Computer simulation study of folding thermodynamics and kinetics of proteins in osmolytes and denaturants

Abstract

In living cells, the presence of macromolecular crowders, such as osmolytes or denaturants, strongly affects the stability of folded proteins. The overall effects depend on the size, concentration, and chemical properties of the crowding agents. This work uses an all-atom G model of the Trp-cage in spherical solvents to probe the physical origin of protein stabilization/destabilization by osmolytes/denturants. The solvent quality is controlled by the solvent-protein contact εPS that can represent repulsive osmolytes (εPS > 0) or attractive denaturants (εPS < 0). The model is used to show that protein stabilization by osmolytes proceeds by an excluded volume, entropy-driven mechanism. Protein destabilization by denaturant is shown to be driven by changes in enthalpy. It is found that small osmolytes are the most effective stabilizer of proteins. Folding simulations of the Trp-cage in osmolytes observe a two-fold increase in folding rates, for small osmolytes. This is due to an osmolyte-induced shift to more compact unfolded protein conformations. © IOP Publishing Ltd.