For the ligand parametrization, OpenFF 2.1.0 80 was used, and for the protein AM-BERFF14SB. To allow an integration speedup, the masses of the hydrogens were set to 3.0 amu following the hydrogen mass repartitioning (HMR) scheme. During any system simulation or optimization of solvated systems, the short-range nonbonded cutoff was set to 1 nm with long-range interactions handled using PME scheme. For vacuum simulations in the RHFE calculations, no nonbonded cutoff was applied. All simulations employed constraints for hydrogen containing bonds, using SHAKE for solutes and SETTLE for water molecules. The tolerance was was set to 10 -6 kJ mol -1 nm -1 for the SHAKE and SETTLE 86 combination used by OpenMM.