pH-dependent conformational dynamics of beta-secretase 1: A molecular dynamics study

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Beta-secretase 1 (BACE-1) is a key enzyme in amyloid precursor protein processing.
• Dysregulation of BACE-1 contributes to the pathogenesis of Alzheimer disease.
• BACE-1 activity is known to be pH-dependent, with optimal function in acidic conditions.

Purpose of the Study:

• To investigate the pH-dependent dynamics of BACE-1.
• To elucidate the mechanism underlying BACE-1 activity in the physiologically relevant pH range for amyloidogenesis.
• To explore the role of aspartyl dyad protonation states in BACE-1 function.

Main Methods:

• GPU-accelerated constant pH molecular dynamics simulations using AMBER.
• Conventional molecular dynamics simulations to analyze protonation state differences.
• Analysis of active site water lifetime and key residue proximity.

Main Results:

• Distinct dynamic differences were observed between double-protonated, mono-protonated, and double-deprotonated BACE-1 states.
• Tyrosine 71 (Tyr 71) proximity to the aspartyl dyad varied across protonation states.
• Catalytic water lifetime within the active site was found to be dependent on protonation states.

Conclusions:

• The protonation state of the aspartyl dyad significantly influences BACE-1 dynamics.
• Tyr 71 plays a crucial role in stabilizing catalytic water in the BACE-1 active site.
• This stabilization mechanism is essential for BACE-1 enzymatic activity, particularly in the pH range associated with Alzheimer disease progression.