Table 3.

Simulation parameters for each FEP/MD simulation system.

Ligand	PDB ID	Rlig	$R_{\text{wat}}^{\text{site}}$	$R_{\text{wat}}^{\text{bulk}}$	$n_{\text{wat}}^{\text{site}}$ §	$n_{\text{wat}}^{\text{bulk}}$ §
benzene	181L	2.3 Å	14 Å	13 Å	46 (155)	288
indole	185L	3.3 Å	14 Å	14 Å	42 (150)	351
n-butylbenzene	186L	4.1 Å	14 Å	15 Å	45 (152)	439
SB3	1FKG	6.6 Å	14 Å	17 Å	130 (208)	630
SBX	1FKH	6.6 Å	14 Å	17 Å	128 (208)	628
FK5	1FKJ	8.1 Å	14 Å	19 Å	147 (235)	865

^§ $n_{\text{wat}}^{\text{site}}$ and $n_{\text{wat}}^{\text{bulk}}$ are the numbers of water molecules in SITE and BULK systems, respectively. The numbers in the parenthesis is the number of water molecules in SITE system after 20 cycles of GCMC/MD simulations (averaged over three independent simulations).