Reply to the 'Comment on "On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility" Phys. Chem. Chem. Phys., 2018, 20, DOI: '.

In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too "small" to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole-methanol and indole-water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole-methanol-water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.