Comparison of RESP and IPolQ-Mod Partial Charges for Solvation Free Energy Calculations of Various Solute/Solvent Pairs.

The calculation of solvation free energies ΔGsolv by molecular simulations is of great interest as they are linked to other physical properties such as relative solubility, partition coefficient, and activity coefficient. However, shortcomings in molecular models can lead to ΔGsolv deviations from experimental data. Various studies have demonstrated the impact of partial charges on free energy results. Consequently, calculation methods for partial charges aimed at more accurate ΔGsolv predictions are the subject of various studies in the literature. Here we compare two methods to derive partial charges for the general AMBER force field (GAFF), i.e. the default RESP as well as the physically motivated IPolQ-Mod method that implicitly accounts for polarization costs. We study 29 solutes which include characteristic functional groups of drug-like molecules, and 12 diverse solvents were examined. In total, we consider 107 solute/solvent pairs including two water models TIP3P and TIP4P/2005. Comparison with experimental results yields better agreement for TIP3P, regardless of the partial charge scheme. The overall performance of GAFF/RESP and GAFF/IPolQ-Mod is similar, though specific shortcomings in the description of ΔGsolv for both RESP and IPolQ-Mod can be identified. However, the high correlation between free energies obtained with GAFF/RESP and GAFF/IPolQ-Mod demonstrates the compatibility between the modified charges and remaining GAFF parameters.