RBFEs for all the ligand pairs within a standard deviation of 0.7 kcal mol -1 (Table ). In our simulations for the BTK system, we observed an exchange between the trapped water and a solvent water in the simulation of the unrestrained stage, in all three replicates (Figure ). We post-processed the trajectory of the unrestrained stage to identify the exchanged solvent water as the new trapped water (see Section 2.3.1 for details). Our post-processing efforts resulted in good phase space overlap between the restrained and unrestrained states of the system given the water exchange (Figure ), and hence, in a correct estimate of the free energy to apply the restraints (edge M, Figure ).