Following the proposed protocol, we selected as representative the ligand in the 2QLZ PDB structure. From the dissociation trajectories obtained with τRAMD, we confirmed the one-step dissociation mechanism and a high residence time (Figure .A). BACE1 has a loop closing the binding pocket, which opens during the unbinding event. This conformational change has slow kinetics but does not interfere with the ligand dissociation pathway creating meaningful metastable states. When isolating the DUck chunk (i.e., reduced receptor representation), this loop is however removed. This is necessary due to the heavily restrained nature of the simulations. The ΔGQB profile of the 2QZL ligand shows a very narrow distribution and a high free energy barrier of 18.4 kcal•mol -1 (Figure .B). As the system met the two a priori conditions, we predicted activity cliffs as expected with high predictive power. BACE1 ligands presented a bimodal ΔGQB distribution (Figure ). Most compounds have a labile H-bond with values close to 4-5 kcal mol -1 and a small peak at very high quasi-bond free energies (15-20 kcal mol