Li Fangying, Zhan Chendi, Dong Xuewei, Wei Guanghong
Department of Physics, State Key Laboratory of Surface Physics, and Key Laboratory for Computational Physical Sciences (Ministry of Education), Fudan University, Shanghai, 200438, People's Republic of China.
Phys Chem Chem Phys. 2021 Sep 14;23(34):18843-18854. doi: 10.1039/d1cp01913a. Epub 2021 Aug 23.
The aggregation of amyloid-β protein (Aβ) into fibrillary deposits is implicated in Alzheimer's disease (AD), and inhibiting Aβ aggregation and clearing Aβ fibrils are considered as promising strategies to treat AD. It has been reported that resveratrol (RSV) and epigallocatechin-3-gallate (EGCG), two of the most extensively studied natural polyphenols, are able to inhibit Aβ fibrillization and remodel the preformed fibrillary aggregates into amorphous, non-toxic species. However, the mechanisms by which RSV inhibits Aβ aggregation and disrupts Aβ protofibril, as well as the inhibitory/disruptive mechanistic similarities and differences between RSV and EGCG, remain mostly elusive. Herein, we performed extensive all-atom molecular dynamics (MD) simulations on Aβ dimers (the early aggregation state of Aβ) and protofibrils (the intermediate of Aβ fibril formation and elongation) in the absence/presence of RSV or EGCG molecules. Our simulations show that both RSV and EGCG can bind with Aβ monomers and inhibit the dimerization of Aβ. The binding of RSV with Aβ peptide is mostly viaπ-π stacking interactions, while the binding of EGCG with Aβ is mainly through hydrophobic, π-π stacking, and hydrogen-bonding interactions. Moreover, both RSV and EGCG disrupt the β-sheet structure and K28-A42 salt bridges, leading to a disruption of Aβ protofibril structure. RSV mainly binds with residues whose side-chains point inwards from the surface of the protofibril, while EGCG mostly binds with residues whose side-chains point outwards from the surface of the protofibril. Furthermore, RSV interacts with Aβ protofibrils mostly viaπ-π stacking interactions, while EGCG interacts with Aβ protofibrils mainly via hydrogen-bonding and hydrophobic interactions. For comparison, we also explore the effects of RSV/EGCG molecules on the aggregation inhibition and protofibril disruption of the Iowa mutant (D23N) Aβ. Our findings may pave the way for the design of more effective drug candidates as well as the utilization of cocktail therapy using RSV and EGCG for the treatment of AD.
淀粉样β蛋白（Aβ）聚集成纤维状沉积物与阿尔茨海默病（AD）有关，抑制Aβ聚集和清除Aβ纤维被认为是治疗AD的有前景的策略。据报道，白藜芦醇（RSV）和表没食子儿茶素-3-没食子酸酯（EGCG）是研究最广泛的两种天然多酚，它们能够抑制Aβ纤维化，并将预先形成的纤维状聚集体重塑为无定形的、无毒的物种。然而，RSV抑制Aβ聚集和破坏Aβ原纤维的机制，以及RSV和EGCG之间抑制/破坏机制的异同，仍然大多不清楚。在此，我们对不存在/存在RSV或EGCG分子的情况下的Aβ二聚体（Aβ的早期聚集状态）和原纤维（Aβ纤维形成和延伸的中间体）进行了广泛的全原子分子动力学（MD）模拟。我们的模拟表明，RSV和EGCG都可以与Aβ单体结合并抑制Aβ的二聚化。RSV与Aβ肽的结合主要通过π-π堆积相互作用，而EGCG与Aβ的结合主要通过疏水、π-π堆积和氢键相互作用。此外，RSV和EGCG都破坏了β-折叠结构和K28-A42盐桥，导致Aβ原纤维结构的破坏。RSV主要与原纤维表面向内指向的侧链残基结合，而EGCG主要与原纤维表面向外指向的侧链残基结合。此外，RSV与Aβ原纤维的相互作用主要通过π-π堆积相互作用，而EGCG与Aβ原纤维的相互作用主要通过氢键和疏水相互作用。为了进行比较，我们还研究了RSV/EGCG分子对爱荷华突变体（D23N）Aβ的聚集抑制和原纤维破坏的影响。我们的发现可能为设计更有效的候选药物以及利用RSV和EGCG的联合疗法治疗AD铺平道路。
