Identifying Systematic Force Field Errors Using a 3D-RISM Element Counting Correction

Abstract

Hydration free energies of small molecules are commonly used as benchmarks for solvation models. However, errors in predicting hydration free energies are partially due to the force fields used and not just the solvation model. To address this, we have used the 3D reference interaction site model (3D-RISM) of molecular solvation and existing benchmark explicit solvent calculations with a simple element count correction (ECC) to identify problems with the non-bond parameters in the general AMBER force field (GAFF). 3D-RISM was used to calculate hydration free energies of all 642 molecules in the FreeSolv database, and a partial molar volume correction (PMVC), ECC, and their combination (PMVECC) were applied to the results. The PMVECC produced a mean unsigned error of 1.01±0.04kcal/mol and root mean squared error of 1.44±0.07kcal/mol, better than the benchmark explicit solvent calculations from FreeSolv, and required less than 15 s of computing time per molecule on a single CPU core. Importantly, parameters for PMVECC showed systematic errors for molecules containing Cl, Br, I, and P. Applying ECC to the explicit solvent hydration free energies found the same systematic errors. The results strongly suggest that some small adjustments to the Lennard–Jones parameters for GAFF will lead to improved hydration free energy calculations for all solvent models.

Solvation entropy, enthalpy and free energy prediction using a multi-task deep learning functional in 1D-RISM

“…Labute et al calculated HFE values for a dataset of 504 neutral organic molecules, obtaining an RMSD of 1.18 kcal mol −1 . 17 A similar approach has been proposed by Casillas et al , 64 in which an RMSD of 1.44 kcal mol −1 was achieved for 642 molecules from the Freesolv database. Sumi et al performed hydration free energy calculations on an earlier version of the Freesolv database using the reference-modified density functional formulation, with which an RMSD of 1.46 kcal mol −1 was reached.…”