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In atomic force spectroscopic studies of the elastomeric protein ubiquitin, the [beta]-strands 1-5 serve as the force clamp. Simulations show how the rupture force in the force-induced unfolding depends on the kinetics of water molecule insertion into positions where they can eventually form hydrogen bonding bridges with the backbone hydrogen bonds in the force-clamp region. The intrusion of water into this region is slowed down by the hydrophobic shielding effect of carbonaceous groups on the surface residues of [beta]-strands 1-5, which thereby regulates water insertion prior to hydrogen bond breakage. The experiments show that the unfolding of the mechanically stressed protein is nonexponential due to static disorder. Our simulations show that different numbers and/ or locations of bridging water molecules give rise to a long-lived distribution of transition states and static disorder. We find that slowing down the translational (not rotational) motions of the water molecules by increasing the mass of their oxygen atoms, which leaves the force field and thereby the equilibrium structure of the solvent unchanged, increases the average rupture force; however, the early stages of the force versus time behavior are very similar for our 'normal' and fictitious 'heavy' water models. Finally, we construct six mutant systems to regulate the hydrophobic shielding effect of the surface residues in the force-clamp region. The mutations in the two termini of [beta]-sheets 1-5 are found to determine a preference for different unfolding pathways and change mutant's average rupture force. molecular dynamics simulation | single molecule spectroscopy | unfolding kinetics doi/ 10.1073/pnas.1013159107

Huntington's disease is linked to the insertion of glutamine (Q) in the protein huntingtin, resulting in polyglutamine (polyQ) expansions that self-associate to form aggregates. While polyQ aggregation has been the subject of intense study, a correspondingly thorough understanding of individual polyQ chains is lacking. Here we demonstrate a single molecule force-clamp technique that directly probes the mechanical properties of single polyQ chains. We have made polyQ constructs of varying lengths that span the length range of normal and diseased polyQ expansions. Each polyQ construct is flanked by the 127 titin module, providing a clear mechanical fingerprint of the molecule being pulled. Remarkably, under the application of force, no extension is observed for any of the polyQ constructs. This is in direct contrast with the random coil protein PEVK of titin, which readily extends under force. Our measurements suggest that polyQ chains form mechanically stable collapsed structures. We test this hypothesis by disrupting polyQ chains with insertions of proline residues and find that their mechanical extensibility is sensitive to the position of the proline interruption. These experiments demonstrate that polyQ chains collapse to form a heterogeneous ensemble of conformations that are mechanically resilient. We further use a heat-annealing molecular dynamics protocol to extensively search the conformation space and find that polyQ can exist in highly mechanically stable compact globular conformations. The mechanical rigidity of these collapsed structures may exceed the functional ability of eukaryotic proteasomes, resulting in the accumulation of undigested polyQ sequences in vivo. mechanical | polyglutamine | protein folding | single molecule

The mechanism of denaturation of proteins by urea is explored by using all-atom microseconds molecular dynamics simulations of hen lysozyme generated on BlueGene/L. Accumulation of urea around lysozyme shows that water molecules are expelled from the first hydration shell of the protein. We observe a 2-stage penetration of the protein, with urea penetrating the hydrophobic core before water, forming a 'dry globule.' The direct dispersion interaction between urea and the protein backbone and side chains is stronger than for water, which gives rise to the intrusion of urea into the protein interior and to urea's preferential binding to all regions of the protein. This is augmented by preferential hydrogen bond formation between the urea carbonyl and the backbone amides that contributes to the breaking of intrabackbone hydrogen bonds. Our study supports the 'direct interaction mechanism' whereby urea has a stronger dispersion interaction with protein than water. denaturing mechanism | dry globule | molecular dynamics | preferential binding | lysozyme unfolding

Thioredoxins are enzymes that catalyse disulphide bond reduction in all living organisms (1). Although catalysis is thought to proceed through a substitution nucleophilic bimolecular ([S.sub.N]2) reaction (1,2), the role of [...]

