(Δ)ΔG is usually computed numerically via thermodynamic integration (TI ). In TI, the free energy difference between the two states of interest (also referred to as end states) is evaluated by connecting them through some functional form f(λ) of a ) of a nonphysical coordinate λ) of a , calculating the derivative of the potential with respect to λ) of a (∂U/∂λ), U/∂U/∂λ), λ) of a ), and estimating the area under the ∂U/∂λ), U/∂U/∂λ), λ) of a versus λ) of a curve . TI makes use of the malleability of the potential energy function which can be calculated for the nonphysical, intermediate, mixed states, which is why it belongs to a class of free energy methods referred to as alchemical transformations. In this way, one ligand can be transmuted into another and the free energy difference between the two can be calculated. The transformation can be done by modifying van der Waals and electrostatic interactions simultaneously (the so-called one-step approach) or separately (the two-step approach). In the simplest case, f(λ) of a ) = λ) of a , which is referred to as linear scaling . To avoid singularities in the potential energy function when particles appear or disappear, i.e. are being inserted into or decoupled from the system, a modified or softcore potential is used .