It has been hypothesized that bulkier groups at the R 1 position in the 2-napthyl ethers might be accommodated, and confer extra benefit in the common Y181C mutant viral strain of HIV-1 RT. Hence, compounds 1f-1h were added to our benchmark data set. There is evidence of a change in binding mode of these bulkier ligands (Figure ), particularly for 1g and 1h. Although we have investigated typical convergence of the free energies over simulation time scales of 2-4 ns (Table ), it may be that significantly longer simulation times and/or enhanced sampling are required here. The two compounds (1i and 1j) with R 3 = F show high potency gains with the QUBE force field. Figure shows significant movement of the catechol diether group of compound 1j towards the space between Tyr181 and Lys103, which represents a larger change in conformation than was observed for the other inhibitors. Table reports a series of repeat runs for several transformations involving compounds 1i and 1j. We do not observe very large differences between repeated runs, but do see large hysteresis between forward/reverse transformations. Across the group 1 set, the average hysteresis is 0.76 kcal/mol, which is dominated by transformations involving compounds 1i and 1j, as well as 1f and 1h, which further supports sampling inadequacies in these cases.