where q i and q j are the charges of the two particles. For an edge from ligand A to ligand B, we employ 13 intermediate alchemical states. These states progressively deactivate the nonbonded interactions involving ligand A's R group with the system, while simultaneously activating those involving ligand B's R group with the system. To prevent singularities, the electrostatic interactions between a ligand's R group and the system are only present when the corresponding Leonard-Jones interactions are fully turned on. The specific values of the alchemical variables for states along the path from ligand A to ligand B are detailed in Table , with states 1 and 15 corresponding to ligands A and B, respectively, and states 2 to 14 representing intermediates. For our molecular dynamics simulations, we use the Amber ff14SB force field for the protein, the general Amber force field for ligands, and the TIP3P model for water. Both water and protein phase simulations are conducted in a periodic water box. We calculate electrostatic interactions using the particle mesh Ewald method, while Leonard-Jones interactions are smoothly truncated at 10 Å using a switching function that starts at 9 Å.