For an arbitrary set of receptor-ligand restraints, there is no straightforward way to evaluate this expression. The standard solution to obtain ∆G o Release is to select a set of receptor-ligand restraints for which the restraint energy, U r (x Ext ), is a function of only the receptor-ligand relative external degrees of freedom. In this case, ∆G Preorg. = ∆G Distort. = 0, because changing the relative coordinates of the decoupled ligand and receptor has no effect on the internal DoF and W r (x Ext ) = U r (x Ext ). Restraints of this form are described as not coupling the internal and external degrees of freedom of the receptor and ligand. Intuitively, such restraints do no "squeeze" or "stretch" the receptor or decoupled ligand. The free energy of releasing these restraints is