Another contribution to the high protocol work experienced during these simulations appears to come from proposing moves between binding pockets. We compared MolDarting moves proposing inter-pocket moves to intrapocket moves (Table ) and found that the inter-pocket move proposals resulted in more highly positive work (thus, were less likely to be accepted). This suggests improving the acceptance of these inter-pocket moves would also require additional consideration of the protein side-chains around the pocket the ligand is being moved to. The protocol work distribution of NCMC with MolDarting move attempts with 1,000 (a), 10,000 ((b), and 50,000 ((c) NCMC switching steps with the HIV integrase and the ligand found in 4CGD. The protocol work done over the course of the NCMC moves generally is highly positive (unfavorable), leading those moves to be rejected by the acceptance criteria. There are a small number of cases when the work values approach zero or are negative, but these were still rejected. In these cases, rejection was due to the ligand ending up outside the defined regions at one of the checks during the course of the move. Essentially, this shows how asymmetric the protocol is, and helps us identify that the largest asymmetry and greatest problems originate from the steric component of the protocol. To look at this issue further we looked at the inter-atomic distance between the ligand atoms and the protein atoms across all the MolDarting simulations for HIV integrase. We saw from the average distance between the ligand and protein before MolDarting (0.74 angstroms) was further than after MolDarting (0.57 angstroms). This suggests that another area of improvement might involve the translational and/or rotational darting regions; possibly the deterministic way these degrees of freedom are being handled could be resulting in them being inserted too close to the protein. We can see a situation where this occurs in Figure , in which after MolDarting the ligand ends up being close to some of the sidechain residues.