Abstract
In spite of significant experimental effort dedicated to the study of Cu2+ binding to the amyloid beta (Aβ) peptide, involved in Alzheimer’s disease, the nature of the oxygen-based ligand in the low pH component of the Cu2+-Aβ(1−16) complex is still under debate. This study reports density-functional-theory-based calculations that explore the potential energy surface of Cu2+ complexes including N and O ligands at the N-terminus of the Aβ peptide, with a focus on evaluating the role of Asp1 carboxylate in copper coordination. Model conformers including 3, 6, and 17 amino acids have been used to systematically study several aspects of the Cu2+-coordination such as the Asp1 side chain conformation, local peptide backbone geometry, electrostatic and/or hydrogen bond interactions, and number and availability of Cu2+ligands. Our results show that the Asp1 peptide carbonyl binds to Cu2+ only if the coordination number is less than four. In contrast, if four ligands are available, the most stable structures include the Asp1 carboxylate in equatorial position instead of the Asp1 carbonyl group. The two lowest energy Cu2+-Aβ(1−17) models involve Asp1 COO−, the N-terminus, and His6 and His14 as equatorial ligands, with either a carbonyl or a water molecule in the axial position. These models are in good agreement withexperimental data reported for component I of the Cu2+-Aβ(1−16) complex, including EXAFS- and X-ray-derived Cu2+−ligand distances, Cu2+ EPR parameters, and 14N and 13C superhyperfine couplings. Our results suggest that at low pH, Cu2+-Aβ species with Asp1 carboxylate equatorial coordination coexist with species coordinating the Asp1 carbonyl. Understanding the bondingmechanism in these species is relevant to gain a deeper insight on the molecular processes involving copper-amyloid-β complexes, such as aggregation and redox activity.