title: Computational insights into aspartyl protease activity of presenilin 1 (PS1) generating Alzheimer amyloid beta-peptides (Abeta40 and Abeta42).
abstract: 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.
authors.affiliation: Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, Florida 33146, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Singh
authors.forename: Arghya
authors.initials: A
authors.lastname: Barman
authors.forename: Rajeev
authors.initials: R
authors.lastname: Prabhakar
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000737:chemistry*; D053764:Presenilin-1 / Q000737:chemistry*; D011485:Protein Binding; D011789:Quantum Theory; D013379:Substrate Specificity
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016282:Aspartic Acid Endopeptidases