Free-energy analysis of the hydration and cosolvent effects on the β-sheet aggregation through all-atom molecular dynamics simulation.

Energetics was analyzed for the aggregation of an 11-residue peptide. An all-atom molecular dynamics simulation was conducted with explicit solvent, and the energy-representation theory of solution was employed to compute the solvation free energies of the peptide and its aggregates. The aggregation in the pure-water solvent was observed to be inhibited by the solvation. The driving force of aggregate formation is the interactions among the peptide molecules, and the sum of the intra-aggregate and solvation terms per monomer is more favorable for larger aggregates. The effect of the cosolvent was then examined by focusing on the mixtures of water with urea and dimethyl sulfoxide (DMSO). It was actually shown that the derivative of the excess chemical potential of a flexible solute species with respect to the cosolvent concentration is determined exactly by the corresponding derivative of the free energy of solvation. The cosolvent effect on the equilibrium of aggregate formation can thus be addressed by comparing the solvation free energies with and without the cosolvent, and both the urea and DMSO cosolvents were found to inhibit the aggregation. The cosolvent-induced change in the solvation free energy was further decomposed into the contributions from the cosolvent and water. Their dependencies on the degree of aggregation were seen to be weak for large aggregates, and the roles of the electrostatic, van der Waals, and excluded-volume components in the solvation energetics were discussed.