MD simulations.

Simplified free energy calculations based on force field energy estimates of ligand-receptor interactions and thermal conformational sampling have emerged as a useful tool in structure-based ligand design. Here we give an overview of the linear interaction energy (LIE) method for calculating ligand binding free energies from molecular dynamics simulations. A notable feature is that the binding energetics can be predicted by considering only the intermolecular interactions of the ligand in the associated and dissociated states. The approximations behind this approach are examined, and different parametrizations of the model are discussed. LIE-type methods appear particularly promising for computational "lead optimization". Recent applications to protein-protein interactions and ion channel blocking are also discussed.

Animals↗
PubMed1995

Comparison of MD simulations and NMR experiments for hen lysozyme. Analysis of local fluctuations, cooperative motions, and global changes.

Three 1000 ps molecular dynamics simulations of hen lysozyme have been compared with a range of experimental NMR parameters in order to gain insight into the dynamical properties of the protein and to assess the significance of the motional events observed in the simulations. The simulations, one in vacuum and two in water, were used to estimate interproton distances (for comparison with NOE data), 3JHN alpha and 3J alpha beta coupling constants and 1H-15N order parameters. Comparison of these values with experimental data, particularly NOEs, enabled force field-induced changes to the structure during the simulations to be recognized. It has been shown, however, that these changes can be largely eliminated by slight modifications to the force field. Using a simulation performed in water with this modified force field, it has been found that 1H-15N order parameters calculated for side chain groups in particular correlate well with experimental values and reflect the substantial dependence of these motional properties on the environment, particularly surface exposure, in which the side chain is found. In this case, the simulation then provides models for the motional processes giving rise to the observed experimental data. The results indicate that the order parameter values reflect primarily the number of torsion angles about which rotameric interchange occurs. In addition to local motions, the two different domains of lysozyme have been found to behave differently in the simulations. Possible implications of these differences for the interpretation of unfolding simulations and experimental observations of folding intermediates for lysozyme are discussed.

Animals↗
PubMed2006

MD simulations of Mistic: conformational stability in detergent micelles and water.

Mistic is an unusual membrane protein from Bacillus subtilis. It appears to fold and insert autonomously into a lipid bilayer and has been suggested as a tool that aids the targeting of eukaryotic membrane proteins to bacterial membranes. The NMR structure of Mistic in detergent (LDAO) micelles has revealed it to be a four alpha-helix bundle. From a structural perspective, Mistic does not resemble other membrane proteins. Its external surface is not very hydrophobic, and standard methods do not predict any of its helices to be in the transmembrane orientation. Molecular dynamics simulations (simulation times approximately 30 ns) in water and in detergent micelles have been used to explore the conformational stability of Mistic as a function of its environment. In water, the protein is stable, exhibiting no significant change in fold on a 30 ns time scale. In contrast, in three simulations in detergent micelles, the partial unfolding of Mistic occurred, whereby the H4 helix drifted away from the H1-H3 core. This was due to the penetration of detergent molecules between H4 and the remainder of the protein. This is unlike the behavior of several other membrane proteins, both alpha-helix bundles and beta-barrels, in comparable detergent micelle simulations. The unfolding of H4 from the H1-H3 core of Mistic could be partially reversed by a simulation in which the detergent molecules were removed, and the unfolded protein was simulated in water. These results suggest that Mistic may not be a stable integrated membrane protein but rather that it may undergo a conformational change upon interaction with a membrane or membrane-like environment.

Bacillus subtilis↗
PubMed2004

Structure and dynamics of Au+ ion in aqueous solution: ab initio QM/MM MD simulations.

