Department of Sport and Exercise Science, College of Education, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, P. R. China.
State Key Laboratory of Surface Physics and Department of Physics, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China.
Phys Chem Chem Phys. 2022 Aug 31;24(34):20454-20465. doi: 10.1039/d2cp02353a.
The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the rational therapeutic strategies to combat tauopathy. Previous studies reported that curcumin (Cur, a molecule of a labile natural product) and epinephrine (EP, an important neurotransmitter) could effectively inhibit the formation of Tau fibrillar aggregates and disassociate preformed fibrils. However, the underlying molecular mechanisms remain elusive. In this study, we performed multiple molecular dynamics simulations for 17.5 μs in total to investigate the influence of Cur and EP on the C-shaped Tau protofibril associated with CTE. Our simulations show that the protofibrillar pentamer is the smallest stable Tau R3-R4 protofibril. Taking the pentamer as a protofibril model, we found that both Cur and EP molecules could affect the shape of the Tau pentamer by changing the β2-β3 and β7-β8 angles, leading to a more extended structure. Cur and EP display a disruptive effect on the local β-sheets and the formation of hydrogen bonds, and thus destabilize the global protofibril structure. The contact number analysis shows that Cur has a higher binding affinity with the Tau pentamer than EP, especially in the nucleating segment PHF6. Hydrophobic, π-π and cation-π interactions together facilitate the binding of Cur and EP with the Tau pentamer. Cur exhibits stronger hydrophobic and π-π interactions with Tau than EP, and EP displays a stronger cation-π interaction. Our findings provide molecular insights into the disruptive mechanisms of the Tau R3-R4 protofibrils by curcumin and epinephrine, which may be useful for the design of effective drug candidates for the treatment of CTE.
tau 蛋白聚集体的积累是包括慢性创伤性脑病（CTE）在内的 tau 病的病理标志。抑制 Tau 聚集或破坏预先形成的 Tau 原纤维被认为是对抗 tau 病的合理治疗策略之一。先前的研究报告称，姜黄素（Cur，一种不稳定天然产物的分子）和肾上腺素（EP，一种重要的神经递质）可以有效抑制 Tau 纤维状聚集体的形成并使预先形成的纤维解聚。然而，其潜在的分子机制仍不清楚。在这项研究中，我们总共进行了 17.5 μs 的多次分子动力学模拟，以研究 Cur 和 EP 对与 CTE 相关的 C 形 Tau 原纤维的影响。我们的模拟表明，原纤维五聚体是最小的稳定 Tau R3-R4 原纤维。以五聚体作为原纤维模型，我们发现 Cur 和 EP 分子都可以通过改变β2-β3 和β7-β8 角来影响 Tau 五聚体的形状，导致更伸展的结构。Cur 和 EP 对局部β-折叠和氢键的形成显示出破坏作用，从而使全局原纤维结构不稳定。接触数分析表明，Cur 与 Tau 五聚体的结合亲和力高于 EP，尤其是在核形成段 PHF6 中。疏水、π-π 和阳离子-π 相互作用共同促进了 Cur 和 EP 与 Tau 五聚体的结合。Cur 与 Tau 的相互作用比 EP 表现出更强的疏水性和π-π 相互作用，而 EP 则表现出更强的阳离子-π 相互作用。我们的研究结果为 curcumin 和 epinephrine 破坏 Tau R3-R4 原纤维的机制提供了分子见解，这可能有助于设计治疗 CTE 的有效药物候选物。
