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针对淀粉样β蛋白(Aβ)聚集的自组装六肽抑制剂的计算研究。

A computational study of self-assembled hexapeptide inhibitors against amyloid-β (Aβ) aggregation.

作者信息

Qiao Yuan, Zhang Mingzhen, Liang Ya'nan, Zheng Jie, Liang Guizhao

机构信息

Key Laboratory of Biorheological Science and Technology Ministry of Education, Bioengineering college, Chongqing University, Chongqing 400044, P. R. China.

Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA.

出版信息

Phys Chem Chem Phys. 2016 Dec 21;19(1):155-166. doi: 10.1039/c6cp07341g.

Abstract

The fibrillation and deposition of amyloid-β (Aβ) peptides in human brains are pathologically linked to Alzheimer's disease (AD). Development of different inhibitors (peptides, organic molecules, and nanoparticles) to prevent Aβ aggregation becomes a promising therapeutic strategy for AD treatment. We recently propose a "like-interacts-like" design principle to computationally design/screen and experimentally validate a new set of hexapeptide inhibitors with completely different sequences from the Aβ sequence. These hexapeptide inhibitors inhibit Aβ aggregation and reduce Aβ-induced cytotoxicity. However, inhibitory mechanisms of these hexapeptides and the underlying interactions between hexapeptides and Aβ remain unclear. Herein we apply multi-scale computational methods (quantum-chemical calculations, molecular docking and explicit-solvent molecular dynamic simulation) to explore the structure, dynamics, and interaction between 3 identified hexapeptides (CTLWWG, GTVWWG, and CTIYWG) and different Aβ-derived fragments and an Aβ17-42 pentamer. When interacting with 6 Aβ-derived fragments, 3 hexapeptide inhibitors show stronger interactions with two lysine-included fragments (KLVFFA and NKGAII) than other fragments, indicating different sequence-specific interactions with Aβ. When interacting with the Aβ17-42 pentamer, the 3 peptides show similar binding modes and interaction mechanisms by preferentially binding to the edge of the Aβ17-42 pentamer to potentially block the Aβ elongation pathway. This work provides structural-based binding information on further modification and optimization of these peptide inhibitors to experimentally enhance their inhibitory abilities against Aβ aggregation.

摘要

淀粉样β(Aβ)肽在人脑中的纤维化和沉积与阿尔茨海默病(AD)存在病理联系。开发不同的抑制剂(肽、有机分子和纳米颗粒)以防止Aβ聚集成为一种有前景的AD治疗策略。我们最近提出了一种“相似相互作用”的设计原则,用于通过计算设计/筛选并通过实验验证一组新的六肽抑制剂,其序列与Aβ序列完全不同。这些六肽抑制剂可抑制Aβ聚集并降低Aβ诱导的细胞毒性。然而,这些六肽的抑制机制以及六肽与Aβ之间的潜在相互作用仍不清楚。在此,我们应用多尺度计算方法(量子化学计算、分子对接和显式溶剂分子动力学模拟)来探索3种已鉴定的六肽(CTLWWG、GTVWWG和CTIYWG)与不同的Aβ衍生片段以及一个Aβ17 - 42五聚体之间的结构、动力学和相互作用。当与6种Aβ衍生片段相互作用时,3种六肽抑制剂与两个包含赖氨酸的片段(KLVFFA和NKGAII)的相互作用比与其他片段更强,表明与Aβ存在不同的序列特异性相互作用。当与Aβ17 - 42五聚体相互作用时,这3种肽通过优先结合到Aβ17 - 42五聚体的边缘以潜在地阻断Aβ延伸途径,表现出相似的结合模式和相互作用机制。这项工作提供了基于结构的结合信息,用于进一步修饰和优化这些肽抑制剂以通过实验增强其对Aβ聚集的抑制能力。

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