BACE1, a major therapeutic target for treatment of Alzheimer's disease, functions within a narrow pH range. Despite tremendous effort and progress in the development of BACE1 inhibitors, details of the underlying pH-dependent regulatory mechanism remain unclear. In this talk I will discuss our recent work in exploring the pH-dependent conformational mechanism that regulates BACE1 activity and substrate/inhibitor binding using continuous constant-pH molecular dynamics. The new insights greatly extend the knowledge of BACE1 and have implications for further optimization of inhibitors and understanding potential side effects of targeting BACE1.

Insights into the pH-dependent activity and inhibition of BACE1

251st National Meeting (2016)

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