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At least 217 records · Page 12Linked to original sources
PubMed1998

Molecular dynamics simulation of a 13-mer duplex DNA: a PvuII substrate.

Parallel version of AMBER 4.1 was ported and optimised on the Indian parallel supercomputer PARAM OpenFrame built around Sun Ultra Sparc processors. This version of AMBER program was then used to carry out molecular dynamics (MD) simulations on 5'-TGACCAGCTGGTC-3', a substrate for PvuII enzyme. MD simulations in water are carried out under following conditions: (i) unconstrained at 300 K (230 ps); (ii) unconstrained at 283 K (500 ps); (iii) Watson-Crick basepair constrained at 283 K (1 ns); and (iv) Watson-Crick basepair constrained with ions at 283 K (1.2 ns). In all these simulation studies, the molecule was observed to be bending and maximum distortions in the double helix around was seen around the G7:C7' basepair, which is the phosphodiester bond that is cleaved by PvuII. Analysis of MD simulation with ions carried out for 1.2 ns also pointed out that the conformation of double helix alternates between a conformation close to B-form and close to A-form. It is argued that a bent non-standard conformation is recognised by the PvuII enzyme. The maximum bend occurs at the G7:C7' region, weakening the phosphodiester bond and allows His48 to get placed in such a fashion to permit the scission through a general base mechanism. The bending and distortion observed is a property of the sequence which acts as a substrate for PvuII enzyme. This is confirmed by carrying out MD studies on the Dickerson's sequence d(CGCGAATTCGCG)2 as a reference molecule, which practically does not bend or get deformed.

Base Composition↗
PubMed1995

Molecular mechanics and dynamics studies on two structurally related amide-modified DNA backbones for antisense technology.

The effect of the replacement of the natural phosphodiester linkage -C3'-O-PO2-O-CH2-C4'- in the DNA strand of RNA.DNA hybrid duplexes by either of the two amide linkages -C3'-CH2-CO-NH-CH2-C4'- or -C3'-CH2-NH-CO-CH2-C4' has been investigated by molecular mechanics (MM) and molecular dynamics (MD) simulations. Conformational analysis has been used to assess various low-energy conformers of the amide-modified backbones. MD simulations have been carried out to study the dynamic behavior of the modified duplexes. The modified RNA.DNA hybrid double helices kept a conservative base pairing scheme during the MD simulations. Although the general behavior has been found to be similar to that of the corresponding wild-type hybrid duplexes, some notable differences, especially regarding the sugar puckering in the amide-modified DNA strands, have been observed. The behavior of the RNA strands in the hybrid duplexes has not been affected by the modified DNA strands and is similar to that in wild-type RNA.DNA duplexes.

Amides↗
PubMed2001

Molecular dynamics study of the energetic, mechanistic, and structural implications of a closed phosphate tube in ncd.

The switch 1 region of myosin forms a lid over the nucleotide phosphates as part of a structure known as the phosphate-tube. The homologous region in kinesin-family motors is more open, not interacting with the nucleotide. We used molecular dynamics (MD) simulations to examine a possible displacement of switch 1 of the microtubule motor, ncd, from the open conformation to the closed conformation seen in myosin. MD simulations were done of both the open and the closed conformations, with either MgADP or MgATP at the active site. All MD structures were stable at 300 K for 500 ps, implying that the open and closed conformers all represented local minima on a global free energy surface. Free energy calculations indicated that the open structure was energetically favored with MgADP at the active site, suggesting why only the open structure has been captured in crystallographic work. With MgATP, the closed and open structures had roughly equal energies. Simulated annealing MD showed the transformation from the closed phosphate-tube ncd structure to an open configuration. The MD simulations also showed that the coordination of switch 1 to the nucleotide dramatically affected the position of both the bound nucleotide and switch 2 and that a closed phosphate-tube may be necessary for catalysis.

Adenosine Diphosphate↗
PubMed1996

260 ps molecular dynamics simulation of substance P with hydrated dimyristoyl phosphatidyl choline bilayer.

We present here results on 260 pico seconds (ps) molecular dynamics (MD) simulation of substance P (SP) in hydrated bilayer of dimyristoyl phosphatidyl choline (DMPC) (39 molecules of DMPC with 776 water molecules). 260 ps MD simulation has been carried out in 0.001 ps time interval with united atom force field, using AMBER 4.0 package. Non bonded pair list was updated every 20 cycles using 12.5 Angstrom cut off distance. Analysis of MD data is done using our package ANALMD. The obtained models are presented using graphics package RASMOL. All simulations, analysis of MD data and graphics is done on INDIGO-2, R-4400 extreme graphics work station. Our results show no systematic change in order parameter, but reduction in transfraction of the chain torsional angles, compared to our earlier results on MD simulation on hydrated DMPC bilayer without SP. C-terminal and central peptide residues adopt partial helical conformation. Helix type as classified on the basis of H-bonds is between alpha and 3(10). The peptide backbone shows flexibility during heating runs. Later, it is stabilized and there was not much change in the spatial position of the backbone. Lipid matrix serves the role of immobilization of the peptide backbone in a preferred conformation.

