Zhan Chendi, Chen Yujie, Tang Yiming, Wei Guanghong
Department of Physics, State Key Laboratory of Surface Physics, and Key Laboratory for Computational Physical Sciences (Ministry of Education), Multiscale Research Institute of Complex Systems, Fudan University, Shanghai 200438, People's Republic of China.
ACS Chem Neurosci. 2020 Jun 17;11(12):1841-1851. doi: 10.1021/acschemneuro.0c00277. Epub 2020 Jun 5.
The amyloid beta (Aβ) fibrillar aggregate is the hallmark of Alzheimer's disease (AD). Disassembling preformed fibril or inhibiting Aβ aggregation is considered as a therapeutic strategy for AD. Increasing evidence shows that green tea extracts, epigallocatechin-3-gallate (EGCG, containing an extra gallic acid ester group compared to EGC) and epigallocatechin (EGC), can disassociate Aβ fibrils and attenuate Aβ toxicity. However, the underlying molecular mechanism is poorly understood. Herein, we performed microsecond all-atom molecular dynamics (MD) simulations to investigate the influences of EGCG/EGC on the newly cryo-EM resolved LS-shaped Aβ protofibrils and their detailed interactions. MD simulations demonstrate that both EGCG and EGC can disrupt Aβ protofibril and EGCG displays a higher disruptive capacity than EGC. EGCG alters the L-shape of Aβ protofibril by breaking the hydrogen bond between H6 and E11 through π-π interactions with residues H14/Y10 and hydrogen-bonding interactions with E11, while EGC remodels the L-shape by inserting into the hydrophobic core formed by A2, F4, L34, and V36 and via aromatics interaction with H6/Y10. EGCG disrupts the salt bridges between the K28 side chain and A42 COO through hydrogen-bonding interaction with A42 and cation-π interaction between its gallic acid ester group and K28, while EGC damages the salt bridges through hydrophobic interactions with V39 and I41 as well as with I32, M35, and V40 located in the C-terminal hydrophobic core. This study demonstrates the pivotal role of the gallic acid ester group of EGCG in disrupting Aβ protofibril and provides atomic-level insights into the distinct mechanism by which EGCG and EGC disrupt Aβ protofibril, which could be useful for designing amyloid inhibitors.
淀粉样β蛋白（Aβ）纤维聚集体是阿尔茨海默病（AD）的标志。拆解预先形成的纤维或抑制Aβ聚集被认为是治疗AD的一种策略。越来越多的证据表明，绿茶提取物、表没食子儿茶素-3-没食子酸酯（EGCG，与表没食子儿茶素相比含有一个额外的没食子酸酯基团）和表没食子儿茶素（EGC）可以使Aβ纤维解离并减弱Aβ毒性。然而，其潜在的分子机制仍知之甚少。在此，我们进行了微秒级全原子分子动力学（MD）模拟，以研究EGCG/EGC对新通过低温电子显微镜解析的LS形Aβ原纤维的影响及其详细相互作用。MD模拟表明，EGCG和EGC都能破坏Aβ原纤维，且EGCG的破坏能力比EGC更高。EGCG通过与H14/Y10残基的π-π相互作用以及与E11的氢键相互作用打破H6和E11之间的氢键，从而改变Aβ原纤维的L形，而EGC则通过插入由A2、F4、L34和V36形成的疏水核心并通过与H6/Y10的芳香族相互作用来重塑L形。EGCG通过与A42的氢键相互作用以及其没食子酸酯基团与K28之间的阳离子-π相互作用破坏K28侧链与A42 COO之间的盐桥，而EGC则通过与V39和I41以及位于C端疏水核心的I32、M35和V40的疏水相互作用来破坏盐桥。本研究证明了EGCG的没食子酸酯基团在破坏Aβ原纤维中的关键作用，并提供了关于EGCG和EGC破坏Aβ原纤维的不同机制的原子水平见解，这可能有助于设计淀粉样蛋白抑制剂。
