The solvent legs of the RBFE calculations were run starting from the solvated structures of the hybrid ligands obtained from the procedure described in Section 2.6.1. Each of the solvated structures of the hybrid ligands was equilibrated using the equilibration procedure described in Section 2.6.2. For each of the two ligands in the hybrid structure, 6 ns of production run was generated in the NPT ensemble. 2.6.4. NES simulations. In both the ABFE and RBFE thermodynamic cycles, NES simulations were performed for the alchemical transformations, i.e., trapped water decoupling and ligand transformation. The Gapsys soft-core potential was used to turn on/off vdw interactions to avoid singularities in the alchemical transformations.