Structure and dynamics of hydrated Au(+) have been investigated by means of molecular dynamics simulations based on ab initio quantum mechanical molecular mechanical forces at Hartree-Fock level for the treatment of the first hydration shell. The outer region of the system was described using a newly constructed classical three-body corrected potential. The structure was evaluated in terms of radial and angular distribution functions and coordination number distributions. Water exchange processes between coordination shells and bulk indicate a very labile structure of the first hydration shell whose average coordination number of 4.7 is a mixture of 3-, 4-, 5-, 6-, and 7-coordinated species. Fast water exchange reactions between first and second hydration shell occur, and the second hydration shell is exceptionally large. Therefore, the mean residence time of water molecules in the first hydration shell (5.6 ps/7.5 ps for t*= 0.5 ps/2.0 ps) is shorter than that in the second shell (9.4 ps/21.2 ps for t*= 0.5 ps/2.0 ps), leading to a quite specific picture of a "structure-breaking" effect.

Journal Article↗
PubMed2004

MD simulations of spontaneous membrane protein/detergent micelle formation.

The in vitro study of membrane proteins for the purpose of physicochemical analysis or structure determination often relies upon successful reconstitution into detergent micelles. Moreover, a number of biological processes such as membrane protein folding and transport rely on lipid interactions which may resemble the micellar environment. Little is known about the structures of these micelles or the processes which lead to their formation. We therefore present two 50 ns all-atom molecular dynamics simulations of spontaneous dodecylphosphocholine micelle formation around representatives of the two major families of membrane proteins, a small beta-barrel protein, OmpA, and a model alpha-helical protein, glycophorin A. Despite differences in protein architecture, we highlight common mechanistic pathways in micelle formation, which are consistent with experimental studies. We characterize the exponential kinetics of detergent-protein adsorption and suggest a simple model which may explain the aggregation process. We also compare the results with 25 and 50 ns simulations of preformed micelles containing the same proteins. We confirm that the end structures of the self-assembled micelles are similar to those from their preformed counterparts, with each micelle presenting a bilayerlike environment to the enclosed protein.

Bacterial Outer Membrane Proteins↗
PubMed2005

Enhanced concentration of polarizable anions at the liquid water surface: SHG spectroscopy and MD simulations of sodium thiocyanate [corrected].

Contrasting current textbook descriptions, a consistent picture of substantial concentration enhancement of highly polarizable anions at the surface of aqueous electrolyte solutions is emerging. Such enhancement may have important implications for chemistry occurring on aqueous aerosols and ocean surfaces. Here we present a combined experimental and theoretical investigation of the liquid/air interface of aqueous sodium thiocyanate [corrected] at varying salt concentrations. Normalized second harmonic generation intensities fitted to Langmuir isotherms yield a Gibbs free energy of adsorption of -1.80 kcal/mol. These results are in accord with molecular dynamics simulations in slab geometry, which predict an appreciable surface enhancement of SCN-.

Journal Article↗
PubMed2005

Mechanism of helix nucleation and propagation: microscopic view from microsecond time scale MD simulations.

Microsecond time scale molecular dynamics simulations of the 13-residue peptide RN24 were carried out to investigate the mechanism of helix nucleation and propagation. An extended and an ideal alpha-helical conformation were used as starting structures. NOE-derived interatomic distances were compared with distances calculated from the simulations, showing good agreement between experimental and simulation results. Based on almost 200 helix nucleation events observed, beta-turn and 3(10)-helix play an important role in helix nucleation; in most cases, helix nucleation is preceded by the formation of a short-lived beta-turn (60% probability) or 3(10)-helix (20% probability), and the conversion from beta-turn to alpha-turn involves bifurcated hydrogen bonds. Helix propagation in RN24 appears to occur preferentially from the N-terminus to the C-terminus, and helix unfolding preferentially in the opposite direction.

C-Peptide↗
PubMed2006

Ab initio and empirical model MD simulation studies of solvent effects on the properties of N-methylacetamide along a cis-trans isomerization pathway.

