A limitation of our separation of states approach is related to the efficiency of the NES simulations. We have observed that the NES simulations are sensitive to the environment of the alchemical transformation. For a high overlap in the work distributions of the forward and reverse NES, the two end states must have a high phase space overlap stemming from the surrounding part of the alchemical transformation. In the short NES switches, a phase space gap stemming from the surroundings can not be bridged. We have observed that the ligands' binding poses in the end states of the NES simulation is an important factor in this. Ligands that have a large conformational flexibility while bound to the protein can have different poses in the end states, which can significantly affect the NES work overlap. The phase space of a highly flexible ligand, however, can be greatly reduced to be close to its experimentally reported binding pose by weak dihedral restraints or orientational restraints on the ligand's rotatable bonds.