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 (Aβ) peptides (Aβ40 and Aβ42, 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 Aβ42, the generation of Aβ40 is more favorable and supports the experimental observation that the production of Aβ40 is 9 times greater than that of Aβ42.
| Original language | English |
|---|---|
| Pages (from-to) | 2990-2999 |
| Number of pages | 10 |
| Journal | Journal of Physical Chemistry B |
| Volume | 113 |
| Issue number | 10 |
| DOIs | |
| State | Published - Mar 12 2009 |
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ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Materials Chemistry
- Surfaces, Coatings and Films
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Computational insights into aspartyl protease activity of presenilin 1 (ps1) generating alzheimer amyloid β-peptides (aβ40 and aβ42). / Singh, Rajiv; Barman, Arghya; Prabhakar, Rajeev.
In: Journal of Physical Chemistry B, Vol. 113, No. 10, 12.03.2009, p. 2990-2999.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Computational insights into aspartyl protease activity of presenilin 1 (ps1) generating alzheimer amyloid β-peptides (aβ40 and aβ42)
AU - Singh, Rajiv
AU - Barman, Arghya
AU - Prabhakar, Rajeev
PY - 2009/3/12
Y1 - 2009/3/12
N2 - 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 (Aβ) peptides (Aβ40 and Aβ42, 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 Aβ42, the generation of Aβ40 is more favorable and supports the experimental observation that the production of Aβ40 is 9 times greater than that of Aβ42.
AB - 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 (Aβ) peptides (Aβ40 and Aβ42, 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 Aβ42, the generation of Aβ40 is more favorable and supports the experimental observation that the production of Aβ40 is 9 times greater than that of Aβ42.
UR - http://www.scopus.com/inward/record.url?scp=65249160667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65249160667&partnerID=8YFLogxK
U2 - 10.1021/jp811154w
DO - 10.1021/jp811154w
M3 - Article
C2 - 19708161
AN - SCOPUS:65249160667
VL - 113
SP - 2990
EP - 2999
JO - Journal of Physical Chemistry B Materials
JF - Journal of Physical Chemistry B Materials
SN - 1520-6106
IS - 10
ER -