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At least 433 records · Page 24Linked to original sources
PubMed2005

The alpha-helical propensity of the cytoplasmic domain of phospholamban: a molecular dynamics simulation of the effect of phosphorylation and mutation.

We have used molecular dynamics simulations to investigate the effect of phosphorylation and mutation on the cytoplasmic domain of phospholamban (PLB), a 52-residue protein that regulates the calcium pump in cardiac muscle. Simulations were carried out in explicit water systems at 300 K for three peptides spanning the first 25 residues of PLB: wild-type (PLB(1-25)), PLB(1-25) phosphorylated at Ser16 and PLB(1-25) with the R9C mutation, which is known to cause human heart disease. The unphosphorylated peptide maintains a helical conformation from 3 to 15 throughout a 26-ns simulation, in agreement with spectroscopic data. Comparison with simulations of a fourth peptide truncated at Pro21 showed the importance of the region from 17 to 21 in preventing local unfolding of the helix. The results suggest that residues 11-16 are more likely to unfold when specific capping motifs are not present. It is proposed that protein kinase A exploits the intrinsic flexibility of the 11-21 region when binding PLB. In agreement with available CD and NMR data, the simulations show a decrease in the helical content upon phosphorylation. The phosphorylated peptide is characterized by helix spanning residues 3-11, followed by a turn that optimizes the salt-bridge interaction between the side chains of the phosphorylated Ser-16 and Arg-13. Replacing Arg-9 with Cys results in unfolding of the helix from C9 and an overall decrease of the helical conformation. The simulations show that initiation of unfolding is due to increased solvent accessibility of the backbone atoms near the smaller Cys. It is proposed that the loss of inhibitory potency upon Ser-16 phosphorylation or R9C mutation of PLB is due to a similar mechanism, in which the partial unfolding of the cytoplasmic helix of PLB results in a conformation that interacts with the cytoplasmic domain of the calcium pump to relieve its inhibition.

Algorithms↗
PubMed2006

Molecular dynamics simulations of the tetracycline-repressor protein: the mechanism of induction.

Molecular dynamics simulations on the tetracycline-repressor (TetR) protein, both in the absence of an inducer and complexed with the inducers tetracycline and 5a,6-anhydrotetracycline, show significant differences in the structures and dynamics of the induced and non-induced forms of the protein. Calpha-density-difference plots, low-frequency normal vibrations and inter-residue interaction energies all point to a common mechanism of induction. The inducer displaces Asp156 from the magnesium ion in the binding pocket, leading to a short cascade of rearrangements of salt bridges that results in the allosteric change. The increased flexibility of the induced form of the protein is suggested to contribute to the decrease in binding affinity to DNA on induction.

Aspartic Acid↗
PubMed1996

DL_POLY_2.0: a general-purpose parallel molecular dynamics simulation package.

DL_POLY_2.0 is a general-purpose parallel molecular dynamics simulation package developed at Daresbury Laboratory under the auspices of the Council for the Central Laboratory of the Research Councils. Written to support academic research, it has a wide range of applications and is designed to run on a wide range of computers: from single processor workstations to parallel supercomputers. Its structure, functionality, performance, and availability are described.

Computer Simulation↗
PubMed2004

Optimal laser control of ultrafast photodissociation of I2- in water: mixed quantum/classical molecular dynamics simulation.

A linearized optimal control method in combination with mixed quantum/classical molecular dynamics simulation is used for numerically investigating the possibility of controlling photodissociation wave packets of I(2)(-) in water. Optimal pulses are designed using an ensemble of photodissociation samples, aiming at the creation of localized dissociation wave packets. Numerical results clearly show the effectiveness of the control although the control achievement is reduced with an increase in the internuclear distance associated with a target region. We introduce effective optimal pulses that are designed using a statistically averaged effective dissociation potential, and show that they semiquantitatively reproduce the control achievements calculated by using optimal pulses. The control mechanisms are interpreted from the time- and frequency-resolved spectra of the effective optimal pulses.

Journal Article↗
PubMed2005

Molecular-dynamics simulations for nonclassical kinetics of diffusion-controlled bimolecular reactions.

Molecular-dynamics simulations are presented for the diffusion-controlled bimolecular reaction A+B<==>C in two and three dimensions. The reactants and solvent molecules are modeled as spheres interacting via continuous potential-energy functions. The interaction potential between two reactants contains a deep well that results in a reaction. When the solvent concentration is low and the reactant dynamics is essentially ballistic, the system reaches equilibrium rapidly, and the reaction follows classical kinetics with exponential decay to the equilibrium. When the solvent concentration is high the particles enter the normal diffusion regime quickly and nonclassical behavior is observed, i.e., the reactant concentrations approach equilibrium as t(-d/2) where d is the dimensionality of space. When the reaction well depth is large, however, the reaction becomes irreversible within the simulation time. In this case the reactant concentrations decay as t(-d/4). Interestingly this behavior is also observed at intermediate times for reversible reactions.

