Department of Physics, State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (Ministry of Education), Fudan University, Shanghai 200438, People's Republic of China.
Phys Chem Chem Phys. 2023 May 24;25(20):14471-14483. doi: 10.1039/d3cp00340j.
α-Synuclein (αSyn) is an intrinsically disordered protein and its abnormal aggregation into amyloid fibrils is the main hallmark of Parkinson's disease (PD). The disruption of preformed αSyn fibrils using small molecules is considered as a potential strategy for PD treatment. Recent experiments have reported that naphthoquinone-dopamine hybrids (NQDA), synthesized by naphthoquinone (NQ) and dopamine (DA) molecules, can significantly disrupt αSyn fibrils and cross the blood-brain barrier. To unravel the fibril-disruptive mechanisms at the atomic level, we performed microsecond molecular dynamics simulations of αSyn fibrils in the absence and presence of NQDA, NQ, DA, or NQ+DA molecules. Our simulations showed that NQDA reduces the β-sheet content, disrupts K45-E57 and E46-K80 salt-bridges, weakens the inter-protofibril interaction, and thus destabilizes the αSyn fibril structure. NQDA has the ability to form cation-π and H-bonding interactions with K45/K80, and form π-π stacking interactions with Y39/F94. Those interactions between NQDA and αSyn fibrils play a crucial role in disaggregating αSyn fibrils. Moreover, we found that NQDA has a better fibril destabilization effect than that of NQ, DA, and NQ+DA molecules. This is attributed to the synergistic fibril-binding effect between NQ and DA groups in NQDA molecules. The DA group can form strong π-π stacking interactions with aromatic residues Y39/F94 of the αSyn fibril, while the DA molecule cannot. In addition, NQDA can form stronger cation-π interactions with residues K45/K80 than those of both NQ and DA molecules. Our results provide the molecular mechanism underlying the disaggregation of the αSyn fibril by NQDA and its better performance in fibril disruption than NQ, DA, and NQ+DA molecules, which offers new clues for the screening and development of promising drug candidates to treat PD.
α-突触核蛋白（αSyn）是一种无规则结构的蛋白质，其异常聚集形成淀粉样纤维是帕金森病（PD）的主要标志。使用小分子破坏预先形成的αSyn 纤维被认为是 PD 治疗的一种潜在策略。最近的实验报告称，由萘醌（NQ）和多巴胺（DA）分子合成的萘醌-多巴胺杂合体（NQDA）可以显著破坏αSyn 纤维并穿过血脑屏障。为了在原子水平上揭示纤维破坏机制，我们对无 NQDA、NQ、DA 或 NQ+DA 分子以及存在 NQDA、NQ、DA 或 NQ+DA 分子时的αSyn 纤维进行了微秒分子动力学模拟。我们的模拟表明，NQDA 降低了β-折叠含量，破坏了 K45-E57 和 E46-K80 盐桥，削弱了原纤维间相互作用，从而使αSyn 纤维结构不稳定。NQDA 能够与 K45/K80 形成阳离子-π 和氢键，并与 Y39/F94 形成π-π 堆积相互作用。NQDA 与αSyn 纤维之间的这些相互作用在使αSyn 纤维解聚中起着至关重要的作用。此外，我们发现 NQDA 比 NQ、DA 和 NQ+DA 分子具有更好的纤维不稳定化作用。这归因于 NQDA 分子中 NQ 和 DA 基团的协同纤维结合效应。DA 基团可以与αSyn 纤维的芳香残基 Y39/F94 形成强的π-π 堆积相互作用，而 DA 分子则不能。此外，NQDA 与 K45/K80 残基形成的阳离子-π 相互作用比 NQ 和 DA 分子更强。我们的研究结果为 NQDA 解聚αSyn 纤维的分子机制及其在纤维破坏方面优于 NQ、DA 和 NQ+DA 分子提供了依据，为筛选和开发有希望的治疗 PD 的药物候选物提供了新的线索。
