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PubMed2002

Conformational states of the glucocorticoid receptor DNA-binding domain from molecular dynamics simulations.

Molecular dynamics simulations (MD) have been performed on variant crystal and NMR-derived structures of the glucocorticoid receptor DNA-binding domain (GR DBD). A loop region five residues long, the so-called D-box, exhibits significant flexibility, and transient perturbations of the tetrahedral geometry of two structurally important Cys4 zinc finger are seen, coupled to conformational changes in the D-box. In some cases, one of the Cys ligands to zinc exchanges with water, although no global distortion of the protein structure is observed. Thus, from MD simulation, dynamics of the D-box could partly be explained by solvent effects in conjunction with structural reformation of the zinc finger.

Amino Acid Sequence↗

PubMed2006

Structural investigation of syringomycin-E using molecular dynamics simulation and NMR.

Syringomycin-E (SR-E) is a cyclic lipodepsinonapeptide produced by certain strains of the bacterium Pseudomonas syringae pv. syringae. It shows inhibitory effects against many fungal species, including human pathogens. Its primary biological target is the plasma membrane, where it forms channels comprised of at least six SR-E molecules. The high-resolution structure of SR-E and the structure of the channels are currently not known. In this paper, we investigate in atomic detail the molecular features of SR-E in water by NMR and in water and octane by molecular dynamics simulation (MD). We built a model of the peptide and examined its structure in water and octane in 200 ns MD simulations both with and without distance restraints derived from NMR NOE data. The resulting trajectories show good agreement with the measured NOEs and circular dichroism data from the literature and provide atomistic models of SR-E that are an important step toward a better understanding of the antifungal and antibacterial activity of this peptide.

Biophysical Phenomena↗

PubMed1990

Insights into the function of the zinc hydroxide-Thr199-Glu106 hydrogen bonding network in carbonic anhydrases.

The exact functional role of the zinc hydroxide (water)-Thr199-Glu106 hydrogen bond network in the carbonic anhydrases is unknown. However, from the results of molecular dynamics simulations (MD) we are able to better define its function. From computer graphics analysis and MD simulations on the zinc hydroxide form of human carbonic anhydrase II we find that this interaction forces the hydroxide hydrogen atom to be in a "down" position relative to the deep water-binding pocket. From previous work we have found that this pocket is a high-affinity binding site for CO2. We also note that during the timescale of our simulation (126 ps) the hydrogen bonds between the hydroxide hydrogen atom and Thr199 and the one between Thr199 and Glu106 are not fluxional. We propose that the role of the zinc hydroxide (water)-Thr199-Glu106 hydrogen bond network is to lock the hydrogen atom in the down position in order to expose the CO2 molecule bound in the deep water pocket to a lone pair of the hydroxide oxygen atom. This would allow for the rapid reaction of the CO2 molecule around the zinc ion. Furthermore, if the hydroxide hydrogen atom were not locked in the down position the binding of CO2 to the deep water pocket could be interfered with by the unrestrained hydroxide hydrogen atom (e.g. the N-Zn-O-H torsion could undergo rotational transitions that would partially block the deep water pocket). In summary, the roles we ascribe to this hydrogen bonding network are (1) to allow for facile access of CO2 to the deep water pocket and (2) to allow for maximal exposure of a hydroxide oxygen lone pair to the CO2 carbon atom.

Binding Sites↗

PubMed2004

PEACH 4 with ABINIT-MP: a general platform for classical and quantum simulations of biological molecules.

A program package for molecular simulations of biological molecules was developed. The package, "PEACH version 4 with ABINIT-MP version 20021029," was constructed by incorporating ABINIT-MP, a program for the fragment molecular orbital (FMO) method [Chem.Phys. Lett. 313 (1999) 701], into PEACH, a program package for classical molecular dynamics simulations (MD). A few capabilities of the package were demonstrated. First, high parallel efficiency of FMO was demonstrated in a single point calculation of a protein. Second,FMO-MD simulations [Chem. Phys. Lett. 372 (2003) 342] of a peptide were performed with and without explicit solvent, and the simulations showed the influence of the solvent on the electronic state of the peptide.

Computational Biology↗

PubMed2005

Simulation and experiment conspire to reveal cryptic intermediates and a slide from the nucleation-condensation to framework mechanism of folding.

