Theoretic information approach to protein stabilization by solvent engineering

A novel approach based on molecular thermodynamics and the information theo ry is proposed to quantify the influence of water-miscible additives on pro tein stability. According to the two-state mechanism of inactivation, solve nt effects are described in terms of perturbation of the equilibrium betwee n the folded and unfolded protein forms. The model provides the dependence of the protein's melting temperature on the additive concentration. Effects of the latter are accounted for by an empirical parameter related to the f ree energy of transfer of the protein from the pure to the mixed solvent. T he model was tested using experimental data relative to the influence of hy droxylic and aminoacidic additives on the thermal unfolding of hen egg lyso zyme and erythrocyte carbonic anhydrase. Fitting parameters were correlated in terms of a theoretic information index characterizing the additive's mo lecule and incorporating an atomic-composition term and a topological contr ibution. Model calculations agreed very well with experimental data, sugges ting that the molecular information content of the additive can be used eff ectively to correlate solvent-induced perturbations of stability. The proce dure was also used to predict melting temperatures in systems containing bi nary mixtures of additives and to reconstruct thermal unfolding curves in t he different media.