The observed hydrogen bond interactions between the ligand and the aspartyl dyad residues in these four differ-ent cases after MD simulations are reported in Fig. . More details about the specific atoms involved in these hydrogen bond interactions are reported in the caption of Table . Among the four cases, only the double protonated aspartyl dyad of BACE_18 do not interact with the ligand (Fig. and). To verify whether the interactions shown in Fig. are preserved during the MD simulations, we measured two different average distances; one between Asp32 and the ligand BACE_18, and another between Asp228 and the ligand BACE_18. We did this for each of the four complexes A, B, C, and D (Table ). The calculated average distances confirm that Asp32 and Asp228 of complexes A and B establish more stable interactions with the BACE_18 ligands than the aspartyl dyad residues of complexes D and C. The superimposition of the BACE_18 ligand pose extracted from each of the modified complexes after MD with the released BACE_-18 crystal structure (Fig. ) shows that all the four ligand poses are different. This analysis suggests that the binding mode of BACE_18 depends on the protonation states of the aspartyl dyad in BACE-1 and is consistent with other studies that evaluate the pH-dependent activity of BACE-1 .