pH-Dependent Population Shift Regulates BACE1 Activity and Inhibition

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Beta-secretase 1 (BACE1) is a primary therapeutic target for Alzheimer's disease.
• BACE1 activity is pH-dependent, but the regulatory mechanisms are not fully understood.
• Inhibitor development for BACE1 has progressed, yet optimal strategies require deeper mechanistic insight.

Purpose of the Study:

• To elucidate the pH-dependent conformational mechanism regulating BACE1 activity.
• To investigate how pH influences BACE1's conformational states and binding properties.
• To provide a molecular basis for understanding BACE1 inhibition and potential side effects.

Main Methods:

• Continuous constant-pH molecular dynamics (MD) simulations were employed.
• Analysis of BACE1 conformational states across a range of pH values.
• Investigation of protonation states of key residues, including the catalytic dyad.

Main Results:

• BACE1 exists in three main conformational states, with populations varying by pH.
• An intermediate pH favors a binding-competent state (monoprotonated catalytic dyad).
• Low and high pH conditions favor a Tyr-inhibited state, reducing binding competence.

Conclusions:

• Conformational selection is a key mechanism for substrate and inhibitor binding to BACE1.
• pH-dependent conformational changes significantly impact BACE1 activity.
• Accurate modeling of protonation states in MD is crucial for understanding enzyme mechanisms and guiding drug design.