The properties of N-methylacetamide along a cis-trans isomerization pathway described by twisting about the C(O)-N bond are examined at finite temperature both in vacuo and in explicit water solvent. Two distinctly different theoretical descriptions, an ab initio (DFT-BLYP) and an empirical (CHARMM22) model, are studied in order to permit an assessment of the dominant forces active in the system. An analysis of the solvent structure at equilibrium and changes in solvation structure accompanying isomerization is, therefore, given for each model. Many-body polarization effects absent under CHARMM22 but present in the ab initio model are found to have a profound influence on the system. The electronic structure of the NMA molecule predicted by the ab initio method along the reaction coordinate is examined in order to shed further light on changes in peptide "partial-double" bond character [C(O)-N] as isomerization takes place. A new statistical-mechanical interpretation of the entropy change during a chemical reaction is presented to help interpret the thermochemistry of the simple reaction.

Acetamides↗
PubMed2004

Alkali halide nanocrystal growth and etching studied by AFM and modeled by MD simulations.

NaCl hillocks have been grown on the NaCl(100) monocrystalline surface by simply making the tip of an atomic force microscope cantilever interact with the surface. A quantitative discussion about the hillock dissolution process as well as physical stability of these ionic surfaces has been made. Molecular dynamics simulations helped us to interpret the experimental data. An explanation for the hillock formation and dissolution phenomena is also discussed.

Journal Article↗
PubMed2005

X-ray and neutron diffraction studies and MD simulation of atomic configurations in polyamorphic Y2O3-Al2O3 systems.

Supercooled liquids in the Y(2)O(3)-Al(2)O(3) system undergo a liquid-liquid phase transition between a high-temperature, high-density amorphous (HDA) polymorph form and one with lower density (LDA form) that is stable at lower temperature. The two amorphous polymorphs have the same chemical composition, but they differ in their density (ca. 4% difference) and in their heat content (enthalpy) and entropy determined by calorimetry. Here we present new results of structural studies using neutron and high-energy X-ray diffraction to study the structural differences between HDA and LDA polyamorphs. The combined datasets show no large differences in the average nearest-neighbour Al-O or Y-O bond lengths or coordination numbers between the low- and high-density liquids. However, the data indicate that substantial changes occur among the packing geometries and clustering of the Al-O and Y-O coordination polyhedra, i.e. within the second-nearest-neighbour shell defined by the metal-metal (i.e. Y-Y, Y-Al, Al-Al) interactions. Polarizable ion model molecular dynamics simulations of Y(2)O(3)-Al(2)O(3) liquids are used to help interpret the pair-correlation functions obtained from X-ray and neutron scattering data. Unexpectedly large density fluctuations are observed to occur during the simulation of nominally equilibrated systems. These are interpreted as being due to dynamic sampling of high- and low-density configurations within the single-phase liquid at temperatures above the critical point or phase transition line. Calculated partial radial distribution functions indicate that the primary differences between HDA and LDA configurations occur among the Y-Y correlations.

Aluminum Oxide↗
PubMed2005

Potentials of mean force for the interaction of blocked alanine dipeptide molecules in water and gas phase from MD simulations.

We calculate potentials of mean force (PMFs) for the intermolecular interaction of two blocked alanine dipeptide (AcAlaNHMe) molecules in water and gas phase at two temperatures, 278 and 300 K, from all-atom molecular dynamics simulations. Simple models based on buried solvent accessible surface and one-dimensional potentials derived from distance-based radial distribution functions are not capable of expressing the short- and long-range complexity of the solute-solute interactions in water. Instead, radial and angular variations in the PMFs are observed with the two-dimensional potentials. The strength of the interactions for specific relative orientations of the molecules in the two-dimensional PMFs is more than double that observed in the one-dimensional PMFs. The populations of specific blocked alanine dipeptide conformations in water, such as alpha(R) and PPII, vary with temperature, and most significantly, with the distance between the centers of mass. A preference for helical conformations is observed at close encounter between molecules.

Alanine↗
PubMed2002

Protein engineering of nitrile hydratase activity of papain: molecular dynamics study of a mutant and wild-type enzyme.

