The largest difference between 2WF3 and 4EWO is in the 'flap' region (Fig. ), which interacts extensively with BACE-1 ligands. Interestingly, docking scores are generally lower when docking to 4EWO (Fig. ), while MM-GBSA scores are lower when simulated in 2WF3 (Fig. and). The exact reasons behind this opposite trend are unknown, but we speculate that none of the 10 protein conformations used for docking was "good enough" to accommodate the 75 ligands that displayed lower (i.e. better) docking scores in 4EWO. Arguably, the docking score was better in 4EWO because the flap is slightly more open, thereby accommodating ligands that could not fit as well in 2WF3. On the other hand, we argue that 2WF3 is more representative of the actual protein-ligand complex, resulting in lower (i.e. better) MM-GBSA scores on average.