SAMPL9 blind predictions for toluene/water partition coefficients using nonequilibrium alchemical approaches

Abstract

We present our blind prediction of the toluene–water partition coefficients in the context of the SAMPL9 challenge. For the calculation of the solvation free energies in water, toluene, and 1-octanol, we used an efficient MD-based nonequilibrium alchemical technique relying on the GAFF2 non-polarizable force field. The method is based on the fast-growth of an initially decoupled solute. Canonical sampling of the associated end-state is efficiently obtained by performing a Hamiltonian replica exchange simulation of the gas-phase solute molecule alone, combined with equilibrium configurations of the solvent. Before submitting the prediction, a pre-assessment of the method and of the force field was made by comparing with the known experimental counterpart the calculated octanol–water partition coefficients using different set of atomic charges. The analysis allowed to optimize our blind prediction for the toluene–water partition coefficients, providing at the same time valid clues for improving the performance and reliability of the non-polarizable force field in free energy calculations of drug-receptor systems.