Restraints are required to keep the weakly coupled and fully decoupled ligand in the binding site region and thereby reduce the phase space that needs to be sampled. In this study we apply orientational restraints, which we call "Boresch-style" restraints (after the seminal work of Boresch et al. which first employed these to make ABFE calculations practical). In principle, however, numerous other kinds of restraints could be used for this step (affecting only the efficiency) and an assessment of the convergence of different pose restraint strategies is outside the scope of the present study. The efficiency of the approach naturally depends on the choice of restraints, e.g. if two ligands share a similar shape, simulations would likely be most efficient if the shapes of the two ligands overlap well in all alchemical states. If the two ligands have a similar shape, one could restrain the shape of the first ligand to the shape of the second ligand so that in states where one of the ligands is only weakly interacting or fully decoupled, it samples the phase space of the interacting ligand it is restrained to. Such issues have not yet been carefully explored and are not the focus of the present work.