Evaluation of nine condensed-phase force fields of the GROMOS, CHARMM, OPLS, AMBER, and OpenFF families against experimental cross-solvation free energies

Abstract

Experimental solvation free energies are nowadays commonly included as target properties in the validation of condensed-phase force fields, sometimes even in their calibration. In a previous article [Kashefolgheta et al., J. Chem. Theory. Comput., 2020, 16, 7556–7580], we showed how the involved comparison between experimental and simulation results could be made more systematic by considering a full matrix of cross-solvation free energies . For a set of N molecules that are all in the liquid state under ambient conditions, such a matrix encompasses N × N entries for considering each of the N molecules either as solute (A) or as solvent (B). In the quoted study, a cross-solvation matrix of 25 × 25 experimental value was introduced, considering 25 small molecules representative for alkanes, chloroalkanes, ethers, ketones, esters, alcohols, amines, and amides. This experimental data was used to compare the relative accuracies of four popular condensed-phase force fields, namely GROMOS-2016H66, OPLS-AA, AMBER-GAFF, and CHARMM-CGenFF. In the present work, the comparison is extended to five additional force fields, namely GROMOS-54A7, GROMOS-ATB, OPLS-LBCC, AMBER-GAFF2, and OpenFF. Considering these nine force fields, the correlation coefficients between experimental values and simulation results range from 0.76 to 0.88, the root-mean-square errors (RMSEs) from 2.9 to 4.8 kJ mol⁻¹, and average errors (AVEEs) from −1.5 to +1.0 kJ mol⁻¹. In terms of RMSEs, GROMOS-2016H66 and OPLS-AA present the best accuracy (2.9 kJ mol⁻¹), followed by OPLS-LBCC, AMBER-GAFF2, AMBER-GAFF, and OpenFF (3.3 to 3.6 kJ mol⁻¹), and then by GROMOS-54A7, CHARM-CGenFF, and GROMOS-ATB (4.0 to 4.8 kJ mol⁻¹). These differences are statistically significant but not very pronounced, and are distributed rather heterogeneously over the set of compounds within the different force fields.