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Epigallocatechin Gallate Destabilizes α-Synuclein Fibril by Disrupting the E46–K80 Salt-Bridge and Inter-protofibril Interface
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2020-11-13 , DOI: 10.1021/acschemneuro.0c00598
Yifei Yao 1 , Yiming Tang 1 , Guanghong Wei 1
Affiliation  

The accumulation and deposition of fibrillar aggregates of α-synuclein (α-syn) into Lewy bodies are the major hallmarks of Parkinson’s disease (PD) for which there is no cure yet. Disrupting preformed α-syn fibrils is considered one of the rational therapeutic strategies to combat PD. Experimental studies reported that epigallocatechin gallate (EGCG), a polyphenol extracted from green tea, can disrupt α-syn fibrils into benign amorphous aggregates. However, the molecular mechanism of action is poorly understood. Herein, we performed molecular dynamics simulations on a newly released Greek-key-like α-syn fibril with or without EGCG to investigate the influence of EGCG on α-syn fibril. Our simulations show that EGCG disrupts the local β-sheet structure, E46–K80 salt-bridge crucial for the stabilization of the Greek-key-like structure, and hydrophobic interactions stabilizing the inter-protofibril interface and destabilizes the global structure of the α-syn fibril. Interaction analyses reveal that hydrophobic and hydrogen-bonding interactions between EGCG and α-syn fibrils play important roles in the destabilization of the fibril. We find that the disruption of the E46–K80 salt-bridge closely correlates with the formation of hydrogen-bonds (H-bonds) between EGCG and E46/K80. Our results provide mechanistic insights into the disruption modes of α-syn fibril by EGCG, which may pave the way for designing drug candidates targeting α-syn fibrillization to treat PD.

中文翻译:

表没食子儿茶素没食子酸酯通过破坏E46–K80盐桥和原纤维间界面破坏α-突触核蛋白原纤维的稳定性

α-突触核蛋白(α-syn)的纤维状聚集体的积累和沉积在路易体中是帕金森氏病(PD)的主要标志,目前尚无法治愈。破坏预制的α-syn原纤维被认为是对抗PD的合理治疗策略之一。实验研究表明,表没食子儿茶素没食子酸酯(EGCG)是一种从绿茶中提取的多酚,可将α-syn原纤维分解为良性无定形聚集体。但是,对作用的分子机理了解甚少。在本文中,我们对有或没有EGCG的新发布的希腊钥匙状α-syn原纤维进行了分子动力学模拟,以研究EGCG对α-syn原纤维的影响。我们的模拟结果表明,EGCG破坏了局部β-折叠结构,即E46–K80盐桥,对稳定希腊键状结构至关重要,和疏水相互作用稳定了原纤维间的界面,并破坏了α-syn原纤维的整体结构。相互作用分析表明,EGCG和α-syn原纤维之间的疏水和氢键相互作用在原纤维的去稳定化中起重要作用。我们发现E46–K80盐桥的破坏与EGCG和E46 / K80之间的氢键(H键)的形成密切相关。我们的研究结果为EGCG破坏α-syn原纤维的机制提供了机械方面的见解,这可能为设计针对α-syn原纤维化治疗PD的候选药物铺平了道路。相互作用分析表明,EGCG和α-syn原纤维之间的疏水和氢键相互作用在原纤维的去稳定化中起重要作用。我们发现E46–K80盐桥的破坏与EGCG和E46 / K80之间的氢键(H键)的形成密切相关。我们的研究结果为EGCG破坏α-syn原纤维的机制提供了机械方面的见解,这可能为设计针对α-syn原纤维化治疗PD的候选药物铺平了道路。相互作用分析表明,EGCG和α-syn原纤维之间的疏水和氢键相互作用在原纤维的去稳定化中起重要作用。我们发现E46–K80盐桥的破坏与EGCG和E46 / K80之间的氢键(H键)的形成密切相关。我们的研究结果为EGCG破坏α-syn原纤维的机制提供了机械方面的见解,这可能为设计针对α-syn原纤维化治疗PD的候选药物铺平了道路。
更新日期:2020-12-16
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