文献类型：期刊文献

英文题名：Mechanistic insight into the disruption of Tau R3-R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study

作者：Zou, Yu[1];Qi, Bote[1];Tan, Jingwang[1];Sun, Yunxiang[2,3,4];Gong, Yehong[5];Zhang, Qingwen[6]

机构：[1]Zhejiang Univ, Coll Educ, Dept Sport & Exercise Sci, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China;[2]Fudan Univ, State Key Lab Surface Phys, 220 Handan Rd, Shanghai 200433, Peoples R China;[3]Fudan Univ, Dept Phys, 220 Handan Rd, Shanghai 200433, Peoples R China;[4]Ningbo Univ, Dept Phys, 818 Fenghua Rd, Ningbo 315211, Zhejiang, Peoples R China;[5]East China Univ Sci & Technol, Sch Sports Sci & Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[6]Shanghai Univ Sport, Coll Phys Educ & Training, 399 Changhai Rd, Shanghai 200438, Peoples R China

年份：2022

卷号：24

期号：34

起止页码：20454

外文期刊名：PHYSICAL CHEMISTRY CHEMICAL PHYSICS

收录：;EI(收录号：20223512673506);WOS:【SCI-EXPANDED(收录号:WOS:000842493900001)】；

基金：This work was supported financially by the Natural Science Foundation of Zhejiang Province (LQ21A040013). All the simulations were performed using the GPU cluster of our group.

语种：英文

外文关键词：Aggregates - Binding energy - Hydrogen bonds - Hydrophobicity - Molecules - Positive ions

摘要：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 mu s 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 beta 2-beta 3 and beta 7-beta 8 angles, leading to a more extended structure. Cur and EP display a disruptive effect on the local beta-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, pi-pi and cation-pi interactions together facilitate the binding of Cur and EP with the Tau pentamer. Cur exhibits stronger hydrophobic and pi-pi interactions with Tau than EP, and EP displays a stronger cation-pi 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.