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Coordination state probabilities for the [Zn(H(2)O)(n)(CH(3)OH)(m)](2+) complex in aqueous methanol solutions are calculated as a function of the bulk solution concentration, and the number of methanol ligands, m = 0, 1, ..., 6 with n+m = 6. Zinc ion solvation free energies, which serve to normalize these probabilities, also reproduce the methanol concentration dependence of the experimentally derived free energy of zinc ion transfer from water to aqueous methanol solutions. Coordination state probabilities, p(n, m), are derived by extending quasi-chemical theory of ion hydration to solvent mixtures and mixed ligands. Free energy contributions to p(n, m) include the free energy of forming the mixed-ligand complex in the ideal gas, obtained by quantum chemical calculations, and the solvation free energy of the complex, approximated by a dielectric continuum model. We find that replacing water ligands with methanol ligands preferentially stabilizes methanol-rich complexes in the ideal gas. Conversely, water-rich complexes are stabilized by the solvation free energy contribution, such that the [Zn(H(2)O)(6)](2+) complex is the dominant species in solution for all methanol concentrations considered. Stabilization of the methanol-rich complexes is a consequence of the local coordination chemistry, dominated by the delocalization of charge on the zinc ion, while the stabilization of water-rich complexes is a consequence of favorable ion-solvent electrostatic interactions and smaller dielectric cavities for the water-rich complexes at fixed total charge in the dielectric continuum model. Our analysis also highlights an entropic contribution associated with the reversible work required to remove n water and m methanol molecules from bulk solution to form the [Zn(H(2)O)(n)(CH(3)OH)(m)](2+) complex, which captures the methanol concentration dependence of the solvation free energy of the zinc ion.

Cosolvent hydrophobic preferential interactions with methane in aqueous methanol solutions are evaluated on the basis of the solute excess chemical potential derived from molecular simulations using the quasi-chemical (QC) theory generalization of the potential distribution theorem (PDT). We find that the methane-methanol preferential interaction parameter derived from QC theory quantitatively captures the favorable solvation of methane in methanol solutions in terms of important local solute-solvent (water and methanol) intermolecular interactions within a defined inner shell around the solute, and nonlocal solute interactions with solvent molecules outside this inner shell. Moreover, a unique inner shell can be defined such that the preferential interaction parameter is derived exclusively from the free energy of cavity formation in the aqueous cosolvent solution without the solute, where this cavity corresponds to the specified inner shell, and the mean interaction or binding energy of the solute with solvent molecules outside this inner shell. This inner-shell definition leads to a description of solute-cosolvent preferential interactions in which the molecular details of those interactions are derived from the effect of cosolvent on cavity statistics in the aqueous cosolvent solution alone. The finding suggests that solution thermodynamic behavior beyond steric exclusion (macromolecular crowding) contribute to the molecular mechanisms by which cosolvent preferential interactions influence protein stability and activity.