An innovative replica exchange (parallel tempering) method called replica exchange with solute tempering (REST) for the efficient sampling of aqueous protein solutions is presented here. The method bypasses the poor scaling with system size of standard replica exchange and thus reduces the number of replicas (parallel processes) that must be used. This reduction is accomplished by deforming the Hamiltonian function for each replica in such a way that the acceptance probability for the exchange of replica configurations does not depend on the number of explicit water molecules in the system. For proof of concept, REST is compared with standard replica exchange for an alanine dipeptide molecule in water. The comparisons confirm that REST greatly reduces the number of CPUs required by regular replica exchange and increases the sampling efficiency. This method reduces the CPU time required for calculating thermodynamic averages and for the ab initio folding of proteins in explicit water. molecular dynamics | Monte Carlo | parallel tempering | protein solutions | rough energy landscapes

The results of molecular dynamics simulations of the bovine pancreatic trypsin inhibitor (BPTI) in water with force fields that explicitly include polarization for both the protein and the water are presented. The findings reveal that the solvating water's relaxation is most affected when both the protein and the water models are polarizable.

We examine the role of electronic polarizability in water on short (tens of femtoseconds), intermediate (hundreds of femtoseconds), and long ([approximately equal to]1 ps) time scales by comparing molecular dynamics results to experimental data for vibrational spectroscopy of HOD in liquid [D.sub.2]O. Because the OH absorption frequency is sensitive to the details of the atomic forces experienced in the liquid, our results provide important quantitative comparisons for several popular empirical water potentials. When compared with their fixed-charge counterparts, the polarizable models give similar slower long time constants for the decay of vibrational correlations and reorientational motion that is in better agreement with experiments. Polarizable potentials yield qualitatively dissimilar predictions for frequency fluctuations and transition dipole moment fluctuations at equilibrium. Models that confine the polarizability to the plane of the molecule (i.e., TIP4P-FQ) overestimate the width of the distribution describing frequency fluctuations by more than a factor of two. These models also underestimate the amplitude of the hydrogen-bond stretch at 170 [cm.sup.-1]. A potential that has both an out-of-plane polarization and fluctuating charges, POL5-TZ, compares best with experiments. We interpret our findings in terms of microscopic dynamics and make suggestions that may improve the quality of emerging polarizable force fields for water. hydrogen-bond dynamics | molecular dynamics | polarizable force fields

A new approach is developed to study the dynamics of the localized process in solution and other condensed phase system. The approach employs a fluctuating elastic boundary (FEB) model, which encloses the simulated system in an elastic bag that mimics the effects of the bulk solvent.

A polarizable force field is produced for a series of small molecules, representative of functional groups found in organic and biochemical series. High-level ab initio results are used for fitting values of all the parameters except for the dispersion-term coefficient B in the B/r (super 6) energy term.

A molecular dynamics study of the depletion of water (drying) around a single and between two hydrophobic nanoscale oblate plates in explicit water as a function of the distance of separation between them, their size, and the strength of the attraction between the plates and the water molecules is presented. A simple macroscopic thermodynamic model based on Young's law successfully predicts drying between the stacked plates and accounts for the free-energy barriers to this drying. However, because drying around a single plate is not macroscopic, a molecular theory is required to describe it. The data are consistent with the rate-determining step in the hydrophobic collapse of the two plates being a large-scale drying fluctuation, characterized by a free-energy barrier that grows with particle size.

A method for calculating the quantum canonical rate constant of chemical reactions in a many body system with the help of a short-time flux autocorrelation function combined with a maximum entropy numerical analytical continuation scheme is described. The rate constant is expressed as the time integral of real-time flux autocorrelation function.

This article discusses quantum mechanical and mixed quantum-classical approaches for studying vibrational energy relaxation function in condensed phase systems. Results indicate that vibronic absorption spectrum depends on both electronic transitions and vibrational relaxation.

The solvation behavior of C1- was investigated at both planar and curved interfaces.

A study of the classical limit of nonradiative electronic relaxation in condensed phase systems is presented. Time domain analysis of the results is included.

A study was conducted to analyze the fluctuating charge, fluctuating dipole and combined models for substituted benzenes. A general linear response framework containing both fluctuating charges and dipoles was formulated. An electrostatic model was then completed by adding fixed charges fit to the zero-field quantum chemical electrostatic potential. Results indicated the accuracy of the many-body response of the peptide models and was in good agreement with ab initio computations of the changes in the electrostatic potential.

The bulk density and oxygen-oxygen radial distribution function of neat water can be used to determine solution thermodynamics of small hydrophobic hard sphere solutes. Information theory and computer simulations of neat liquid water can also be used to calculate the hydration free energies and the potential of mean force for realistic solute-solvent force fields. However, studying solute particles that display dewetting requires corrections in binomial moments and spatial correlations.

