Solvent accessible surface area-assessed molecular basis of osmolyte-induced protein stability

In the solvent modulated protein folding, under certain physiological conditions, an equilibrium exists between the unfolded and folded states of the protein without any need to break or make a covalent bond. Here, interactions between various protein groups (peptides) and solvent molecules play a major role in determining the directionality of the chemical reaction. However, quantitative determination of such interactions lacks any unified theory. To this end, a solvation model is developed based on statistical mechanics, and the thermodynamic transfer free energy model. According to this model, polarity and the fractional solvent accessible surface areas contribute to the interaction energies. The current work is inspired by Street et al., Proc. Natl. Acad. Sci. USA 2006, 103, 13997; that was specifically developed for predicting transfer free energies for protein backbone. The present model further develops the method in order to include various orientations of participating interactant surfaces of suitable areas. The model is evaluated for amino acid side chains besides backbone. As model systems, we consider naturally occurring amino acid residues solvated in ten different osmolytes which are small organic compounds known to modulate protein stability. The present model is able to predict the correct trend of the osmolyte-peptide interactions ranging from the stabilizing to destabilizing. The versatility of this model facilitates calculating any solute-solvent interaction energies.