title: Elucidating the catalytic mechanism of β-secretase (BACE1): a quantum mechanics/molecular mechanics (QM/MM) approach.
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.
authors: Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
authors: Arghya
authors: A
authors: Barman
authors: Rajeev
authors: R
authors: Prabhakar
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D006868:Hydrolysis; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D011789:Quantum Theory; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D053829:Amyloid Precursor Protein Secretases