کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
443394 | 692718 | 2013 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Elucidating the catalytic mechanism of β-secretase (BACE1): A quantum mechanics/molecular mechanics (QM/MM) approach Elucidating the catalytic mechanism of β-secretase (BACE1): A quantum mechanics/molecular mechanics (QM/MM) approach](/preview/png/443394.png)
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.
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► Elucidating the catalytic mechanism of beta-secretase for two different substrates.
► Inclusion of the electrostatic and steric effects of the protein environment.
► The cleavage of the peptide bond occurs in the rate-determining step.
► Enzyme cleaves the SW substrate with higher efficiency than the WT substrate.
► The computed results are in excellent agreement with experimental observations.
Journal: Journal of Molecular Graphics and Modelling - Volume 40, March 2013, Pages 1–9