We examined the effects of E cut and NMC for the MUP protein-ligand test system. Setting E cut to 15, 12, and 10 kcal mol -1 resulted in 0.002, 0.0006 and 0.0002, of MC tries, respectively, being sent for full energy calculations. However, the fraction of tries accepted does not change significantly between these E cut thresholds (Figure ). This indicates that using the lower threshold tried here, 10 kcal mol -1 is sufficient and that there is no need for a higher, and thus more rigorous, energy threshold, which results in a slowdown of the program, as shown in Figure . In addition, as expected, increasing the number of MC tries (NMC) increases the number of acceptances, though with somewhat diminishing acceptance rates for higher values of this parameter (Figure ). Presumably, there are some MC cycles where the water molecule chosen is particularly stable and/or there are few trial sites available where the water could make favorable interactions with its surrounding atoms. This speed enhancement has important implications for the integration of the present technology into absolute and relative binding free energy calculations. Thus, for one of our prior relative binding free energy calculations (the W1→W2 perturbation, decharge windows), using MC/MD to equilibrate a single λ window took ~9 hours, while in the current version, this only requires ~30 seconds, a 1000x speedup.