The mechanism of hydrolysis of the nitrile (N-acetyl-phenylalanyl-2-amino-propionitrile, I) catalyzed by Gln19Glu mutant of papain has been studied by nanosecond molecular dynamics (MD) simulations. MD simulations of the complex of mutant enzyme with I and of mutant enzyme covalently attached to both neutral (II) and protonated (III) thioimidate intermediates were performed. An MD simulation with the wild-type enzyme.I complex was undertaken as a reference. The ion pair between protonated His159 and thiolate of Cys25 is coplanar, and the hydrogen bonding interaction S(-)(25).HD1-ND1(159) is observed throughout MD simulation of the mutant enzyme.I complex. Such a sustained hydrogen bond is absent in nitrile-bound wild-type papain due to the flexibility of the imidazole ring of His159. The nature of the residue at position 19 plays a critical role in the hydrolysis of the covalent thioimidate intermediate. When position 19 represents Glu, the imidazolium ion of His159-ND1(+).Cys25-S(-) ion pair is distant, on average, from the nitrile nitrogen of substrate I. Near attack conformers (NACs) have been identified in which His159-ImH(+) is positioned to initiate a general acid-catalyzed addition of Cys-S(-) to nitrile. Though Glu19-CO(2)H is distant from nitrile nitrogen in the mutant.I structure, MD simulations of the mutant.II covalent adduct finds Glu19-CO(2)H hydrogen bonded to the thioimide nitrogen of II. This hydrogen bonded species is much less stable than the hydrogen bonded Glu19-CO(2)(-) with mutant-bound protonated thioimidate (III). This observation supports Glu19-CO(2)H general acid catalysis of the formation of mutant.III. This is the commitment step in the Gln19Glu mutant catalysis of nitrile hydrolysis.

Computer Simulation↗
PubMed1999

Effect of conformation on the conversion of cyclo-(1,7)-Gly-Arg-Gly-Asp-Ser-Pro-Asp-Gly-OH to its cyclic imide degradation product.

The objective of this study was to explain the increased propensity for the conversion of cyclo-(1,7)-Gly-Arg-Gly-Asp-Ser-Pro-Asp-Gly-OH (1), a vitronectin-selective inhibitor, to its cyclic imide counterpart cyclo-(1,7)-Gly-Arg-Gly-Asu-Ser-Pro-Asp-Gly-OH (2). Therefore, we present the conformational analysis of peptides 1 and 2 by NMR and molecular dynamic simulations (MD). Several different NMR experiments, including COSY, COSY-Relay, HOHAHA, NOESY, ROESY, DQF-COSY and HMQC, were used to: (a) identify each proton in the peptides; (b) determine the sequential assignments; (c) determine the cis-trans isomerization of X-Pro peptide bond; and (d) measure the NH-HCalpha coupling constants. NOE- or ROE-constraints were used in the MD simulations and energy minimizations to determine the preferred conformations of cyclic peptides 1 and 2. Both cyclic peptides 1 and 2 have a stable solution conformation; MD simulations suggest that cyclic peptide 1 has a distorted type I beta-turn at Arg2-Gly3-Asp4-Ser5 and cyclic peptide 2 has a pseudo-type I beta-turn at Ser5-Pro6-Asp7-Gly1. A shift in position of the type I beta-turn at Arg2-Gly3-Asp4-Ser5 in peptide 1 to Ser5-Pro6-Asp7-Gly1 in peptide 2 occurs upon formation of the cyclic imide at the Asp4 residue. Although the secondary structure of cyclic peptide 1 is not conducive to succinimide formation, the reaction proceeds via neighbouring group catalysis by the Ser5 side chain. This mechanism is also supported by the intramolecular hydrogen bond network between the hydroxyl side chain and the backbone nitrogen of Ser5. Based on these results, the stability of Asp-containing peptides cannot be predicted by conformational analysis alone; the influence of anchimeric assistance by surrounding residues must also be considered.