Journal Article↗
PubMed2005

Interaction potentials from periodic density-functional theory calculations: molecular-dynamics simulations of Au clusters deposited on the TiN (001) surface.

Molecular-dynamics simulations of gold particles deposited on a TiN (001) surface have been accounted for through classical pair potentials describing the atom force field. The interaction between Ti-N, Ti-Ti, N-N, Au-Au, Au-Ti, and Au-N pairs was estimated by following a procedure in which the interaction energy between two sets of atoms is estimated from density-functional calculations performed with periodic boundary conditions using plane waves as basis set. The pair potentials were expressed as the sum of two contributions: long range in a Coulomb form and a short-range term, which included the rest of the energy contributions. Simulations of the TiN (001) isolated surface reproduced the already described surface relaxation, with a rippling parameter in agreement with that found from a purely first-principles approach. Simulations of gold deposition on such surfaces showed the formation of metal clusters with well-defined fcc structure and epitaxially grown.

Journal Article↗
PubMed1984

Phenylalanine transfer RNA: molecular dynamics simulation.

Yeast phenylalanine transfer RNA was subjected to a 12-picosecond molecular dynamics simulation. The principal features of the x-ray crystallographic analysis are reproduced, and the amplitudes of atomic displacements appear to be determined by the degree of exposure of the atoms. An analysis of the hydrogen bonds shows a correlation between the average length of a bond and the fluctuation in that length and reveals a rocking motion of bases in Watson-Crick guanine X cytosine base pairs. The in-plane motions of the bases are generally of larger amplitude than the out-of-plane motions, and there are correlations in the motions of adjacent bases.

Chemical Phenomena↗
PubMed2006

Investigation of finite system-size effects in molecular dynamics simulations of lipid bilayers.

In the absence of external stress, the surface tension of a lipid membrane vanishes at equilibrium, and the membrane exhibits long wavelength undulations that can be described as elastic (as opposed to tension-dominated) deformations. These long wavelength fluctuations are generally suppressed in molecular dynamics simulations of membranes, which have typically been carried out on membrane patches with areas <100 nm2 that are replicated by periodic boundary conditions. As a result, finite system-size effects in molecular dynamics simulations of lipid bilayers have been subject to much discussion in the membrane simulation community for several years, and it has been argued that it is necessary to simulate small membrane patches under tension to properly model the tension-free state of macroscopic membranes. Recent hardware and software advances have made it possible to simulate larger, all-atom systems allowing us to directly address the question of whether the relatively small size of current membrane simulations affects their physical characteristics compared to real macroscopic bilayer systems. In this work, system-size effects on the structure of a DOPC bilayer at 5.4 H2O/lipid are investigated by performing molecular dynamics simulations at constant temperature and isotropic pressure (i.e., vanishing surface tension) of small and large single bilayer patches (72 and 288 lipids, respectively), as well as an explicitly multilamellar system consisting of a stack of five 72-lipid bilayers, all replicated in three dimensions by using periodic boundary conditions. The simulation results are compared to X-ray and neutron diffraction data by using a model-free, reciprocal space approach developed recently in our laboratories. Our analysis demonstrates that finite-size effects are negligible in simulations of DOPC bilayers at low hydration, and suggests that refinements are needed in the simulation force fields.

Computer Simulation↗
PubMed2000

Molecular dynamics simulation accurately predicts the experimentally-observed distributions of the (C, N, O) protein atoms around water molecules and sodium ions.

A molecular dynamics simulation of the operator binding domain of the lambda repressor protein has been carried out. The protein was embedded in explicit waters, Na(+) and CL(-) ions. The Amber 4.1 computer package and the Cornell et al. Force field were used for energy-minimization and molecular dynamics simulation. We find that the atoms distributions in the environment of waters and Na(+) ions are in excellent agreement with those derived from the analysis of water molecules in crystal structures and ion-binding proteins. We also find that, on the whole, both distributions are similar to each other.

Carbon↗
PubMedDate not supplied

Molecular dynamics simulation of nucleic acids: successes, limitations, and promise.

