Elucidating the catalytic mechanism of β-secretase (BACE1): A quantum mechanics/molecular mechanics (QM/MM) approach

Arghya Barman, Rajeev Prabhakar

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

In this quantum mechanics/molecular mechanics (QM/MM) study, the mechanisms of the hydrolytic cleavage of the Met2-Asp3 and Leu2-Asp3 peptide bonds of the amyloid precursor protein (WT-substrate) and its Swedish mutant (SW) respectively catalyzed by β-secretase (BACE1) have been investigated by explicitly including the electrostatic and steric effects of the protein environment in the calculations. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely acknowledged as a promising therapeutic target. The general acid-base mechanism followed by the enzyme proceeds through the following two steps: (1) formation of the gem-diol intermediate and (2) cleavage of the peptide bond. The formation of the gem-diol intermediate occurs with the barriers of 19.6 and 16.1 kcal/mol for the WT- and SW-substrate respectively. The QM/MM energetics predict that with the barriers of 21.9 and 17.2 kcal/mol for the WT- and SW-substrate respectively the cleavage of the peptide bond occurs in the rate-determining step. The computed barriers are in excellent agreement with the measured barrier of ∼18.0 kcal/mol for the SW-substrate and in line with the experimental observation that the cleavage of this substrate is sixty times more efficient than the WT-substrate.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Molecular Graphics and Modelling
Volume40
DOIs
StatePublished - Mar 1 2013

Keywords

  • Acid-base mechanism
  • Alzheimer's disease
  • Aspartyl proteases
  • Beta-secretase
  • Protein hydrolysis

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Spectroscopy
  • Computer Graphics and Computer-Aided Design
  • Materials Chemistry

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