Free-Energy Calculations of Ionic Hydration Consistent with the Experimental Hydration Free Energy of the Proton

Computational free-energy correction strategies and the choice of experimental proton hydration free energy, Δ G s * (H + ), are analyzed to investigate the apparent controversy in experimental thermodynamics of ionic hydration. Without corrections, the hydration free-energy (Δ G hyd ) calculations match experiments with Δ G s * (H + ) = −1064 kJ/mol as reference. Using the Galvani surface potential the resulting (real) Δ G hyd are consistent with Δ G s * (H + ) = −1098 kJ/mol. When applying, in an ad hoc manner, the discrete solvent correction, Δ G hyd matching the “consensus” Δ G s * (H + ) of −1112 kJ/mol are obtained. This analysis rationalizes reports on Δ G hyd calculations for ions using different experimental references. For neutral amino acid side chains Δ G hyd are independent of the water model, whereas there are large differences in Δ G hyd due to the water model for charged species, suggesting that long-range ordering of water around ions yields an important contribution to the Δ G hyd . These differences are reduced significantly when applying consistent corrections, but to obtain the most accurate results it is recommended to use the water model belonging to the force field.