Department of Chemistry, Indian Institute of Technology, Guwahati, Assam 781039, India.
J Phys Chem B. 2022 Jul 7;126(26):4761-4775. doi: 10.1021/acs.jpcb.2c01768. Epub 2022 Jun 27.
The aggregation of Tau protein, which are involved in Alzheimer's disease, are associated with the self-assembly of the hexapeptide sequence, paired helical filament 6 (PHF6) from repeat 3 of Tau. In order to treat Alzheimer's disease and other such tauopathies, one of the therapeutic strategies is to inhibit aggregation of Tau and its nucleating segments. Therefore, we have studied the effect of adenosine triphosphate (ATP) on the aggregation of PHF6. ATP has, interestingly, demonstrated its ability to inhibit and dissolve protein aggregates. Using classical molecular dynamics simulations, we observed that the hydrophobic core of PHF6 segment displays extended β-sheet conformation, which stabilizes PHF6 aggregates. However, the distribution of ATP around the vicinity of the peptides enables PHF6 to remain discrete and attain random coil conformers. The interpeptide interactions are substituted by PHF6-ATP interactions through hydrogen bonding and hydrophobic interactions (including π-π stacking). Furthermore, the adenosine moiety of ATP contributes more than the triphosphate chain toward PHF6-ATP interaction. Ultimately, this work establishes the inhibitory activity of ATP against Tau aggregation; hence, the therapeutic effect of ATP should be explored further in regard to the effective treatment of Alzheimer's disease.
Tau 蛋白的聚集与阿尔茨海默病有关，它们与 Tau 重复 3 中的六肽序列配对螺旋丝 6 (PHF6) 的自组装有关。为了治疗阿尔茨海默病和其他 Tau 病，治疗策略之一是抑制 Tau 及其成核片段的聚集。因此，我们研究了三磷酸腺苷 (ATP) 对 PHF6 聚集的影响。有趣的是，ATP 表现出抑制和溶解蛋白质聚集的能力。使用经典分子动力学模拟，我们观察到 PHF6 片段的疏水核心显示出扩展的β-折叠构象，从而稳定 PHF6 聚集体。然而，ATP 在肽附近的分布使 PHF6 保持离散并获得无规卷曲构象。通过氢键和疏水相互作用（包括 π-π 堆积）取代了肽间相互作用。此外，ATP 的腺苷部分对 PHF6-ATP 相互作用的贡献大于三磷酸酯链。最终，这项工作确立了 ATP 对 Tau 聚集的抑制活性；因此，应该进一步探索 ATP 的治疗效果，以有效治疗阿尔茨海默病。
