Computational insights into aspartyl protease activity of presenilin 1 (PS1) generating Alzheimer amyloid beta-peptides (Abeta40 and Abeta42).
Computational insights into aspartyl protease activity of presenilin 1 (PS1) generating Alzheimer amyloid beta-peptides (Abeta40 and Abeta42).
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对早老素 1 (PS1) 生成阿尔茨海默淀粉样蛋白 β 肽（Abeta40 和 Abeta42）的天冬氨酰蛋白酶活性的计算见解。
DOI：
10.1021/jp811154w
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
Rajeev Prabhakar
中科院分区：
文献类型：
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作者：
Rajiv Singh;Arghya Barman;Rajeev Prabhakar
本研究结合生物信息学、分子动力学和密度泛函理论，阐明了细胞膜内天冬氨酸蛋白酶-早老素1 （PS1）水解淀粉样前体蛋白Val-Ile和Ala-Thr肽键的机制。这些过程导致形成40-42个氨基酸长的阿尔茨海默淀粉样蛋白（Abeta）肽（分别为Abeta40和Abeta42）。在没有PS1 x射线结构的情况下，基于底物特异性和活性位点的结构特征，我们选择了另一种天冬氨酸蛋白酶BACE1作为PS1的模型。PS1利用的一般酸/碱机制分为以下两个步骤：(1)形成gem-diol中间体，(2)切割Val-Ile或Ala-Thr肽键。MD模拟表明，切割位点（Val-Ile和Ala-Thr）的电子性质在酶-底物复合物的形成中起着关键作用。Val-Ile和Ala-Thr肽键裂解途径中gem-二醇中间体的产势垒（在B3LYP水平上）分别为16.6和24.4 kcal/mol，其产势垒分别为6.2和17.4 kcal/mol。这一步是两个反应的限速步骤。在第二步中，Val-Ile键和Ala-Thr键的分裂分别遇到10.9和21.3 kcal/mol的势垒。计算的能量学表明，与Abeta42相比，Abeta40的生成更有利，这支持了Abeta40的产量是Abeta42的9倍的实验观察。
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.