Applied to protein-ligand binding problems, alchemical methods involve changing chemical moieties in the studied system and calculating the free energy differences associated with these changes. Since in atomistic simulations systems are parameterized by force-fields, the transformation of chemical moieties can be achieved by modifying the atomistic parameters of the system. The variable λ is designated to control the modified parameters of the system, turning on and off relevant inter and intra molecular potentials. The reduced potential u(x, λ) of such a system can therefore be written as a function of the controlling parameter,