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Elucidating the catalytic mechanism of ß-secretase (BACE1): a quantum mechanics/molecular mechanics (QM/MM) approach.
Barman, Arghya; Prabhakar, Rajeev.
Afiliación
  • Barman A; Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
J Mol Graph Model ; 40: 1-9, 2013 Mar.
Article en En | MEDLINE | ID: mdl-23337572
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 ß-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Secretasas de la Proteína Precursora del Amiloide Idioma: En Revista: J Mol Graph Model Asunto de la revista: BIOLOGIA MOLECULAR Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Secretasas de la Proteína Precursora del Amiloide Idioma: En Revista: J Mol Graph Model Asunto de la revista: BIOLOGIA MOLECULAR Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos