文献类型：期刊文献

英文题名：Dissecting the Inhibitory Mechanism of the αB-Crystallin Domain against Aβ42 Aggregation and Its Effect on Aβ42 Protofibrils: A Molecular Dynamics Simulation Study

作者：Xu, Zhengdong[1];Gong, Yehong[1,2];Zou, Yu[3];Wan, Jiaqian[1];Tang, Jiaxing[1];Zhan, Chendi[4,5];Wei, Guanghong[4,5];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 310007, Zhejiang, Peoples R China;[4]Fudan Univ, Minist Educ, 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：13

期号：19

起止页码：2842

外文期刊名：ACS CHEMICAL NEUROSCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000868879300001)】；

基金：Funding This project was supported by the Natural Science Foundation of Shanghai (Grant No. 19ZR1453100) and the National Natural Science Foundation of China (Grant No. 12074079) .

语种：英文

外文关键词：amyloid-?; aB-crystallin; HSPB5; molecular dynamics simulation; Alzheimer?s disease; inhibitory mechanism

摘要：Alzheimer ' s disease (AD) is related to the misfolding and aggregation of amyloid-P (AP) protein, and its major pathological hallmark is fibrillary P-amyloid plaques. Impeding the formation of AP P-structure-rich aggregates and dissociating AP fibrils are considered potent strategies to suppress the onset and progression of AD. As a molecular chaperone, human aB-crystallin has received extensive attention in the inhibition of protein aggregation. Previous experiments reported that the structured core region of aB-crystallin (aBC) exhibits a better preventive effect on AP aggregation and toxicity than the full-length protein. However, the molecular mechanism behind the effect of inhibition remains mostly unknown. Herein, we carried out six 500 ns molecular dynamics (MD) simulations to investigate the inhibitory mechanism of aBC on AP42 aggregation. Our simulations show that aBC greatly impedes the formation of P-structure contents. We find that the binding of aBC to the AP42 monomer is driven by polar, hydrophobic, and H-bonding interactions. To explore whether aBC could destabilize AP42 protofibrils, we also carried out MD simulations of AP42 protofibrils with and without aBC. The results show that aBC interacts with three binding sites of the AP42 protofibril, and the binding is mainly driven by polar and H-bonding interactions. The binding of aBC at these three sites has a preferred dissociation effect on the P-structure content, kink angle, and K28-A42 salt bridges. Overall, this study not only discloses the molecular mechanism of aBC against AP42 aggregation but also demonstrates the disruption effects of aBC on AP42 protofibrils, which yields an avenue for designing anti-AD drug candidates.