Fast Computation of Solvation Free Energies with Molecular Density Functional Theory: Thermodynamic-Ensemble Partial Molar Volume Corrections

TL;DR

This paper demonstrates that Molecular Density Functional Theory can efficiently compute solvation free energies with accuracy comparable to molecular dynamics, by applying thermodynamic-ensemble partial molar volume corrections, significantly reducing computational cost.

Contribution

It introduces a thermodynamic-ensemble partial molar volume correction to MDFT, improving solvation free energy calculations and extending the correction to 3D-RISM methods.

Findings

MDFT achieves similar accuracy to molecular dynamics for solvation energies.

The partial volume correction enables ensemble-appropriate free energy estimates.

The correction can be applied to 3D-RISM, supporting empirical approaches.

Abstract

Molecular Density Functional Theory (MDFT) offers an efficient implicit- solvent method to estimate molecule solvation free-energies whereas conserving a fully molecular representation of the solvent. Even within a second order ap- proximation for the free-energy functional, the so-called homogeneous reference uid approximation, we show that the hydration free-energies computed for a dataset of 500 organic compounds are of similar quality as those obtained from molecular dynamics free-energy perturbation simulations, with a computer cost reduced by two to three orders of magnitude. This requires to introduce the proper partial volume correction to transform the results from the grand canoni- cal to the isobaric-isotherm ensemble that is pertinent to experiments. We show that this correction can be extended to 3D-RISM calculations, giving a sound theoretical justifcation to empirical partial molar volume corrections that have been proposed recently.