Advanced Electron Paramagnetic Resonance Studies of a Ternary Complex of Copper, Amyloid-β, and a Chemical Regulator

Although there has been extensive effort to develop chemical regulators, progress has been static, in part because of these regulators' unclear mechanisms. Here, we report using advanced electron paramagnetic resonance (EPR) spectroscopy to obtain the first molecular-level structural information regarding a ternary complex of Cu^II-amyloid-β (Aβ) with a chemical regulator that can specifically modulate Cu-induced Aβ aggregation. Our advanced EPR spectroscopic results revealed that a chemical regulator (1) for Cu^II-Aβ_1-16 disrupted the coordination environment of Cu^II in Aβ, resulting in the detachment of the primary amine at the N-terminal and a carbonyl group between Asp1 and Ala2 from the Cu^II center and the subsequent formation of a ternary complex, chemical regulator-Cu^II-Aβ_1-16. Therefore, our results demonstrate how a chemical regulator interacts with metal-Aβ at the molecular level. These findings provide novel insight into working mechanisms and thereby contribute to the establishment of a rational design for chemical regulators of metal-Aβ complexes.