A study has been conducted to develop a computationally polarizable force field which can model fluctuations of the point charges on atomic sites in response to the environment in aqueous solvation of acetamide and trans- and cis-N-methylacetamide. These fluctuating charge models were applied to the calculation of solvation free energies using an explicit molecular solvent and a dielectric continuum solvent. The results of these experiments are presented and discussed.

The potential of mean force (PMF) for two spherical methane molecules in a nonpolar water model (WK) and in a corresponding polarizable water mode (PSRWK) for the sample Me-W interaction are compared. By using molecular dynamics with Ewald boundary conditions it is shown that the water models have the same dielectric and structural properties. PSRWK modelling favors solvent-separating pairing but the WK model favors contact pairing.

Continuum method calculations are compared with molecular dynamics for the calculation of the solvation properties of a single water molecule. The single water molecule has partial charges on the atomic sites. The continuum theory calculation shows a quadratic dependence on charge for the free energy and a linear dependence for electric fields and electrostatic potential. Two models of solvent reorganizations are exhibited to improve continuum theory. Simple continuum theory is not able to predict accurate electric fields and electrostatic potentials.

Molecular dynamic simulations have shown that a 7 M aqueous urea solution has disclosed a chain of purely hydrophobic groups that otherwise adopts a compact structure in pure water. The studies have shown that, in denaturing proteins, urea has formed stronger dispersion interactions with the protein side chains and backbone than water and hence, is able to dissolve the core hydrophobic region.

The role of poor-solvent effects is clarified by using a simplified coarse-grained model of a protein-like entropic chain consisting of 76 spheres at the positions of C-[alpha] atoms of ubiquitin connected by springs. It is shown that the incorporation of correct entropic chain persistence into coarse-grain models used for collapse and folding simulations is vital, while the elasticity theory is of minor importance, because the dominant contributions are not due to chain entropy.

Molecular dynamics simulations are used for studying the temperature dependence of hydrophobic association and drying transition of large-scale solutes. The deviations of the predicted have emerged due to increased fluctuations, characterizing finite systems, as the temperature has increased.

The efficiency of newly developed replica exchange with solute tempering (REST) was assessed by applying it to three large solvated peptide systems ([alpha]-helix, [beta]-hairpin, TrpCage). It was found that the original implementation of REST, with the protein as the central group, performs poorly on systems where the folded (F) and unfolded (U) conformations have vastly different structural energies.

Molecular dynamics simulations are used to examine the solvent mediated attraction and drying between two nanoscale hydrophobic surfaces in aqueous salt solutions. The results have shown the unique effects of electrolytes on the hydrophobic properties of solutes of various sizes, ranging from small nanoscale particles to large nanoscale surfaces.

An investigation on the effect of salts on the solvent-induced interactions between hydrophobic particles dispersed in explicit aqueous solution is conducted as a function of the salt's ionic charge density by molecular dynamics simulations. The aggregate is found to form a 'micelle-like' structure, in which the ions are preferentially adsorbed at the surface of the aggregate, at low concentrations of low charge density ions.

The hydrophobic aided replica exchange method (HAREM) is introduced to accelerate the simulation of all-atom protein folding in explicit solvent. The method is applied to a small representative protein, the alpha-helix 3K(I), and it is found that the HAREM method successfully folds the protein with 4 ns, while the regular replicas exchange method does not fold the same protein within 5 ns, even with many more replicas.

The fluctuating elastic boundary (FEB) model is extended for molecular dynamics simulation of bulk water and solvated alanine dipeptide. The applicability of this FEB model to biomolecular simulations is examined through the analysis of conformational population distribution of solvated alanine dipeptide.

Molecular dynamics simulations are performed to study the dynamics of interfacial water confined in the interdomain region of a two-domain protein, BphC enzyme. The results show that near the protein surface the water diffusion constant is much smaller and the water-water hydrogen bond lifetime is much longer than that in bulk.

A modified Delphi model combined with a molecular dynamics method is devised to calculate the free energy landscape of a small protein. Based on the replica exchange method (REM), the molecular dynamics method is used to sample the conformational space of the beta-hairpin, the C-terminus beta-hairpin of protein G, as before.