There is a change from three-state to two-state kinetics of folding across the homeodomain superfamily of proteins as the mechanism slides from framework to nucleation-condensation. The tendency for framework folding in this family correlates with inherent helical propensity. The cellular myeloblastis protein (c-Myb) falls in the mechanistic transition region. An earlier, preliminary report of protein engineering experiments and molecular dynamics simulations (MD) showed that the folding mechanism for this protein has aspects of both the nucleation-condensation and framework models. In the more in-depth analysis of the MD trajectories presented here, we find that folding may be attributed to both of these mechanisms in different regions of the protein. The folding of the loop, middle helix, and turn is best described by nucleation-condensation, whereas folding of the N and C-terminal helices may be described by the framework model. Experimentally, c-Myb folds by apparent two-state kinetics, but the MD simulations predict that the kinetics hide a high-energy intermediate. We stabilized this hypothetical folding intermediate by deleting a residue (P174) in the loop between its second and third helices, and the mutant intermediate is long-lived in the simulations. Equilibrium and kinetic experiments demonstrate that folding of the DeltaP174 mutant is indeed three-state. The presence and shape of the intermediate observed in the simulations were confirmed by small angle X-ray scattering experiments.

Computer Simulation↗

PubMed2000

Studies on the solution conformation and dynamics of a polysaccharide from Sinorhizobium fredii HH103 and its monosaccharide repeating unit.

The conformational behavior of the homopolysaccharide isolated from Sinorhizobium fredii HH103 and its monosaccharide repeating unit (5-acetamido-3,5,7,9-tetradeoxy-7-(3-hydroxybutyramido)-L-glycero- L- manno-nonulosonic acid) was analyzed by nuclear magnetic resonance (NMR) spectroscopy and extensive molecular dynamics simulations (MD). The results indicate that the glycosidic linkages and lateral chains may adopt a variety of conformations. MD simulations using the generalized Born solvent-accessible surface area (GB/SA) continuum solvent model for water and the MM3* force field provide a population distribution of conformers that satisfactorily agrees with the experimental NMR data for the torsional degrees of freedom of the molecule.

Carbohydrate Conformation↗

PubMed2006

Asymmetric stability among the transmembrane helices of lactose permease.

Combining structure determinations from nuclear magnetic resonance (NMR) data and molecular dynamics simulations (MD) under the same environmental conditions revealed a startling asymmetry in the intrinsic conformational stability of secondary structure in the transmembrane domain of lactose permease (LacY). Eleven fragments, corresponding to transmembrane segments (TMs) of LacY, were synthesized, and their secondary structure in solution was determined by NMR. Eight of the TMs contained significant regions of helical structure. MD simulations, both in DMSO and in a DMPC bilayer, showed sites of local stability of helical structure in these TMs, punctuated by regions of conformational instability, in substantial agreement with the NMR data. Mapping the stable regions onto the crystal structure of LacY reveals a marked asymmetry, contrasting with the pseudosymmetry in the static structure: the secondary structure in the C-terminal half is more stable than in the N-terminal half. The relative stability of secondary structure is likely exploited in the transport mechanism of LacY. Residues supporting proton conduction are in more stable regions of secondary structure, while residues key to substrate binding are found in considerably unstable regions of secondary structure.

Amino Acid Sequence↗

PubMed2003

Hetaryleneaminopolyols and hetarylenecarbopeptoids: a new type of glyco- and peptidomimetics. Syntheses and studies on solution conformation and dynamics.

Ready access to a new class of oligomers has been demonstrated by the synthesis of hetaryleneaminopolyols and hetarylenecarbopeptoids using 3-hydroxymethyl-5-(4-amino-4-deoxy-d-arabinotetritol-1-yl)-2-methylfuran and 5-(4-amino-4-deoxy-d-arabinotetritol-1-yl)-2-methyl-3-furoic acid as novel scaffolds. The conformational behavior of peptidomimetics 22, 23, 25, 26, and 36 have been analyzed by NMR spectroscopy and extensive molecular dynamics simulations. MD simulations using the GB/SA continuum solvent model for water and the MM3 force field provide a population distribution of conformers which satisfactorily agrees with the experimental NMR data for the torsional degrees of freedom of the molecule.

