While BLUES compares favorably to standard MD in the case of toluene bound to lysozyme, and has a better acceptance ratio (10 ± 1 %) than standard MC (0.091 ± 0.004 %), the difference in acceptance ratio between BLUES and standard MC is not actually enough to justify the additional computational expense of the NCMC relaxation. Specifically, instead of doing 10000 NCMC steps (as in BLUES) to achieve a reasonable acceptance rate, we could simply do a very large number of MC trials (e.g. 10000, for a similar computational expense) with the low acceptance rate and still see a reasonable number of moves accepted. We believe this relative advantage of standard MC may be a peculiarity of toluene in this particular binding site (which is relatively large compared to the size of toluene, and known to be especially rigid ), and not representative of typical MC performance in condensed phase systems. To further test the relative performance of MC and NCMC, we examined performance of NCMC versus MC move proposals for a larger ligand in the lysozyme binding site, 3-iodotoluene; we find that the presence of the bulky iodo substituent dramatically impairs acceptance of MC moves, presumably due to the larger size of the ligand relative to the size of the binding site (see Section 2.9 for methods). 3-iodotoluene is another known binder in the lysozyme L99A site; however, due to its lack of symmetry, we are unable to take advantage of ligand symmetry to provide a simple metric for convergence of binding mode populations. It is nevertheless useful here as a good example of a larger ligand which should have several different metastable binding modes in this site.