Z<sub>Aβ3</sub>和A<sub>β16-40</sub>亲和作用的分子机理解析

引用本文: 刘夫锋, 范玉波, 刘珍, 白姝. Z_Aβ3和A_β16-40亲和作用的分子机理解析[J]. 物理化学学报, 2017, 33(9): 1905-1914. doi: 10.3866/PKU.WHXB201704274 shu

Citation: LIU Fu-Feng, FAN Yu-Bo, LIU Zhen, BAI Shu. Molecular Mechanism Underlying Affinity Interactions between Z_Aβ3 and the A_β16-40 Monomer[J]. Acta Physico-Chimica Sinica, 2017, 33(9): 1905-1914. doi: 10.3866/PKU.WHXB201704274 shu

Z_Aβ3和A_β16-40亲和作用的分子机理解析

1.
天津大学化工学院生物工程系, 天津 300072;
2.
工业发酵微生物教育部重点实验室, 天津 300457;
3.
代谢控制发酵技术国家地方联合工程实验室, 天津 300457;
4.
天津科技大学生物工程学院, 天津 300457
基金项目:
国家自然科学基金（21576199）资助项目

摘要: 淀粉样多肽（amyloid-β peptide，Aβ）聚集是引起阿尔兹海默症（Alzheimer's disease，AD）的主要原因。开发Aβ聚集抑制剂是治疗AD的最有效手段之一。利用噬菌体展示技术筛选出来的Z_Aβ3蛋白质能够有效抑制Aβ聚集，但Z_Aβ3和Aβ之间的作用区域和关键氨基酸残基尚不清楚。针对此问题，本研究利用分子动力学模拟、MM-PBSA自由能计算和分解方法研究了Z_Aβ3-A_β16-40复合物之间的相互作用机制。结果表明，Z_Aβ3的β-股和A_β16-40之间的亲和作用占主导，而Z_Aβ3的α-螺旋贡献很小。利用分子力学-帕松波尔茨曼溶剂可及化表面积方法（MM-PBSA）自由能分解发现Z_Aβ3的热点残基为E15、I16、V17、Y18、L19、P20、N21和L22，而A_β16-40的热点残基为F19、F20、A21、E22、D23、K28、I31、I32、G33、L34、M35、V36、G38和V40。Z_Aβ3通过将发夹型Aβ单体包埋在α-螺旋围成的疏水性腔体内来阻碍Aβ聚集。这种结合模式为设计高效的Aβ蛋白质类抑制剂提供了三个基本要素：高亲和性的结合片段（β-股）、附属结构（α-螺旋）和通过二硫键形成的稳定构象。高亲和性结合片段能竞争性地与Aβ单体结合，附属结构α-螺旋可以阻碍其它Aβ单体靠近，而稳定的构象是上述两种要素发挥作用的基础，三者协同作用可以有效地抑制Aβ聚集。

关键词:

English

Molecular Mechanism Underlying Affinity Interactions between Z_Aβ3 and the A_β16-40 Monomer

1.
Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. China;
2.
Key Laboratory of Industrial Fermentation Microbiology Ministry of Education, Tianjin 300457, P. R. China;
3.
National and Local United Engineering Lab of Metabolic Control Fermentation Technology, Tianjin 300457, P. R. China;
4.
College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, P. R. China
Received Date: 26 January 2017
Revised Date: 19 April 2017
Available Online: 27 April 2017
Fund Project:
The project was supported by the National Natural Science Foundation of China (21576199).

Abstract: Alzheimer's disease (AD) is mainly caused by the aggregation of amyloid-β (Aβ) protein. Development of inhibitors to prevent Aβ aggregation is the most efficient method to devise a cure for AD. Aβ aggregation has been found to be inhibited by the affibody protein Z_Aβ3, selected via phage display. However, the molecular basis of affinity interactions between Aβ and Z_Aβ3, the interaction region, and important residues of Aβ and Z_Aβ3 remain unclear. Herein, molecular dynamics simulations and free energy calculation and decomposition using the molecular mechanics-Poisson-Boltzmann surface area method (MM-PBSA) were coupled to investigate the molecular mechanism underlying interactions between Aβ and Z_Aβ3. Interactions between the β-strand of Z_Aβ3 and A_β16-40 were found to contribute greatly to their binding free energy, while that between the α-helix of Z_Aβ3 and Z_Aβ3 has a smaller contribution. Based on the free energy decomposition, hotspot residues of Z_Aβ3 are E15, I16, V17, Y18, L19, P20, N21, and L22 and those of A_β16-40 include F19, F20, A21, E22, D23, K28, I31, I32, G33, L34, M35, V36, G38, and V40. Z_Aβ3 stabilizes the β-sheet by burying the two mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity formed by the α-helix. The identified binding motif can be used as a starting point for rational design of protein inhibitors with high affinity for Aβ to prevent Aβ aggregation. The three key characteristics of efficient protein inhibitors are the presence of a high-affinity site (β-strand), a large accessory structure (α-helix), and a stable conformation owing to disulfide bonds. The high-affinity site can competitively bind to the Aβ monomer, and the large accessory structure can block other Aβ monomers; both these elements require a stable conformation via disulfide bonds. These three characteristics of a protein inhibitor can be employed together to suppress Aβ aggregation.

Key words:

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Z_Aβ3和A_β16-40亲和作用的分子机理解析

English

Molecular Mechanism Underlying Affinity Interactions between Z_Aβ3 and the A_β16-40 Monomer

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

ZAβ3和Aβ16-40亲和作用的分子机理解析

English

Molecular Mechanism Underlying Affinity Interactions between ZAβ3 and the Aβ16-40 Monomer

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs