Molecular dynamics simulations reveal the mechanism of graphene oxide nanosheet inhibition of Aβ1-42 peptide aggregation
Molecular dynamics simulations reveal the mechanism of graphene oxide nanosheet inhibition of Aβ1-42 peptide aggregation
复制标题
分子动力学模拟揭示氧化石墨烯纳米片抑制Aβ(1-42)肽聚集的机制
DOI：
10.1039/c9cp01803d
复制
发表时间：
2019-06-07
影响因子：
3.3
通讯作者：
Wei, Guanghong
中科院分区：
文献类型：
--
作者：
Jin, Yibo;Sun, Yunxiang;Wei, Guanghong
淀粉样蛋白-β（Ab）肽聚集成毒性的富含b-折叠的寡聚体、原纤维和成熟纤维是阿尔茨海默病（AD）的主要病理标志。抑制Ab肽的b-折叠形成和折叠被认为是AD的重要治疗策略。氧化石墨烯（GO）由于其良好的穿过血脑屏障（BBB）的能力，低细胞毒性和良好的生物相容性，在抗淀粉样蛋白聚集方面引起了特别的兴趣。最近的实验报道，GO纳米片可以强烈抑制A β（1-42）的原纤维形成并降低其细胞毒性。然而，通过GO纳米片抑制A β（1-42）氟化的机制还没有很好地理解。A β（1-42）二聚体是A β（1-42）聚集的最小毒性寡聚体。作为理解GO纳米片对A β（1-42）聚集的抑制作用的起始步骤，我们通过进行显式溶剂复制交换分子动力学模拟来研究具有或不具有GO纳米片的A β（1-42）二聚体的构象分布。我们的模拟表明，A β（1-42）肽可以形成不同的富含b-折叠的二聚体构象，而这些构象在添加GO纳米片后被显著抑制。我们发现GO主要通过减弱肽间相互作用来抑制A β（1-42）的b-折叠形成，所述肽间相互作用主要经由盐桥、氢键和与带电残基D1、E3、R5、D 7、E11、K16、E22、K28和A42的阳离子-p相互作用。GO和A β（1-42）之间的p-p和疏水相互作用也在抑制Ab聚集中起作用。该研究提供了GO纳米片对A β（1-42）聚集和淀粉样蛋白抑制的机制见解，这可能为开发抗AD的治疗候选物提供新的线索。
The aggregation of the amyloid-beta (Ab) peptides into toxic b-sheet-rich oligomers, protofibrils and mature fibrils is the major pathological hallmark of Alzheimer's disease (AD). Inhibiting the b-sheet formation and fibrillization of Ab peptides is considered an important treatment strategy for AD. Graphene oxide (GO) has attracted particular interest in the anti-aggregation of amyloid proteins due to its good ability of crossing the blood-brain barrier (BBB), low cytotoxicity and good biocompatibility. Recent experiments reported that GO nanosheets could strongly inhibit the fibril formation of A beta(1-42) and reduce its cytotoxicity. However, the mechanism of suppressing A beta(1-42) fibrillization by GO nanosheets is not well understood. A beta(1-42) dimer is the smallest toxic oligomer of A beta(1-42) aggregation. As a starting step to understand the inhibitory effect of GO nanosheets towards A beta(1-42) aggregation, we investigated the conformational distribution of the A beta(1-42) dimer with or without GO nanosheets by performing explicit-solvent replica exchange molecular dynamics simulations. Our simulations showed that A beta(1-42) peptides could form diverse b-sheet rich dimeric conformations, whereas those conformations were significantly inhibited after the addition of GO nanosheets. We found that GO suppressed the b-sheet formation of A beta(1-42) mostly by weakening inter-peptide interactions mostly via salt bridge, hydrogen bonding and cation-p interactions with charged residues D1, E3, R5, D7, E11, K16, E22, K28 and A42. The p-p and hydrophobic interactions between GO and A beta(1-42) also play a role in the inhibition of Ab aggregation. This study provides mechanistic insights into A beta(1-42) aggregation and amyloid inhibition by GO nanosheets, which may provide new clues for the development of therapeutic candidates against AD.