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J Phys Chem B. 2009 Mar 12;113(10):2990-9. doi: 10.1021/jp811154w.

Computational insights into aspartyl protease activity of presenilin 1 (PS1) generating Alzheimer amyloid beta-peptides (Abeta40 and Abeta42).

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Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, Florida 33146, USA.


In this combined bioinformatics, molecular dynamics (MD), and density functional theory study, mechanisms for the hydrolytic cleavage of Val-Ile and Ala-Thr peptide bonds of amyloid precursor protein by the intramembrane aspartyl protease presenilin 1 (PS1) have been elucidated. These processes lead to the formation of 40-42 amino acids long Alzheimer amyloid beta (Abeta) peptides (Abeta40 and Abeta42, respectively). In the absence of an X-ray structure of PS1, based on the substrate specificity and structural characteristics of the active site, another aspartyl protease BACE1 was selected as a model for PS1. The general acid/base mechanism utilized by PS1 is divided into the following two steps: (1) formation of the gem-diol intermediate, and (2) cleavage of the Val-Ile or Ala-Thr peptide bond. The MD simulations indicate that the electronic nature of the cleavage site (Val-Ile and Ala-Thr) plays a critical role in the formation of the enzyme-substrate complex. The calculated barrier (at B3LYP level) for the generation of the gem-diol intermediate in the Val-Ile and Ala-Thr peptide bond cleaving pathways is 16.6 and 24.4 kcal/mol, respectively, and it is endothermic by 6.2 and 17.4 kcal/mol, respectively. This step is the rate-limiting step in both reactions. In the second step, the splitting of the Val-Ile and Ala-Thr bonds encounters the barrier of 10.9 and 21.3 kcal/mol, respectively. The computed energetics exhibit that, in comparison to Abeta42, the generation of Abeta40 is more favorable and supports the experimental observation that the production of Abeta40 is 9 times greater than that of Abeta42.

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