As noted here and elsewhere, alchemical free energy calculations are hampered by a number of sampling challenges. Some of these issues -notably knowledge and treatment of multiple binding modes -are addressed by GCNCMC. However, other sampling challenges remain -in particular, when the alchemical transformation (in this case, fragment insertion/deletion) requires the concomitant binding or displacement of solvent molecules, or protein conformational change. For example, if a fragment insertion move fails to displace bound water molecules, the move will likely either be rejected or fail to insert the fragment into the binding site. Future work will therefore seek to combine fragment GCNCMC with other enhanced sampling techniques to address these limitations.