Sampling the displacement of trapped water in binding free energy calculations is a challenging problem. In this work, we have introduced an MD-based separation of states method to calculate RBFEs between two ligands, focusing on the case where one ligand binds to the protein with a trapped water while the other ligand displaces that water. We have calculated precise estimates of the RBFEs between five such ligand pairs with our method, and our results are in good agreement with the literature RBFEs. Our separation of states protocol provides a fast and efficient method to precisely and accurately calculate the RBFE between ligands when a water displacement is involved. Our protocol is designed to efficiently use large distributed computational resources, to reduce the computational cost and the time to solution, and to automate the setup and analysis of the simulations. The Python scripts for running and analyzing the RBFE calculations can be downloaded from the GitHub repository waterNES In this separation of states study, we have proposed to deconvolute the challenging problem of sampling of the trapped waters from the free energy calculation of ligand transformation. Our method requires the determination of the respective positions of the trapped waters for the two ligands a priori, but then uses this information to make the binding free energy calculation significantly more efficient than it would be if the free energy calculations themselves had to adequately capture water rearrangement. We introduced an intermediate state in the ligand transformation process, where the trapped water is removed from the system and the cavity created by it is stabilized, such that a bigger ligand can be grown in the cavity. Our work on stabilizing the trapped water cavity was an optimization of previous efforts of Ge et al., in which the separation of states method was applied to calculate the ABFE of the trapped waters in protein-ligand complexes. Extending their protocol, we calculated and compared the ABFE of the trapped waters in test systems from the reference study, and developed it into a protocol for ligand transformation study, where a trapped water is involved in the ligand binding.