In the last five years we have witnessed a significant increase in the number publications describing accurate and reliable all-atom molecular dynamics simulations of nucleic acids. This increase has been facilitated by the development of fast and efficient methods for treating the long-range electrostatic interactions, the availability of faster parallel computers, and the development of well-validated empirical molecular mechanical force fields. With these technologies, it has been demonstrated that simulation is not only capable of consistently reproducing experimental observations of sequence specific fine structure of DNA, but also can give detailed insight into prevalent problems in nucleic acid structure, ion association and specific hydration of nucleic acids, polyadenine tract bending, and the subtle environmental dependence of the A-DNA-B-DNA duplex equilibrium. Despite the advances, there are still issues with the methods that need to be resolved through rigorous controlled testing. In general, these relate to deficiencies of the underlying molecular mechanical potentials or applied methods (such as the imposition of true periodicity in Ewald simulations and the need for energy conservation), and significant limits in effective conformational sampling. In this perspective, we provide an overview of our experiences, provide some cautionary notes, and provide recommendations for further study in molecular dynamics simulation of nucleic acids.

Artifacts↗
PubMed1996

Novel methods for molecular dynamics simulations.

In the past year, significant progress was made in the development of molecular dynamics methods for the liquid phase and for biological macromolecules. Specifically, faster algorithms to pursue molecular dynamics simulations were introduced and advances were made in the design of new optimization algorithms guided by molecular dynamics protocols. A technique to calculate the quantum spectra of protein vibrations was introduced.

Algorithms↗
PubMed1999

Conformational variety for the ansa chain of rifamycins: comparison of observed crystal structures and molecular dynamics simulations.

The antibiotic activity (via inhibition of DNA-dependent RNA polymerase, DDRP) of rifamycins has been correlated to the conformation of the ansa chain, which can be described by means of 17 torsion angles defined along the ansa backbone. It has been shown that favourable or unfavourable conformations of the ansa chain in rifamycin crystals are generally diagnostic of activity or inactivity against isolated DDRP. The principles of structure correlation suggest that the torsional variety observed in rifamycin crystals should mimic the dynamic flexibility of the ansa chain in solution. Twenty-six crystal structures of rifamycins are grouped into two classes (active and non-active). For each class the variance of the 17 ansa backbone torsion angles is analysed. Active compounds show a well-defined common pattern, while non-active molecules are more scattered, mainly due to steric constraints forcing the molecules into unfavourable conformations. The experimental distributions of torsion angles are compared to the torsional freedom of the ansa chain simulated by molecular dynamics calculations performed at different temperatures and conditions on rifamycin S and rifamycin O, which represent a typical active and a typical sterically constrained molecule, respectively. It is shown that the torsional variety found in the crystalline state samples the dynamic behaviour of the ansa chain for active compounds. The methods of circular statistics are illustrated to describe torsion angle distributions.

Crystallography, X-Ray↗
PubMed1994

Probing structure-function relationships in human immunodeficiency virus type 1 protease via molecular dynamics simulation.

This chapter has focused on the application of molecular dynamics computer simulations and related molecular modeling techniques to the study of HIV protease structure and structure-function relationships. The abundance of crystallographic data provides ample experimental quantities (average structures, temperature factors, and hydrogen bond topography) to validate the computational techniques employed. Furthermore, these studies provide insight into the structure and functional energetics of HIV-1 protease that would be difficult or impossible to study experimentally. This chapter covers studies that investigate correlated motion between and within subunits of the protease, mutants of the protease that disrupt the tertiary structure and dimer formation, and studies of HIV-1 protease-inhibitor complexes that rationalize both the protonation state of the active site and the observed binding strength of these complexes. These studies demonstrate that MD is capable of contributing to our understanding of structure-function relationships and may aid in the design of potential therapeutics.

Amino Acid Sequence↗
PubMedDate not supplied

Eutectic formation analysis of amino acid mixtures using molecular dynamics simulations.

The mechanism of eutectic formation was investigated via computer-aided molecular dynamics techniques based on experimental results. The CBZ group mixtures CBZ-l-Asp/d-AlaNH2 x HCl/methanol, CBZ-l-Asp/l-PheOMe x HCl/methanol, and CBZ-l-Tyr/l-ArgNH2 x 2HCl/methanol formed transparent eutectic melts. The non-CBZ group mixtures l-Asp/d-AlaNH2 x HCl/methanol, l-Asp/l-PheOMe x HCl/methanol, and l-Tyr/l-ArgNH2 x 2HCl/methanol did not form eutectic melts. According to molecular dynamics simulation results, increase in the kinetic energy values of eutectic forming mixtures was much larger than the increase in potential energy over a temperature shift from 298 to 333 K. However, the results for non-eutectic forming mixtures were reversed. The Coulomb interaction energies of eutectic forming mixtures significantly decreased, because eutectic melting can increase the mobility of molecules in the mixtures. The enhancement of molecular mobility was confirmed by increased self-diffusion constant values, and the change of solid-to-liquid phase was detected by radial distribution function results. The periodic boundary conditions for calculation of molecular dynamics were found to be reliable.

