ABFEs can be computed using an alchemical cycle (Figure ). The standard free energy of binding is calculated by adding up the terms around the cycle: where "Free" and "Bound" indicate that the ligand is in solution or in the receptor binding site, "Discharge" means removal of ligand Coulombic interactions, "Vanish" indicates removal of the ligand Lennard-Jones (LJ) interactions, and "Restrain" means introduction of intermolecular restraints between the receptor and ligand. ∆G o Release is the correction for releasing the receptor-ligand restraints when the ligand has no intermolecular interactions, and ∆G Sym. Corr. accounts for symmetries broken by the introduction of restraints. The bound leg refers to all calculations where the ligand is in the binding site and includes the symmetry correction, and the free leg describes all calculations where the ligand is in solution.