Amino Acids↗

PubMed2006

The effect of methanol on lipid bilayers: an atomistic investigation.

The interactions of methanol with lipid bilayers were studied by means of molecular dynamics (MD) simulations. Our MD simulations focus on the effect of approximately 11.3 mol% methanol on two fully hydrated dipalmitoylphosphatidylcholine (DPPC) and palmitoyloleoylphosphatidylcholine (POPC) lipid bilayers both in the fluid phase and under equilibrium conditions at 323 and 298 K, respectively. The effects of methanol on bilayers structural characteristics were investigated. In both systems the simulations show that the presence of relatively high concentration of methanol leads to a significant increase in the area per lipid. The increase in the area per lipid is accompanied by a corresponding decrease of the bilayer thickness such that the volume occupied per lipid does not change significantly in the presence of methanol. Other properties such as ordering of phospholipid tails and lateral diffusion of the lipids are also affected significantly by the presence of methanol. Consistent with other previously reported MD simulation studies of bilayers in the presence of methanol (albeit at a significantly smaller concentration of 1 mol%) our study shows very few hydrogen bonding formation between lipids and methanol.

Hydrogen Bonding↗

PubMed1996

Dimer asymmetry in superoxide dismutase studied by molecular dynamics simulation.

Molecular dynamics (MD) simulations of 100 ps have been carried out to study the active-site behaviour of the Cu,Zn superoxide dismutase dimer (SOD) in water. The active site of each subunit was monitored during the whole simulation by calculating the distances between functional residues and the catalytic copper. The results indicate that charge orientation is maintained at each active site but the solvent accessibility varies. Analysis of the MD simulation, carried out by using the atomic displacement covariance matrix, has shown a different intra-subunit correlation pattern for the two monomers and the presence of inter-subunit correlations. The MD simulation presented here indicates an asymmetry in the two active sites and different dynamic behaviour of the two SOD subunits.

Animals↗

PubMed2005

Odd-even variations in the wettability of n-alkanethiolate monolayers on gold by water and hexadecane: a molecular dynamics simulation study.

Molecular dynamics (MD) simulations were performed to investigate odd-even chain length dependencies in the wetting properties of self-assembled monolayers (SAMs) of n-alkanethiols [CH3(CH2)n-1SH] on gold by water and hexadecane. Experimentally, the contact angle of hexadecane on the SAMs depends on whether n is odd or even, while contact angles for water show no odd-even dependence. Our MD simulations of this system included a microscopic droplet of either 256 water molecules or 60 hexadecane molecules localized on an n-alkanethiolate SAM on gold with either an even or odd chain length. Contact angles calculated for these nanoscopic droplets were consistent with experimentally observed macroscopic trends in wettability, namely, that hexadecane is sensitive to structural differences between odd- and even-chained SAMs while water is not. Structural properties for the SAMs (including features such as chain tilt, chain twist, and terminal methyl group tilt) were calculated during the MD simulations and used to generate IR spectra of these films that compared favorably with experimental spectra. MD simulations of SAMs in contact with slabs of water and hexadecane revealed that the effects of these solvents on the structure of the SAM was restricted to the chain terminus and had no effect on the inner structure of the SAM. The density profiles for water and hexadecane on the SAMs were different in that water displayed a significant depletion in its density at the liquid/SAM interface from its bulk value, while no such depletion occurred for hexadecane. This difference in contact may explain the lack of an odd-even variation in the wetting characteristics of water on these surfaces, because the water molecules are positioned further away from the surface and, therefore, are not sensitive to the structural differences in the average orientations for the terminal methyl groups in odd- and even-chained SAMs. In contrast, the differences in the wetting properties of hexadecane on the odd- and even-chained SAMs may reflect the closer proximity of these molecules to the SAM surface and a resulting greater sensitivity to the differences in the terminal methyl group orientations in the SAMs. SAM-solvent interaction energies were calculated during the MD simulations, yielding interaction energies that differed on the even- and odd-chained surfaces by approximately 10% for hexadecane and negligibly for water, in accord with estimates using experimental wetting results.

Alkanes↗

PubMed2005

Simulation of screw dislocation motion in iron by molecular dynamics simulations.

