文献类型：期刊文献

英文题名：Inhibitive and Destructive Mechanisms of Chronic Traumatic Encephalopathy-Related R3-R4 Tau Peptide Chains and Protofibril by Epigallocatechin Gallate: Evidence from Molecular Dynamics Simulation

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

机构：[1]Shanghai Univ Sport, Sch Phys Educ, Shanghai 200438, Peoples R China;[2]East China Univ Sci & Technol, Sch Sports Sci & Engn, Shanghai 200237, Peoples R China;[3]Zhejiang Univ, Coll Educ, Dept Sport & Exercise Sci, Hangzhou 310058, Zhejiang, Peoples R China

年份：2023

卷号：14

期号：11

起止页码：2098

外文期刊名：ACS CHEMICAL NEUROSCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001005935900001)】；

基金：This project was supported by the Natural Science Foundation of Shanghai (Grant No. 19ZR1453100).

语种：英文

外文关键词：chronic traumatic encephalopathy; tau protein; collision or contact sports; EGCG; molecularmechanism; molecular dynamics simulation

摘要：Chronic traumatic encephalopathy(CTE), a unique tauopathy, ispathologically associated with the aggregation of hyperphosphorylatedtau protein into fibrillar aggregates. Inhibiting tau aggregationand disaggregating tau protofibril might be promising strategies toprevent or delay the development of CTE. Newly resolved tau fibrilstructures from deceased CTE patients' brains show that theR3-R4 fragment of tau forms the core of the fibrils and the structuresare distinct from other tauopathies. An in vitro experiment findsthat epigallocatechin gallate (EGCG) can effectively inhibit humanfull-length tau aggregation and disaggregate preformed fibrils. However,its inhibitive and destructive effects on the CTE-related R3-R4 tauand the underlying molecular mechanisms remain elusive. In this study,we performed extensive all-atom molecular dynamics simulations onthe CTE-related R3-R4 tau dimer/protofibril with and without EGCG.The results reveal that EGCG could reduce the beta-sheet structurecontent of the dimer, induce the dimer to form loosely packed conformations,and impede the interchain interactions, thus inhibiting the furtheraggregation of the two peptide chains. Besides, EGCG could reducethe structural stability, decrease the beta-sheet structure content,reduce the structural compactness, and weaken local residue-residuecontacts of the protofibril, hence making the protofibril disaggregated.We also identified the dominant binding sites and pivotal interactions.EGCG preferentially binds with hydrophobic, aromatic, and positively/negativelycharged residues of the dimer, while it tends to bind with polar,hydrophobic, aromatic, and positively charged residues of the protofibril.Hydrophobic, hydrogen-bonding, pi-pi stacking, andcation-pi interactions synergistically drive the bindingof EGCG on both the dimer and the protofibril, but anion-pi interaction only exists in the interaction of EGCG with the dimer.Our work unravels EGCG's inhibitive and destructive effectson the CTE-related R3-R4 tau dimer/protofibril and the underlyingmolecular mechanisms, which provides useful implications for the designof drugs to prevent or delay the progression of CTE.