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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

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.

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.

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 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.