Alanine↗
PubMed2004

Molecular dynamics simulation studies of the transport and adsorption of a charged macromolecule onto a charged adsorbent solid surface immersed in an electrolytic solution.

Molecular dynamics simulations were performed in order to study the transport and adsorption of a charged macromolecule (desmopressin) onto a charged solid surface in an electrolytic solution. The strong Coulombic interaction from the charged solid surface represents the major force for accelerating, orienting, entrapping in the electrical double layer, and adsorbing the macromolecule onto the charged solid surface. The macromolecule is flattened as it approaches the charged surface, giving rise to a stronger surface exclusion effect that shields surface sites. When adsorbed, the macromolecule is restrained by a surface interaction more than one hundred times stronger than the thermal energy, of which 99.8% results from the strong dominant Coulombic interaction, and trapped by a hydration layer adjacent to the surface. This leads to zero lateral displacement of the adsorbed macromolecule and indicates that surface diffusion is a physically implausible mechanism in similar systems. Explicit solvent is required for realistic representation of the macromolecular structure and the surface interaction energy. The adsorbed macromolecule also decreased the electrostatic potential gradient perpendicular to the charged solid surface and introduced additional electrostatic potential gradients laterally. The results obtained from the molecular dynamics simulations confirm the importance of electrophoretic migration and support the physical mechanisms used in a macroscopic continuum model that predicts an overshoot in the concentration of a charged macromolecule in the adsorbed phase under certain conditions of pH and ionic strength.

Adsorption↗
PubMed1994

Structure-function studies of DNA damage using ab initio quantum mechanics and molecular dynamics simulation.

Studies of ring-saturated pyrimidine base lesions are used to illustrate an integrated modeling approach that combines quantum-chemical calculations with molecular dynamics simulation. Electronic structure calculations on the lesions in isolation reveal strong conformational preferences due to interactions between equatorial substituents to the pyrimidine ring. Large distortions of DNA should result when these interactions force the methyl group of thymine to assume an axial orientation, as is the case for thymine glycol but not for dihydrothymine. Molecular dynamics simulations of the dodecamer d(CGCGAATTCGCG)2 with and without a ring-saturated thymine lesion at position T7 support this conclusion. Implications of these studies for recognition of thymine lesions by endonuclease III are also discussed.

Base Sequence↗
PubMed1995

Comparative molecular dynamics simulation studies of salmon and bovine trypsins in aqueous solution.

The flexibility and conformational behaviour of salmon and bovine trypsins were modelled with a 300 ps molecular dynamics simulation in aqueous solution. Trajectories from both trypsins were analysed to eventually detect differences in mobility that could explain observed variations in stability and activity. The simulations were performed at 300 K with all the acidic groups deprotonated and the basic groups protonated. The radius of gyration, the overall r.m.s. deviation from the starting structure as a function of time, together with the r.m.s. deviation from the starting structures as a function of residue number, demonstrated that the simulations were stable and representative of the X-ray structures of both enzymes. Isotropic Debye-Waller factors were calculated from the fluctuations for main-chain atoms and were in good agreement with experimental values. The overall dynamic properties of the two enzymes were similar. Based on the present 300 ps molecular dynamics simulation, it cannot be concluded that either of the two enzymes is more 'flexible' than the other. However, there are clearly differences in mobility on a more detailed level and for particular regions.

Amino Acid Sequence↗
PubMed2004

Pores in bilayer membranes of amphiphilic molecules: coarse-grained molecular dynamics simulations compared with simple mesoscopic models.

We investigate pores in fluid membranes by molecular dynamics simulations of an amphiphile-solvent mixture, using a molecular coarse-grained model. The amphiphilic membranes self-assemble into a lamellar stack of amphiphilic bilayers separated by solvent layers. We focus on the particular case of tensionless membranes, in which pores spontaneously appear because of thermal fluctuations. Their spatial distribution is similar to that of a random set of repulsive hard disks. The size and shape distribution of individual pores can be described satisfactorily by a simple mesoscopic model, which accounts only for a pore independent core energy and a line tension penalty at the pore edges. In particular, the pores are not circular: their shapes are fractal and have the same characteristics as those of two-dimensional ring polymers. Finally, we study the size-fluctuation dynamics of the pores, and compare the time evolution of their contour length to a random walk in a linear potential.

Journal Article↗