Molecular dynamics (MD) simulations are used to investigate the response of a/2<111> screw dislocation in iron submitted to pure shear strain. The dislocation glides and remains in a (110) plane; the motion occurs exclusively through the nucleation and propagation of double kinks. The critical stress is calculated as a function of the temperature. A new method is developed and used to determine the activation energy of the double kink mechanism from MD simulations. It is shown that the differences between experimental and simulation conditions lead to a significant difference in activation energy. These differences are explained, and the method developed provides the link between MD and mesoscopic simulations.

Journal Article↗

PubMed2003

Dynamics of Ca2+-saturated calmodulin D129N mutant studied by multiple molecular dynamics simulations.

Fifteen independent 1-nsec MD simulations of fully solvated Ca(2+) saturated calmodulin (CaM) mutant D129N were performed from different initial conditions to provide a sufficient statistical basis to gauge the significance of observed dynamical properties. In all MD simulations the four Ca(2+) ions remained in their binding sites, and retained a single water ligand as observed in the crystal structure. The coordination of Ca(2+) ions in EF-hands I, II, and III was sevenfold. In EF-hand IV, which was perturbed by the mutation of a highly conserved Asp129, an anomalous eightfold Ca(2+) coordination was observed. The Ca(2+) binding loop in EF-hand II was observed to dynamically sample conformations related to the Ca(2+)-free form. Repeated MD simulations implicate two well-defined conformations of Ca(2+) binding loop II, whereas similar effect was not observed for loops I, III, and IV. In 8 out of 15 MD simulations Ca(2+) binding loop II adopted an alternative conformation in which the Thr62 >C=O group was displaced from the Ca(2+) coordination by a water molecule, resulting in the Ca(2+) ion ligated by two water molecules. The alternative conformation of the Ca(2+) binding loop II appears related to the "closed" state involved in conformational exchange previously detected by NMR in the N-terminal domain fragment of CaM and the C-terminal domain fragment of the mutant E140Q. MD simulations suggest that conformations involved in microsecond exchange exist partially preformed on the nanosecond time scale.

Asparagine↗

PubMed2005

A molecular dynamics study of the structural stability of HIV-1 protease under physiological conditions: the role of Na+ ions in stabilizing the active site.

HIV-1 protease is most active under weakly acidic conditions (pH 3.5-6.5), when the catalytic Asp25 and Asp25' residues share 1 proton. At neutral pH, this proton is lost and the stability of the structure is reduced. Here we present an investigation of the effect of pH on the dynamics of HIV-1 protease using MD simulation techniques. MD simulations of the solvated HIV-1 protease with the Asp25/25' residues monoprotonated and deprotonated have been performed. In addition we investigated the effect of the inclusion of Na(+) and Cl(-) ions to mimic physiological salt conditions. The simulations of the monoprotonated form and deprotonated form including Na(+) show very similar behavior. In both cases the protein remained stable in the compact, "self-blocked" conformation in which the active site is blocked by the tips of the flaps. In the deprotonated system a Na(+) ion binds tightly to the catalytic dyad shielding the repulsion between the COO(-) groups. Ab initio calculations also suggest the geometry of the active site with the Na(+) bound closely resembles that of the monoprotonated case. In the simulations of the deprotonated form (without Na(+) ions), a water molecule bound between the Asp25 Asp25' side-chains. This disrupted the dimerization interface and eventually led to a fully open conformation.

Aspartic Acid↗

PubMed2005

O2 interaction and reactivity on a model hydroxylated rutile(110) surface.

Recently several theoretical studies have examined oxygen adsorption on the clean, reduced TiO2(110) surface. However the photocatalytic behavior of TiO2 and the scavenging ability of oxygen are known to be influenced by the presence of surface hydroxyls. In this paper the chemistry of O2 on the hydroxylated TiO2 surface is investigated by means of first-principles total energy calculations and molecular dynamics (MD) simulations. The MD trajectories show a direct, spontaneous reaction between O2 and the surface hydroxyls, thus supporting the experimental hypothesis that the reaction does not necessarily pass through a chemisorbed O2 state. Following this reaction, the most stable chemisorbed intermediates are found to be peroxide species HO2 and H2O2. Although these intermediates are very stable on the short time scale of MD simulations, the energetics suggests that their further transformation is connected to a new 300 K feature observed in the experimental water temperature programmed desorption (TPD) spectrum. The participation of two less stable intermediate states, involving terminal hydroxyls and/or chemisorbed water plus oxygen adatoms, to the desorption process, is not supported by the total energy calculations. Analysis of the projected density of states, however, suggests the possibility that these intermediates have a role in completing the surface oxidation immediately before desorption.

