β-Amyloid aggregates in the brain play critical roles in Alzheimer's disease, a chronic neurodegenerative condition. Amyloid-associated metal ions, particularly zinc and copper ions, have been implicated in disease pathogenesis. Despite the importance of such ions, the binding sites on the β-amyloid peptide remain poorly understood. In this study, we use scanning tunneling microscopy, circular dichroism, and surface-enhanced Raman spectroscopy to probe the interactions between Cu2+ ions and a key β-amyloid peptide fragment, consisting of the first 16 amino acids, and define the copper-peptide binding site. We observe that in the presence of Cu2+, this peptide fragment forms β-sheets, not seen without the metal ion. By imaging with scanning tunneling microscopy, we are able to identify the binding site, which involves two histidine residues, His13 and His14. We conclude that the binding of copper to these residues creates an interstrand histidine brace, which enables the formation of β-sheets.
Keywords: Alzheimer’s disease; binding site; histidine brace; scanning tunneling microscopy; β-amyloid; β-sheet.