Solvation Thermodynamics from the Perspective of Endpoints DFT.

Abstract

Solvation thermodynamics is concerned with the evaluation and physical interpretation of solvation free energies. Endpoints DFT provides a framework for computing solvation free energies by combining molecular simulations with a version of the classical density-functional theory of solutions which focuses on ω, the indirect (solvent-mediated) part of the solute-solvent potential of mean force (indirect PMF). The simulations are performed at the endpoints of a hypothetical charging process which transforms the solvent density from the pure liquid state to that of the solution state. The endpoints DFT expression for solvation free energy can be shown to be equivalent to the standard expression for which the key quantity is the direct correlation function, but it has the advantage that the indirect term ω is more focused on the change in solvent-solvent correlations with respect to the pure liquid as the solute is inserted into the solution. In this Perspective, we review recent developments of endpoints DFT, highlighting a series of papers we have written together beginning in 2017. We emphasize the importance of dimensionality reduction as the key to the evaluation of endpoints DFT expressions and present a recently developed, spatially resolved version of the theory. The role of interfacial water at certain positions which stabilize or destabilize a solute in solution can be analyzed with the spatially resolved version, and it is of considerable interest to investigate how changes in solvation affect protein-ligand binding and conformational landscapes from an endpoints DFT perspective. Endpoints DFT can also be employed in materials science; an example involving the rational design strategy for polymer membrane separation is described. The endpoints DFT method is a scheme to evaluate the solvation free energy by introducing approximations to integrate the classical density functional over a charging parameter. We have further proposed a new functional which captures the correct dependence of the indirect PMF ω at both endpoints of the charging process, and we review how it might be employed in future work.