Amino Acid Sequence↗
PubMed2006

Molecular dynamics of nicotinic acetylcholine receptor correlating biological functions.

The nicotinic acetylcholine receptor (nAChR) that mediates fast intercellular communication in response to neurotransmitters is a paradigm of ligand-gated ion channels. Molecular dynamics (MD) simulations are valuable in understanding membrane protein function at atomic level, providing useful clues for further experimental/theoretical studies. In this brief review, recent progress in MD simulations of the nAChR has been illustrated, mainly focusing on the latest simulation of the whole transmembrane domain of the receptor. On the basis of MD simulations, asymmetrical and asynchronous motions of five subunits were observed both in the ligand binding and transmembrane domains; a closed-to-open conformational shift of the gate was captured in different simulation systems; the contributions from the lipid molecules and other transmembrane segments rather than M2 to the gate switch as well as the conformational change of the whole channel were assessed; the dynamic behavior and related physical/chemical properties of the water molecules and cations within the ion channel were examined; and an experimentally comparable single-channel conductance and ion selectivity were obtained.

Kinetics↗
PubMed2004

A comparison of the dynamic behavior of monomeric and dimeric insulin shows structural rearrangements in the active monomer.

Molecular dynamics (MD) simulations (5-10ns in length) and normal mode analyses were performed for the monomer and dimer of native porcine insulin in aqueous solution; both starting structures were obtained from an insulin hexamer. Several simulations were done to confirm that the results obtained are meaningful. The insulin dimer is very stable during the simulation and remains very close to the starting X-ray structure; the RMS fluctuations calculated from the MD simulation agree with the experimental B-factors. Correlated motions were found within each of the two monomers; they can be explained by persistent non-bonded interactions and disulfide bridges. The correlated motions between residues B24 and B26 of the two monomers are due to non-bonded interactions between the side-chains and backbone atoms. For the isolated monomer in solution, the A chain and the helix of the B chain are found to be stable during 5ns and 10ns MD simulations. However, the N-terminal and the C-terminal parts of the B chain are very flexible. The C-terminal part of the B chain moves away from the X-ray conformation after 0.5-2.5ns and exposes the N-terminal residues of the A chain that are thought to be important for the binding of insulin to its receptor. Our results thus support the hypothesis that, when monomeric insulin is released from the hexamer (or the dimer in our study), the C-terminal end of the monomer (residues B25-B30) is rearranged to allow binding to the insulin receptor. The greater flexibility of the C-terminal part of the beta chain in the B24 (Phe-->Gly) mutant is in accord with the NMR results. The details of the backbone and side-chain motions are presented. The transition between the starting conformation and the more dynamic structure of the monomers is characterized by displacements of the backbone of Phe B25 and Tyr B26; of these, Phe B25 has been implicated in insulin activation.

Amino Acid Sequence↗
PubMed2005

Molecular-dynamics simulation for the characterization of liquid chromatographic stationary phase: effect of temperature.

The influence of temperature on the surface structure of the octadecylsilica (ODS) bonded phase was investigated with a molecular dynamics (MD) simulation. The MD simulation was applied to a molecular model consisting of three parts: amorphous silica base, dimethyloctadecylsilyl ligands and n-hexane as a mobile phase solvent. More detailed information on the effect of temperature was obtained at the low temperature region than that reported in our previous study. The motion of ODS ligands could be estimated by the mean square displacement (MSD) of the terminal carbon atoms of ODS ligands. The gauche fraction in the ODS ligand conformation can also be estimated to obtain the ligand conformation for each simulation condition in detail. It can be seen that an elevated temperature induced the more bent ligand conformation. The trend has a good agreement to that of the results experimentally observed by using various spectroscopic techniques such as nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), and Raman spectroscopy.

Journal Article↗
PubMed2001

Refinement of the NMR structures of alpha-conotoxin MI using molecular dynamics simulation with explicit solvent water and a full molecular force field.

Three NMR structures of alpha-conotoxin MI, a potent antagonist of the nicotinic acetylcholine receptor, have been refined using molecular dynamics (MD) simulation with explicit water. Although the convergence of the NMR structures of alpha-conotoxin MI was not sufficient to provide detailed structural features, the average structures obtained from MD simulations converged to one conformation, providing structural characteristics. The resulting structure was also found to be consistent with the results of amide proton-exchange experiments. These results demonstrate that MD simulation with explicit solvent water is very useful in refining NMR structures.

