With a combination of complementary experimental techniques, namely sedimentation assay, Fourier transform infrared spectroscopy, and x-ray absorption spectroscopy, we are able to determine the atomic structure around the metal-binding site in samples where amyloid-␤ (A␤) peptides are complexed with either Cu(II) or Zn(II). Exploiting information obtained on a selected set of fragments of the A␤ peptide, we identify along the sequence the histidine residues coordinated to the metal in the various peptides we have studied (A␤ 1-40 , A␤ 1-16 , A␤ 1-28 , A␤ 5-23 , and A␤ 17-40 ). Our data can be consistently interpreted assuming that all of the peptides encompassing the minimal 1-16 amino acidic sequence display a copper coordination mode that involves three histidines (His 6 , His 13 , and His 14 ). In zinc-A␤ complexes, despite the fact that the metal coordination appears to be more sensitive to solution condition and shows a less rigid geometry around the binding site, a four-histidine coordination mode is seen to be preferred. Lacking a fourth histidine along the A␤ peptide sequence, this geometrical arrangement hints at a Zn(II)-promoted interpeptide aggregation mode.

Background: ␤-Amyloid aggregates are at the basis of Alzheimer disease development. Short synthetic peptides are seen to inhibit polymerization. Results: Various synthetic peptides have been studied by MD simulations and tested experimentally. Conclusion:Combined results indicate Ac-LPFFN-NH 2 as an effective lead compound able to slow down A␤ 1-40 aggregation. Significance: Designing potential A␤ aggregation inhibitors will help fight Alzheimer disease.

In this work we present and analyse XAS measurements carried out on various portions of Prion-protein tetra-octa-repeat peptides in complexes with Cu(II) ions, both in the presence and in the absence of Zn(II). Because of the ability of the XAS technique to provide detailed local structural information, we are able to demonstrate that Zn acts by directly interacting with the peptide, in this way competing with Cu for binding with histidine. This finding suggests that metal binding competition can be important in the more general context of metal homeostasis.

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