In the solvent phase, the influence of this restraint was accounted for analytically. By accounting for this restraint the ligand state is then equivalent to a non-interacting ligand in a proteinligand complex (state h). The ligand interactions with the environment are then turned back on, first recoupling the van der Waals interactions over 21 λ windows (state g), followed by a further 11 λ windows to add back electrostatics (state f). Finally the orientational restraints are turned off over 12 λ windows resulting in a fully interacting protein-ligand complex (state e).