Cathepsin D (CatD) and BACE2 are two aspartyl proteases homologous to BACE1, an intensively pursued drug target for treatment of Alzheimer’s disease. Employing continuous constant pH molecular dynamics with pH replica exchange, we recently showed that, despite the highly similar structure and binding modes, BACE1 and CatD have markedly different pH profiles in conformational dynamics and binding affinity for the BACE1 inhibitor LY2811376. Here we discuss our findings regarding BACE2. In contrast to the pH-dependent flap dynamics in BACE1, the flap of BACE2 is rigidified due to a hydrogen-bonding network. Interestingly, water is displaced from the S3 pocket when the inhibitor binds BACE2 but not BACE1. Importantly, at low pH, the inhibitor departs from the binding pocket of BACE2 but not BACE1 within the same simulation time. These and other analysis highlight the possible role of entropic contribution in the inhibitor selectivity.

Profiling cathepsin D and BACE2: Flap dynamics and interaction with a BACE1 inhibitor

255th National Meeting (2018)

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