WaterMap 28,29 simulations were conducted with default setting, including waters to the analysis within 10.0Å range of the SII-P bound ligand. The water molecules near the ligand (originating from the crystal structure) were treated as solvent. Simulation time of 2.0 ns were applied. For all systems, if not otherwise stated, we used chain A for the WaterMap simulations (except for 6B0Y the WaterMap was run for chain B only).