Conotoxins↗
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↗
PubMed2005

Free energy landscape of A-DNA to B-DNA conversion in aqueous solution.

The interconversion between the well-characterized A- and B-forms of DNA is a structural transition for which the intermediate states and the free energy difference between the two endpoints are not known precisely. In the present study, the difference between the Root Mean Square Distance (RMSD) from canonical A-form and B-form DNA is used as an order parameter to characterize this free energy difference using umbrella sampling molecular dynamics (MD) simulations with explicit solvent. The constraint imposed along this order parameter allows relatively unrestricted evolution of the intermediate structures away from both canonical A- and B-forms. The free energy difference between the A- and B-forms for the hexamer DNA sequence CTCGAG in aqueous solution is conservatively estimated to be at least 2.8 kcal/mol. A continuum of intermediate structures with no well-defined local minima links the two forms. The absence of any major barriers in the free energy surface is consistent with spontaneous conversion of the A-form DNA to B-form DNA in unconstrained simulations. The extensive sampling in the MD simulations (>0.1 mus) also allowed quantitative energetic characterization of local backbone conformational variables such as sugar pseudorotation angles and BI/BII state equilibria and their dependence on base identity. The absolute minimum in the calculated free energy profile corresponds closely to the crystal structure of the hexamer sequence, indicating that the present method has the potential to identify the most stable state for an arbitrary DNA sequence in water.

Computer Simulation↗
PubMed2006

Energetics of ion permeation, rejection, binding, and block in gramicidin A from free energy simulations.

The rigid force fields currently used in molecular dynamics (MD) simulations of biomolecules are optimized for globular proteins. Whether they can also be used in MD simulations of membrane proteins is an important issue that needs to be resolved. Here we address this issue using the gramicidin A channel, which provides an ideal test case because of the simplicity of its structure and the availability of a wealth of functional data. Permeation properties of gramicidin A can be summarized as "it conducts monovalent cations, rejects anions, and binds divalent cations." Hence, a comprehensive test should consider the energetics of permeation for all three types of ions. To that end, we construct the potential of mean force for K(+), Cl(-), and Ca(2+) ions along the channel axis. For an independent check of the potential-of-mean-force results, we also calculate the free energy differences for these ions at the channel center and binding sites relative to bulk. We find that "rejection of anions" is satisfied but there are difficulties in accommodating the other two properties using the current MD force fields.

Anions↗
PubMed2004

Impact of the solvent on the conformational isomerism of calix[4]arenes: a study based on continuum solvation models.

The influence of solvation on the conformational isomerism of calix[4]arene and p-tert-butylcalix[4]arene has been investigated by using the continuum model reported by Miertus, Scrocco, and Tomasi (MST). The quantum mechanical (QM) and semiclassical (SC) formalisms of the MST model have been considered for two different solvents (chloroform and water). The suitability of the QM-MST and SC-MST methods has been examined by comparison with previous results derived from classical molecular dynamics (MD) simulations with explicit solvent molecules. The application of the continuum model to the solute configurations generated by using in vacuo classical MD simulations provides a fast strategy to evaluate the effects of the solvent on the conformational preferences of calixarenes. These encouraging results allow us to propose the use of continuum models to solutes with complex molecular structures, which are traditionally studied by MD simulations.

Journal Article↗
PubMed2006

Liposomal drug transport: a molecular perspective from molecular dynamics simulations in lipid bilayers.

Computational methods to predict drug permeability across biomembranes prior to synthesis are increasingly desirable to minimize the investment in drug design and development. Significant progress in molecular dynamics (MD) simulation methodologies applied to lipid bilayer membranes, for example, is making it possible to move beyond characterization of the membranes themselves to explore various thermodynamic and kinetic processes governing membrane binding and transport. Such methods are also likely to be directly applicable to the design and optimization of liposomal delivery systems. MD simulations are particularly valuable in addressing issues that are difficult to explore in laboratory experiments due to the heterogeneity of lipid bilayer membranes at the molecular level. Insights emerging from MD simulations are contributing to an understanding of which regions within bilayers are most and least favored by solutes at equilibrium as the solute structure is varied, local diffusivities of permeants, and the origin of the amplified selectivity to permeant size imposed by lipid bilayer membranes, particularly as changes in composition increase acyl chain ordering.

Biological Transport↗
PubMed2006

Shock deformation of face-centred-cubic metals on subnanosecond timescales.

