Simulated Interactions between Endothelin Converting Enzyme and Aβ Peptide: Insights into Subsite Recognition and Cleavage Mechanism

Abstract

Alzheimer’s disease (AD) is a most common form of dementia caused due to aggregation of amyloid beta (Aβ) peptides in brain. The AD brain exhibits extracellular deposition of Aβ-peptides which triggers neuronal death. Thus, degradation of Aβ peptides has evaluated a promising therapeutic target in AD. Human endothelin converting enzyme (hECE-1) has been implicated in Aβ-peptide degradation. In this study, we have performed molecular docking between three different conformations of Aβ peptides and hECE-1 coupled with molecular dynamics to investigate subsite recognition and cleavage mechanism. Molecular docking and MD simulation studies show that β-sheet conformation with particular orientation of Aβ-peptide residues selectively entrap in substrate binding cavity of hECE-1. However, unusual orientation of Aβ-peptide residues and helical conformation undergoes substantial fluctuations resulted in the reduction of enzyme-substrate interactions. Zn ion coordinates with Aβ-peptide near the scissile peptide bond. Based on this information we have proposed catalytic mechanism of hECE-1 for Aβ-peptide degradation in which residue E 608 of hECE-1 plays an important role as a proton shuttle. The molecular basis of Aβ peptide cleavage by hECE-1 could aid in designing enzyme based therapies to control Aβ concentration in AD.