Free-energy analysis of cosolvent effects on biomolecular aggregation

Abstract

A theoretical-computational scheme for analyzing the effect of an added cosolvent on the aggregation equilibrium of a biomolecule is presented. The scheme is based on the relation that the derivative of the excess chemical potential with respect to the cosolvent concentration is determined by the corresponding derivative of the solvation free energy averaged over the solute configurations. The role of solvation is highlighted in the cosolvent-induced shift in the aggregation equilibrium of a biomolecule, and an illustrative analysis with all-atom models is provided for an amyloid peptide by employing the energy-representation method to compute the solvation free energy. Adenosine triphosphate (ATP) and urea are adopted as a cosolvent added to water, and the former is seen to inhibit aggregation more effectively than the latter. The solvation free energy is decomposed into the contributions from intermolecular-interaction components such as electrostatic, van der Waals, and excluded-volume, and it is found that the cosolvent effects are governed by the van der Waals interaction for both of ATP and urea. A theoretical-computational scheme is formulated to analyze the shift in the aggregation equilibrium of a biomolecule upon addition of a cosolvent. The cosolvent-induced change in the solvation free energy plays the central role in the formulation, and it is shown for a model peptide that the ATP and urea cosolvents make the solvent environment more favorable for dissociated monomers than for aggregates. The effect of ATP to inhibit aggregation is brought by van der Waals interactions due to cancellation of the electrostatic effects between ATP and water.