Despite its fundamental importance for a broad range of applications, little is understood about the behaviour of metals during the initial phase of shock compression. Here, we present molecular dynamics (MD) simulations of shock-wave propagation through a metal allowing a detailed analysis of the dynamics of high strain-rate plasticity. Previous MD simulations have not seen the evolution of the strain from one- to three-dimensional compression that is observed in diffraction experiments. Our large-scale MD simulations of up to 352 million atoms resolve this important discrepancy through a detailed understanding of dislocation flow at high strain rates. The stress relaxes to an approximately hydrostatic state and the dislocation velocity drops to nearly zero. The dislocation velocity drop leads to a steady state with no further relaxation of the lattice, as revealed by simulated X-ray diffraction.

Journal Article↗
PubMed2005

Validation of intermolecular pair potential model of SiH4: molecular-dynamics simulation for saturated liquid density and thermal transport properties.

We demonstrate a validation of the intermolecular pair potential model of SiH(4), which is constructed from ab initio molecular-orbital calculations and expressed as the sum of the exponential and the London dispersion terms. The saturated liquid densities of SiH(4) are calculated for temperatures from 100 to 225 K by molecular-dynamics (MD) simulation. The average deviation between the experiment and the MD simulation using the present potential model is 3.9%, while the deviations exceed 10% for other well-known potential models such as the five-center Lennard-Jones (LJ) model. Subsequently, the shear viscosity, the thermal conductivity, and the self-diffusion coefficient of liquid SiH(4) are calculated by an equilibrium MD simulation with the Green-Kubo formula from 100 to 225 K. The average deviations from experiment are 11.8% and 13.7% for the shear viscosity and the thermal conductivity, respectively. Comparing the present model with an empirical one-center LJ model, it turns out that the rotational energy transfer through the intermolecular potential energy, which comes from the anisotropic potential energy, plays an important role in the thermal conductivity of liquid SiH(4). These results indicate that the present intermolecular potential model has an ability to give realistic pictures for liquid SiH(4) through molecular simulations.

Journal Article↗
PubMed2001

Deducing hydration sites of a protein from molecular dynamics simulations.

Invariant water molecules that are of structural or functional importance to proteins are detected from their presence in the same location in different crystal structures of the same protein or closely related proteins. In this study we have investigated the location of invariant water molecules from MD simulations of ribonuclease A, HIV1-protease and Hen egg white lysozyme. Snapshots of MD trajectories represent the structure of a dynamic protein molecule in a solvated environment as opposed to the static picture provided by crystallography. The MD results are compared to an analysis on crystal structures. A good correlation is observed between the two methods with more than half the hydration sites identified as invariant from crystal structures featuring as invariant in the MD simulations which include most of the functionally or structurally important residues. It is also seen that the propensities of occupying the various hydration sites on a protein for structures obtained from MD and crystallographic studies are different. In general MD simulations can be used to predict invariant hydration sites when there is a paucity of crystallographic data or to complement crystallographic results.

Animals↗
PubMed2003

Molecular dynamics simulations of beta-cyclodextrin in aqueous solution.

Molecular dynamics (MD) simulations of beta-cyclodextrin (beta-CD) have been carried out in aqueous solution at 300 K over a period of about 200 ps using Tripos force field. The atomic trajectories obtained by these simulations have been analysed by means of the occurrence of hydrogen bonds. The MD simulations lead to an association of seven water molecules into the beta-CD cavity which is in a good agreement with X-ray crystallography experiments. This demonstrates that the force field used in the simulations is able to reproduce the experimentally observed hydrophilic-hydrophobic characteristics of beta-CD molecule.

Crystallography, X-Ray↗
PubMed2006

Peptide-TiO2 surface interaction in solution by ab initio and molecular dynamics simulations.

Ab initio periodic calculations and classical molecular dynamics (MD) simulations were performed to investigate the adsorption mode of alanine and a number of short peptides, in particular two peptides, alanine-glutamic acid and alanine-lysine, taken as model systems for the ionic self-complementary oligopeptide EAK16-II, onto TiO(2) (110) rutile surface, and their conformational characteristics upon adsorption. The atomistic description of the rutile surface and its interactions with water and peptide molecules were based on ab initio calculations, the TIP3P water model, the AMBER force field, and available parameters. By comparison with ab initio calculations, it is shown that MD simulations of reasonable duration can describe the main characteristics of the peptide-TiO(2) surface interaction in solution, at least on a short time scale. Atom-atom radial distribution functions, atom-surface distances, backbone and side chain dihedral angle distributions, and peptide-surface interaction energies have been analyzed. Once adsorbed onto the TiO(2) rutile surface by a bidentate interaction of both carboxyl oxygens with two adjacent Ti atoms, the small peptide studied showed a clear propensity to remain there and undergo relatively limited hinge-bending motions.

Adsorption↗