Chromatography, High Pressure Liquid↗
PubMed2000

Structure analysis by diffraction of amorphous zones created by Ni ion implantation into pure Al

The implantation of Ni ions into pure Al leads to the formation of approximately 10 nm amorphous zones (AZ) which induce diffuse rings in the diffraction pattern in addition to the diffraction spots of the crystal. Measurements by energy dispersive spectrometry and electron energy loss spectrometry attributed to the amorphous zones an average Ni concentration of 25 at%. The exact structure of these AZ is still unknown. The structure is characterized here by both the total and partial radial distribution functions (RDF). Structure factor deduced from experiments is compared to calculated one. For this purpose, molecular dynamic (MD) simulations are used to model the AZ structure. The RDF are determined using this structure and analytical calculation of the diffraction pattern is achieved. Simulations of the diffraction pattern of the simulated MD sample using both a kinematic and a dynamic approach are achieved to refine the analytical procedure used on the experimental diffraction patterns. It appears that the amorphous structure is well reproduced by the MD simulations. Analytical calculation reveals the presence of a well-established chemical order in the amorphous material.

Journal Article↗
PubMed1992

Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein.

Computer simulation of the conformations of short antigenic peptides (5-10 residues) either free or bound to their receptor, the major histocompatibility complex (MHC)-encoded glycoprotein H-2 Ld, was employed to explain experimentally determined differences in the antigenic activities within a set of related peptides. Starting for each sequence from the most probable conformations disclosed by a pattern-recognition technique, several energy-minimized structures were subjected to molecular dynamics simulations (MD) either in vacuo or solvated by water molecules. Notably, antigenic potencies were found to correlate to the peptides propensity to form and maintain an overall alpha-helical conformation through regular i,i + 4 hydrogen bonds. Accordingly, less active or inactive peptides showed a strong tendency to form i,i + 3 hydrogen bonds at their N-terminal end. Experimental data documented that the C-terminal residue is critical for interaction of the peptide with H-2 Ld. This finding could be satisfactorily explained by a 3-D Q.S.A.R. analysis postulating interactions between ligand and receptor by hydrophobic forces. A 3-D model is proposed for the complex between a high-affinity nonapeptide and the H-2 Ld receptor. First, the H-2 Ld molecule was built from X-ray coordinates of two homologous proteins: HLA-A2 and HLA-Aw68, energy-minimized and studied by MD simulations. With HLA-A2 as template, the only realistic simulation was achieved for a solvated model with minor deviations of the MD mean structure from the X-ray conformation. Water simulation of the H-2 Ld protein in complex with the antigenic nonapeptide was then achieved with the template-derived optimal parameters. The bound peptide retains mainly its alpha-helical conformation and binds to hydrophobic residues of H-2 Ld that correspond to highly polymorphic positions of MHC proteins. The orientation of the nonapeptide in the binding cleft is in accordance with the experimentally determined distribution of its MHC receptor-binding residues (agretope residues). Thus, computer simulation was successfully employed to explain functional data and predicts alpha-helical conformation for the bound peptide.

Computer Simulation↗
PubMed2001

Role of salt bridges in homeodomains investigated by structural analyses and molecular dynamics simulations.

Homeodomains are a class of helix-turn-helix DNA-binding protein motifs that play an important role in the control of cellular development in eukaryotes. They fold in a three alpha-helix structural module, where the third helix is the recognition helix that fits into the major groove of DNA. Structural analysis of the members of the homeodomain family led to the identification of interactions likely to stabilize the protein domains. Linking the helices pairwise, three salt bridges were found to be well preserved within the family. Also well conserved were two cation-pi interactions between aromatic and positively charged side chains. To analyze the structural role of the salt bridges, molecular dynamics simulations (MD) were carried out on the wild-type homeodomain from the Drosophila paired protein (1fjl) and on three mutants, which lack one or two salt bridges and mimic natural mutations in other homeodomains. Analysis of the trajectories revealed only small structural rearrangements of the three helices in all MD simulations, thereby suggesting that the salt bridges have no essential stabilizing role at room temperature, but rather might be important for improving thermostability. The latter hypothesis is supported by a good correlation between the melting midpoint temperatures of several homeodomains and the number of salt bridges and cation-pi interactions that connect secondary structures.

Amino Acid Sequence↗