文献类型：期刊文献

英文题名：Destabilization mechanism of R3-R4 tau protofilament by purpurin: a molecular dynamics study

作者：Wan, Jiaqian[1];Zou, Yu[2];Sun, Ruiqing[1];Xu, Zhengdong[1];Tang, Jiaxing[1];Gong, Yehong[3];Wei, Guanghong[4,5];Zhang, Qingwen[1]

机构：[1]Shanghai Univ Sport, Sch Phys Educ, 399 Changhai Rd, Shanghai 200438, Peoples R China;[2]Zhejiang Univ, Coll Educ, Dept Sport & Exercise Sci, 886 Yuhangtang Rd, Hangzhou 310058, Peoples R China;[3]East China Univ Sci & Technol, Sch Sports Sci & Engn, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[4]Fudan Univ, Dept Phys, State Key Lab Surface Phys, Minist Educ, Shanghai 200438, Peoples R China;[5]Fudan Univ, Key Lab Computat Phys Sci, Minist Educ, Shanghai 200438, Peoples R China

年份：2023

卷号：25

期号：25

起止页码：16856

外文期刊名：PHYSICAL CHEMISTRY CHEMICAL PHYSICS

收录：;EI(收录号：20232614325881);WOS:【SCI-EXPANDED(收录号:WOS:001006792100001)】；

基金：This work has been financially supported by the Natural Science Foundation of Shanghai, grant number 19ZR1453100. All simulations were performed using the High-Performance Computing Server at Shanghai University of Sport and the GPU cluster at Zhejiang University.

语种：英文

外文关键词：Aggregates - Ketones - Neurodegenerative diseases

摘要：The accumulation of tau protein aggregates is a common feature observed in many neurodegenerative diseases. However, the structural characteristics of tau aggregates can vary among different tauopathies. It has been established that the structure of the tau protofilament in Chronic traumatic encephalopathy (CTE) is similar to that of Alzheimer's disease (AD). In addition, a previous study found that purpurin, an anthraquinone, could inhibit and disassemble the pre-formed (306)VQIVYK(311) isoform of AD-tau protofilament. Herein, we used all-atom molecular dynamic (MD) simulation to investigate the distinctive features between CTE-tau and AD-tau protofilament and the influence of purpurin on CTE-tau protofilament. Our findings revealed notable differences at the atomic level between CTE-tau and AD-tau protofilaments, particularly in the beta 6-beta 7 angle and the solvent-accessible surface area (SASA) of the beta 4-beta 6 region. These structural disparities contributed to the distinct characteristics observed in the two types of tau protofilaments. Our simulations substantiated that purpurin could destabilize the CTE-tau protofilament and decrease beta-sheet content. Purpurin molecules could insert the beta 4-beta 6 region and weaken the hydrophobic packing between beta 1 and beta 8 through pi-pi stacking. Interestingly, each of the three rings in purpurin exhibited unique binding preferences with the CTE-tau protofilament. Overall, our study sheds light on the structural distinctions between CTE-tau and AD-tau protofilaments, as well as the destabilizing mechanism of purpurin on CTE-tau protofilament, which may be helpful to the development of drugs to prevent CTE.