where ∆G int 𝑠𝑜𝑙𝑣 is the free energy of the removal of the electrostatic and van der Waals interactions, often termed "annihilation" of the ligand, between the ligand and the environment while in solution (Fig 1B : 1 → 6); ∆G +𝑉𝐵 prot is the free energy of the addition of a virtual bond between the protein and the ligand in the protein-ligand complex simulation (Fig. : 2 → 3, see Gutkin et al. for details); ∆𝐺 int prot is the free energy of the annihilation of the ligand in complex with the protein and while restrained by the virtual bond (Fig. : 3 → 4); and ∆𝐺 -VB prot° is the free energy of removing the virtual bond from the annihilated ligand which is computed analytically (Fig.