The sampling challenges in the systems we investigated made it difficult to directly compare the efficiency of the EQ and the NEQ approaches as we had originally hoped (and as some prior studies have attempted to do ). For the hydration free energy of the three ligands however, calculations converged sufficiently and we were able to compare the efficiency of the EQ and NEQ approaches. Both methods performed very similar on these systems, but the NEQ approach was able to reduce the standard deviation and the bias faster than the EQ approach, suggesting that it is more efficient here, at least. However, differences were very small, and thus a larger data set is needed to investigate this more. 6.3. Similarities and differences of the EQ and NEQ approaches in handling slow DOF. For the decoupling of the ligands in the binding site, we concentrated on providing some understanding as to why each method behaves the way it does.