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

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.