A general method to calculate the self-diffusion coefficient tensor from molecular dynamics (MD) in a finite region is proposed. The results revealed that far from the interface the diffusion tensor is found of distance as expected, and the diffusion coefficient has the value D approximately is 0.22 A degree 2/ps, in agreement with what is found in the bulk liquid.

Proposes a method which uses centroid molecular dynamics (CMD) real-time data in conjunction with the imaginary-time data generated using path integral Monte Carlo simulations. Improvements achieved by including short-time CMD data; Exhibition of how maximum entropy method is used to extract accurate dynamic information from short-time CMD data.

Investigates the accuracy of the recently proposed centroid molecular dynamics (CMD) method in the presence of highly anharmonic steep short range repulsive potentials in real time quantum correlation. Comparison of CMD simulation results with exact quantum results; Range of accuracy.

Reports on the combination of multicanonical sampling and jump walking methods to provide an effective means of overcoming quasiergodicity in Monte Carlo simulations. Infrequent storage of configurations generated during a long multicanonical sampling; Systems used to compare multicanonical jump walking with regular jump walking and straight multicanonical ensemble sampling.

Reports on the path-integral diffusion Monte Carlo (PI-DMC) method to calculate ground state position dependent observables in quantum many-body systems. Ground state observables and imaginary time path integral Monte Carlo; Staging of an uneven polymer chain; One-dimensional harmonic oscillator.

Extends the cage correlation function method for calculating the hopping rate in Zwanzig's model of self-diffusion in liquids to liquids composed of polyatomic molecules. Vibrational density of states of inherent structures in liquids; Calculation of diffusion constants.

Describes a polarizable force field for peptides, using all-atom nonelectrostatic terms and electrostatics based on a fluctuating charge model. Analysis of the fitting procedure and specific techniques to obtain a specific and accurate model; Many-body effects accurately produced by the model.

Evaluates a Monte Carlo algorithm for the sampling of the protein conformation space called Smart-Walking method. Relation of the method to the J-Walking method; Conformational equilibrium of proteins; Ergodic measures used to study the ergodicity of the sampling; Application results on random potential surfaces and protein systems.

Discusses the development of a theory for relating quantum and classical time correlation functions in the context of vibrational energy relaxation. Assumed characteristics of the classical system; Proposed approximation quantum correction; Estimation of the vibrational relaxation time by a fully classical theory than by a mixed quantum-classical theory.

Examines the molecular dynamics influencing the effect of pressure on hydrogen bonding in glycerol ethers. Degree of hydrogen bonding increases with increasing pressure; Discussion of the relevance of the fragility of glycerol increases.

Analyzes the pathological behavior of the imaginary-time discretized path integral for systems interacting through Coulomb potentials and/or bounded by hard walls. Construction of an effective potential that depends on Trotter number; Treatment of Coulombic potentials by means of Monte Carlo at low Trotter numbers.

Focuses on the problem of calculating the electronic absorption spectrum of a chromophore with intramolecular degrees of freedom coupled to a condensed phase environment. Use of imaginary-time path integral Monte Carlo techniques; Alternative analytic continuation methods considered; Expression for the electronic absorption spectrum.

Describes a method for estimating the hopping rate for Zwanzig's model of self-diffusion in liquids on rough potential energy surfaces. Introduction of the cage correlation function; Results from a set of simulations on Lennard-Jones particles; Analytic model for the diffusion constant; Breakdown of Zwanzig's hopping mechanism.

Molecular dynamics simulations of 1-buthyl-3 methylimidazolium hexafluorophosphate ([bmim][PF6]) is presented. Radial distribution functions, average density, and mean-square displacements for the individual ions are computed.

The short-time dynamics of loop unfolding and hydrogen bond formation and breaking in the alanine pentapeptide at room temperature is studied using several constant-energy molecular dynamics simulations of about 4 ns of duration. The results are analyzed in terms of time histories of 'core' alpha-carbon dihedral angles.

A study was conducted, using a diatomic in molecules semiempirical ligand field (DIMSELF) method, to calculate ground and excited many-body potential energy surfaces for an arbitrary transition metal ion in an arbitrary complex system. The result shows how the ligand field theory and diatomics in molecules can be connected to generate ground and excited electronic potential energy surfaces of complex systems with transition metal ions.