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β-分泌酶活性部位的动力学:原子模拟的网络分析。

Dynamics in the active site of β-secretase: a network analysis of atomistic simulations.

机构信息

Department of Biochemistry, University of Zurich, Zurich, Switzerland.

出版信息

Biochemistry. 2011 Nov 1;50(43):9328-39. doi: 10.1021/bi2011948. Epub 2011 Oct 5.

Abstract

The aspartic protease β-secretase (BACE) catalyzes the hydrolysis of the amyloid precursor protein (APP) which leads to amyloid-β aggregation and, ultimately, the perilous Alzheimer's disease. The conformational dynamics and free energy surfaces of BACE at three steps of the catalytic cycle are studied here by explicit solvent molecular dynamics simulations (multiple runs for a total of 2.2 μs). The overall plasticity of BACE is essentially identical for the three states of the substrate: the octapeptide reactant, gem-diol intermediate, and cleavage products. In contrast, the network of hydrogen bonds in the active site is more stable in the complex of BACE with the gem-diol intermediate than the other two states of the substrate. The spontaneous release of the C-terminal (P1'-P4') fragment of the product follows a single-exponential time dependence with a time constant of 50 ns and does not require the opening of the flap. The fast dissociation of the C-terminal fragment is consistent with the transmembrane location and orientation of APP and its further processing by γ-secretase. On the other hand, the N-terminal (P4-P1) fragment of the product does not exit the BACE active site within the simulation time scale of 80 ns. A unified network analysis of the complexes of BACE with the three states of the substrate provides an estimation of the activation free energy associated with the structural rearrangements that involve only noncovalent interactions. The estimated rearrangement barriers are not negligible (up to 3 kcal/mol) but are significantly smaller than the barrier of the peptide bond hydrolysis reaction.

摘要

天冬氨酸蛋白酶β-分泌酶(BACE)催化淀粉样前体蛋白(APP)的水解,导致淀粉样-β聚集,并最终导致危险的阿尔茨海默病。通过显式溶剂分子动力学模拟(总共进行多次模拟,总计 2.2 μs)研究了 BACE 在催化循环的三个步骤中的构象动力学和自由能表面。在三种底物状态下,BACE 的整体可塑性基本相同:八肽反应物、双醇中间产物和裂解产物。相比之下,在 BACE 与双醇中间产物的复合物中,活性位点中的氢键网络比底物的其他两种状态更稳定。产物的 C 末端(P1'-P4')片段的自发释放遵循单指数时间依赖性,时间常数为 50 ns,不需要瓣打开。C 末端片段的快速解离与 APP 的跨膜位置和取向以及其进一步被γ-分泌酶加工一致。另一方面,产物的 N 末端(P4-P1)片段在 80 ns 的模拟时间尺度内没有离开 BACE 活性位点。对 BACE 与底物三种状态的复合物进行统一的网络分析,提供了对仅涉及非共价相互作用的结构重排相关的激活自由能的估计。估计的重排势垒不可忽略(高达 3 kcal/mol),但明显小于肽键水解反应的势垒。

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