文献类型：期刊文献

英文题名：The destructive mechanism of Aβ1-42 protofibrils by norepinephrine revealed via molecular dynamics simulations

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

机构：[1]Shanghai Univ Sport, Sch Phys Educ, Shanghai 200438, Peoples R China;[2]Zhejiang Univ, Coll Educ, Dept Sport & Exercise Sci, 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, Shanghai 200438, Peoples R China;[5]Fudan Univ, Minist Educ, Key Lab Computat Phys Sci, Shanghai 200438, Peoples R China

年份：2022

卷号：24

期号：33

起止页码：19827

外文期刊名：PHYSICAL CHEMISTRY CHEMICAL PHYSICS

收录：;EI(收录号：20223412616473);WOS:【SCI-EXPANDED(收录号:WOS:000838183100001)】；

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

语种：英文

外文关键词：Medical imaging - Molecular dynamics - Neurodegenerative diseases - Norepinephrine - Protonation

摘要：Amyloid-beta (A beta) fibrillary plaques represent the main hallmarks of Alzheimer's disease (AD), in addition to tau neurofibrillary tangles. Disrupting early-formed A beta protofibrils is considered to be one of the primary therapeutic strategies to interfere with AD. Our previous work showed that norepinephrine (NE), an important neurotransmitter in the brain, can effectively inhibit the aggregation of the A beta(1-42) peptide. However, whether and how NE molecules disassemble A beta(1-42) protofibrils remains to be elucidated. Herein we investigate the influence of NE (in protonated and deprotonated states) on the recently cryo-EM solved LS-shaped A beta(1-42) protofibrils and the underlying molecular mechanism by performing all-atom molecular dynamics simulations. Our simulations showed that protonated and deprotonated NE exhibited distinct disruptive mechanisms on A beta(1-42) protofibrils. Protonated NE could significantly disrupt the N-terminal (residues D1-H14) structure of A beta(1-42) protofibrils and destabilize the global structure of the protofibril. It preferentially bound with N-terminal residues of A beta(1-42) protofibrils and formed hydrogen bonds with E3, D7, E11, Q15, E22, and D23 residues and pi-pi stackings with H6, H13, and F20 residues, and thus destroyed the hydrogen bonds between H6 and E11 and increased the kink angle around Y10. Compared to protonated NE, deprotonated NE displayed a higher disruptive capability on A beta(1-42) protofibrils, and stronger hydrophobic and pi-pi stacking interactions with the protofibril structure. This study revealed the molecular mechanism of NE in the destruction of A beta(1-42) protofibrils, which may be helpful in the design of potent drug candidates against AD.