In the alchemical ABFE approach, the two physical states -one with a ligand bound in the binding site of the protein (bound) and one without (unbound) -are linked via some intermediate states along an alchemical path. Due to the very substantial differences in the two endpoints (corresponding to apo and holo proteins), alchemical ABFE is far more demanding to implement reliably compared with alchemical RBFE . To have accurate and precise predictions, many issues need to be taken into account, including uncertainty quantification, reliable sampling of relevant physical and/or non-physical conformations, identification of "correct" ligand poses, accounting for the conformational changes between apo and holo protein states and so on.