Amyloid plaques accumulated by the amyloid-β (Aβ) fibrillar aggregates are the major pathological hallmark of the Alzheimer’s disease (AD). Inhibiting aggregation and disassembling preformed fibrils of Aβ by natural small molecules have developed into a promising therapeutic strategy for AD. Previous experiments reported that the green tea extract epigallocatechin-3-gallate (EGCG) can disrupt Aβ fibril and reduce Aβ cytotoxicity. The inhibitory ability of EGCG can also be affected by cellular membranes. Thus, it is essential to consider the membrane influences in the investigation of protofibril-disruptive capability of EGCG. Here, we performed multiple all-atom molecular dynamic simulations to investigate the effect of EGCG on the Aβ₄₂ protofibril in the presence of a mixed POPC/POPG (7:3) lipid bilayer and the underlying molecular mechanisms of action. Our simulations show that in the presence of membrane bilayers, EGCG has a preference to bind to the membrane, and this binding alters the binding modes between Aβ₄₂ protofibril and the lipid bilayer, leading to a reduced membrane thinning, indicative of a protective effect of EGCG on the membrane. And EGCG still displays a disruptive effect on Aβ₄₂ protofibril, albeit with a lesser extent of disruption than that in the membrane-free environment. EGCG destabilizes the two hydrophobic core regions (L17-F19-I31 and F4-L34-V36), and disrupts the intrachain K28-A42 salt bridges. Our results reveal that in the presence of lipid bilayers, EGCG plays a dual role in Aβ₄₂ protofibril disruption and membrane protection, suggesting that EGCG could be a potential effective drug candidate for the treatment of AD.

由淀粉样蛋白 β (Aβ) 原纤维聚集体积累的淀粉样斑块是阿尔茨海默病 (AD) 的主要病理标志。通过天然小分子抑制 Aβ 的聚集和分解预形成的原纤维已发展成为一种有前途的 AD 治疗策略。先前的实验报告说，绿茶提取物表没食子儿茶素-3-没食子酸酯 (EGCG) 可以破坏 Aβ 原纤维并降低 Aβ 细胞毒性。EGCG的抑制能力也受细胞膜的影响。因此，在研究 EGCG 的原纤维破坏能力时，必须考虑膜的影响。在这里，我们进行了多次全原子分子动力学模拟来研究 EGCG 对 Aβ _{42 的影响}在混合的POPC/POPG (7:3) 脂质双层存在下的原纤维和潜在的分子作用机制。我们的模拟表明，在存在膜双层的情况下，EGCG 优先与膜结合，这种结合改变了 Aβ ₄₂原纤维与脂质双层之间的结合模式，导致膜变薄减少，表明对膜上的EGCG。并且 EGCG 仍然对 Aβ ₄₂原纤维显示出破坏作用，尽管破坏程度低于无膜环境中的破坏程度。EGCG 使两个疏水核心区域（L17-F19-I31 和 F4-L34-V36）不稳定，并破坏链内 K28-A42 盐桥。我们的结果表明，在脂质双层存在的情况下，EGCG 在 Aβ 中发挥双重作用₄₂原纤维破坏和膜保护，表明 EGCG 可能是治疗 AD 的潜在有效候选药物。