Solvent scaling scheme for studying solvent restructuring thermodynamics in solvation processes

We consider the solvent-solvent interaction energy change associated with the solvent restructuring in response to a progressive change in the interaction between the solute and the solvent molecules. We derive expressions for this solvent restructuring energy using a new solvent scaling scheme in which the solvent-solvent potential energy is scaled relative to its reference value. We find that we can naturally extend the familiar single-coupling parameter methodology with a second coupling parameter that controls the solvent-solvent interactions. In doing so we can not only access information about the solvent restructuring energy, but also quantify the statistical correlations between the fluctuations of the solute-solvent and the solvent-solvent interaction energies. Based on these findings we implement a molecular dynamics simulation strategy to evaluate the solvent restructuring energetics associated with turning on the electrostatic interactions between one initially uncharged water molecule dissolved in liquid water, using both the TIP4P-2005 and OPC water models. We also use the theory to explore the dependence of the solvent restructuring energy on solute-solvent coupling, both in general and in the special case in which the solute-solvent coupling is accurately described by the linear response approximation.