Although not exploited in this paper, it can be a good strategy to run simulations starting in apo and holo structures if both are available. Since both calculations should converge to the same answer this can help to determine when sampling is sufficient. We attempted to address these sampling problems and discovered and found ways to work around some of them. We restrained side chains and introduced a bubble approach for water sampling. However, better solutions are needed to make alchemical FEC more general and robust. In the long-term, greater use of enhanced sampling techniques is likely needed, such as perhaps BLUES-like moves to accelerate side chain sampling.