Journal Article↗

PubMed2004

Characterization of the conformational space of a triple-stranded beta-sheet forming peptide with molecular dynamics simulations.

Molecular dynamics (MD) simulations have been performed on a series of mutants of the 20 amino acid peptide Betanova in order to critically assess the ability of MD simulations to reproduce the folding and stability of small beta-sheet-forming peptides on currently accessible timescales. Simulations were performed in both water and in 40% methanol solution, using an explicit solvent model. The simulations suggest that all mutants adopt a wide range of conformations in solution, that the structures are highly flexible, and that stabilization of compact structures is due to a delicate balance of hydrophobic and polar side-chain interactions. Simulations longer than 100 ns, although not sufficient for a complete thermodynamic and kinetic description of the system, sample an ensemble of compact conformations characterized by the loss of ordered beta-sheet secondary structure. This suggests that no significant free energy barrier separates the different conformations available.

Algorithms↗

PubMed2006

Structure and dynamics of N-methyl-N-propylpyrrolidinium bis(trifluoromethanesulfonyl)imide ionic liquid from molecular dynamics simulations.

Molecular dynamics (MD) simulations were performed on N-methyl-N-propylpyrrolidinium bis(trifluoromethanesulfonyl)imide (mppy+TFSI-) from 303 to 393 K to improve understanding of the structure and ion transport of this ionic liquid. The density, ion self-diffusion coefficients, conductivity, and viscosity of mppy+TFSI- predicted from MD simulations are in good agreement with experimental measurements. The time-dependent shear modulus of the ionic liquids was calculated and compared with that for nonionic liquids. On average each mppy+ cation was found to be coordinated by four TFSI- anions. The angular distributions of N(TFSI-)-N(mppy+)-N(TFSI-) and N(mppy+)-N(TFSI-)-N(mppy+) exhibit a maximum at 80-90 degrees and a second maximum at 180 degrees . Correlation of ion motion was found to lower ionic conductivity by approximately one-third from the expected value based upon ion self-diffusion coefficients. Rotational motion of the cation and anion are anisotropic with the degree of anisotropy increasing with decreasing temperature. Electrostatic interactions are responsible for slowing down the dynamics of the ionic liquid by more than an order of magnitude and a dramatic decrease of the time-dependent shear modulus.

Journal Article↗

PubMed2006

Structure, dynamics, and elasticity of free 16s rRNA helix 44 studied by molecular dynamics simulations.

Molecular dynamics (MD) simulations were employed to investigate the structure, dynamics, and local base-pair step deformability of the free 16S ribosomal helix 44 from Thermus thermophilus and of a canonical A-RNA double helix. While helix 44 is bent in the crystal structure of the small ribosomal subunit, the simulated helix 44 is intrinsically straight. It shows, however, substantial instantaneous bends that are isotropic. The spontaneous motions seen in simulations achieve large degrees of bending seen in the X-ray structure and would be entirely sufficient to allow the dynamics of the upper part of helix 44 evidenced by cryo-electron microscopic studies. Analysis of local base-pair step deformability reveals a patch of flexible steps in the upper part of helix 44 and in the area proximal to the bulge bases, suggesting that the upper part of helix 44 has enhanced flexibility. The simulations identify two conformational substates of the second bulge area (bottom part of the helix) with distinct base pairing. In agreement with nuclear magnetic resonance (NMR) and X-ray studies, a flipped out conformational substate of conserved 1492A is seen in the first bulge area. Molecular dynamics (MD) simulations reveal a number of reversible alpha-gamma backbone flips that correspond to transitions between two known A-RNA backbone families. The flipped substates do not cumulate along the trajectory and lead to a modest transient reduction of helical twist with no significant influence on the overall geometry of the duplexes. Despite their considerable flexibility, the simulated structures are very stable with no indication of substantial force field inaccuracies.

Base Pairing↗