Department of Sport and Exercise Science, College of Education, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, P. R. China.
College of Physical Education, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, P. R. China.
ACS Chem Neurosci. 2023 Sep 6;14(17):3265-3277. doi: 10.1021/acschemneuro.3c00434. Epub 2023 Aug 16.
The formation of neurofibrillary tangles by abnormal aggregation of tau protein is considered to be an important pathological characteristic of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Two hexapeptides VQIINK and VQIVYK in the microtubule binding region, named PHF6* and PHF6, are known to be aggregation-prone and responsible for tau fibrillization. Previous experiments reported that naphthoquinone-dopamine (NQDA) could effectively inhibit the aggregation of PHF6* and PHF6 and disrupt the fibrillar aggregates into nontoxic species, displaying a dual effect on the amyloid aggregation. However, the underlying molecular mechanism remains mostly elusive. Herein, we performed all-atom molecular dynamics (MD) simulations for 114 μs in total to systematically investigate the impacts of NQDA on the oligomerization of PHF6* and PHF6. The conformational ensembles of PHF6* and PHF6 peptides generated by replica exchange MD simulations show that NQDA could effectively prevent the hydrogen bond formation, reduce the ability of peptides to self-assemble into long β-strand and large β-sheets, and induce peptides to form a loosely packed and coil-rich oligomer. The interaction analysis shows that the binding of NQDA to PHF6* is mainly through hydrophobic interactions with residue I277 and hydrogen bonding interactions with Q276; for the PHF6 peptides, NQDA displays a strong π-π stacking interaction with residue Y310, thus impeding the Y310-Y310 π-π stacking and I308-Y310 CH-π interactions. The DA group of NQDA displays a stronger cation-π interaction than the NQ group, while the NQ group exhibits a stronger π-π stacking interaction. MD simulations demonstrate that NQDA prevents the conformational conversion to β-sheet-rich aggregates and displays an inhibitory effect on the oligomerization dynamics of PHF6* and PHF6. Our results provide a complete picture of inhibitory mechanisms of NQDA on PHF6* and PHF6 oligomerization, which may pave the way for designing drug candidates for the treatment of tauopathies.
异常聚集的tau 蛋白形成神经原纤维缠结被认为是 tau 病的重要病理特征，包括阿尔茨海默病和慢性创伤性脑病。微管结合区的两个六肽 VQIINK 和 VQIVYK，分别命名为 PHF6和 PHF6，已知容易聚集，并负责 tau 纤维形成。先前的实验报道，萘醌-多巴胺（NQDA）可以有效地抑制 PHF6和 PHF6 的聚集，并将纤维状聚集体转化为无毒物质，对淀粉样蛋白聚集表现出双重作用。然而，其潜在的分子机制仍在很大程度上难以捉摸。在此，我们进行了总共 114 μs 的全原子分子动力学（MD）模拟，以系统研究 NQDA 对 PHF6和 PHF6 寡聚化的影响。通过 replica exchange MD 模拟生成的 PHF6和 PHF6 肽的构象集合表明，NQDA 可以有效地阻止氢键的形成，降低肽自我组装成长β-链和大β-片层的能力，并诱导肽形成松散堆积和富含线圈的寡聚体。相互作用分析表明，NQDA 与 PHF6的结合主要通过与残基 I277 的疏水相互作用和与 Q276 的氢键相互作用；对于 PHF6 肽，NQDA 与残基 Y310 显示出强烈的π-π堆积相互作用，从而阻碍 Y310-Y310 π-π堆积和 I308-Y310 CH-π相互作用。NQDA 的 DA 基团显示出比 NQ 基团更强的阳离子-π相互作用，而 NQ 基团则表现出更强的π-π堆积相互作用。MD 模拟表明，NQDA 阻止了构象向富含β-片层的聚集的转变，并对 PHF6和 PHF6 寡聚化动力学显示出抑制作用。我们的结果提供了 NQDA 抑制 PHF6*和 PHF6 寡聚化的完整机制，这可能为设计治疗 tau 病的药物候选物铺平道路。
