Our improved docking results may stem in part from our choice of target protein structures and/or our use of the Glide SP method. However, for BACE1, the enhanced docking enrichment observed here appears to result more from our treatment of protonation states, because our initial docking experiments with Glide SP but without these refined protonation state protocols gave worse BACE1 enrichment metrics, similar to those from the prior study. First, despite our selecting a pH of 4.5 typical of BACE1 binding assays , Maestro assigned both of the active site aspartic acids, which are critical to binding, as ionized. Although such a low pH might be expected to cause at least one of the aspartic acids to be predominantly neutral, we accepted the Maestro assignments based on prior computational studies of this system . Second, we used LigPrep to generate all ligand protonation states predicted to be plausible for the free ligand over the wide 0 to 10 pH range, instead of the narrower 6 to 8 pH range in the previous study. We then docked all states and chose the state with the best docking score, accounting for any protonation free energy penalty. This approach may be particularly relevant for BACE1, with its two ionized aspartic groups in the binding site, which may shift the ligand to more protonated states.