Molecular Insight into Cu 2+ -Induced Conformational Transitions of Amyloid β-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations

• Published in: ACS chemical neuroscience Vol. 12; no. 2; pp. 300 - 310
• Main Authors: Xu, Shaoying, Wang, Wenjuan, Dong, Xiaoyan, Sun, Yan
• Format: Journal Article
• Language: English
• Published: United States 20.01.2021
• Subjects: amyloid β-protein; copper; fluorescence spectroscopy; Alzheimer’s disease; conformational transitions; molecular dynamics simulation
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.0c00502

Cu -mediated amyloid β-protein (Aβ) aggregation is implicated in the pathogenesis of Alzheimer's disease, so it is of significance to understand Cu -mediated conformational transitions of Aβ. Herein, four Aβ mutants were created by using the environment-sensitive cyanophenylalanine to respectively substitute F4, Y10, F19, and F20 residues of Aβ . By using stopped-flow fluorescence spectroscopy and molecular dynamics (MD) simulations, the early stage conformational transitions of the mutants mediated by Cu binding were investigated. The fast kinetics unveils that Cu has more significant influence on the conformational changes of N-terminal (F4 and Y10) than on the central hydrophobic core (CHC, F19, and F20) under different pH conditions (pH 6.6-8.0), especially Y10. Interestingly, lag periods of the conformational transitions are observed for the F19 and F20 mutants at pH 8.0, indicating the slow response of the two mutation sites on the conformational transitions. More importantly, significantly longer lag periods for F20 than for F19 indicate the conduction of the transition from F19 to F20. The conduction time (difference in lag period) decreases from 4.5 s at Cu = 0 to undetectable (<1 ms) at Cu = 10 μM. The significant difference in the response time of F19 and F20 and the fast local conformational changes of Y10 imply that the conformational transitions of Aβ start around Y10. MD simulations support the observation of hydrophobicity increase at N-terminal during the conformational transitions of Aβ-Cu . It also reveals that Y10 is immediately approached by Cu , supporting the speculation that the starting point of conformational transitions of Aβ is near Y10. The work has provided molecular insight into the early stage conformational transitions of Aβ mediated by Cu .