The initial configurations for a single solute molecule solvated in a periodic box of 1500 water molecules generated using the packmol software package. All MD simulations were performed using using the GROMACS (version 2016.3) program. Initially, A steepestdescent minimization was performed to relax the system and remove any bad contacts, followed by a short (100 ps) N V T equilibration run followed by a 12 ns long N P T simulation with the first 2 ns discarded to determine the system density . Alchemical free energy simulations to decouple the solute molecule from its solvent environment were then started from the previously equilibrated configurations in an N V T ensemble, with simulation box size based on the calculated N P T density.