The two branches of thermodynamic cycle were prepared for simulation: ligand in water and ligand bound to the protein. The systems were placed in a dodecahedral box with the minimal distance of 1.5 nm to the box wall. The solutes were solvated with the TIP3P water and sodium and chloride ions were added to neutralize the system and reach 150 mM salt concentration. Amber99sb*ILDN force field was used to parameterize the proteins for the simulations with OpenFF and GAFF2.1x ligand force fields. The ion parameters for these simulations were taken from Joung & Cheatham. The Charmm36m 38 protein force field was used in combination with the MATCH/CGenFF ligand parameters.