Structural Insight into Redox Dynamics of Copper Bound N-Truncated Amyloid-β Peptides from in Situ X-ray Absorption Spectroscopy.

X-ray absorption spectroscopy of Cu amyloid-β peptide (Aβ) under in situ electrochemical control (XAS-EC) has allowed elucidation of the redox properties of Cu bound to truncated peptide forms. The Cu binding environment is significantly different for the Aβ and the N-truncated Aβ, Aβ, and Aβ (Aβ) peptides, where the N-truncated sequence (FRH) provides the high-affinity amino-terminal copper nickel (ATCUN) binding motif. Low temperature (ca. 10 K) XAS measurements show the adoption of identical Cu ATCUN-type binding sites (Cu) by the first three amino acids (FRH) and a longer-range interaction modeled as an oxygen donor ligand, most likely water, to give a tetragonal pyramid geometry in the Aβ peptides not previously reported. Both XAS-EC and EPR measurements show that Cu:Aβ can be reduced at mildly reducing potentials, similar to that of Cu:Aβ. Reduction of peptides lacking the HH residues, Cu:Aβ, require far more forcing conditions, with metallic copper the only metal-based reduction product. The observations suggest that reduction of Cu species at mild potentials is possible, although the rate of reduction is significantly enhanced by involvement of HH. XAS-EC analysis reveals that, following reduction, the peptide acts as a terdentate ligand to Cu (H, H together with the linking amide oxygen atom). Modeling of the EXAFS is most consistent with coordination of an additional water oxygen atom to give a quasi-tetrahedral geometry. XAS-EC analysis of oxidized Cu:Aβ gives structural parameters consistent with crystallographic data for a five-coordinate Cu complex and the Cu complex. The structural results suggest that Cu and the oxidation product are both accommodated in an ATCUN-like binding site.