Aβ_5- Peptides: N-Terminal Truncation Yields Tunable Cu(II) Complexes

The Aβ_5- peptides (x = 38, 40, 42) are minor Aβ species in normal brains but elevated upon the application of inhibitors of Aβ processing enzymes. They are interesting from the point of view of coordination chemistry for the presence of an Arg-His metal binding sequence at their N-terminus capable of forming a 3-nitrogen (3N) three-coordinate chelate system. Similar sequences in other bioactive peptides were shown to bind Cu(II) ions in biological systems. Therefore, we investigated Cu(II) complex formation and reactivity of a series of truncated Aβ_5- peptide models comprising the metal binding site: Aβ_5-9, Aβ_5-12, Aβ_5-12Y10F, and Aβ_5-16. Using CD and UV-vis spectroscopies and potentiometry, we found that all peptides coordinated the Cu(II) ion with substantial affinities higher than 3 × 10¹² M^-1 at pH 7.4 for Aβ_5-9 and Aβ_5-12. This affinity was elevated 3-fold in Aβ_5-16 by the formation of the internal macrochelate with the fourth coordination site occupied by the imidazole nitrogen of the His13 or His14 residue. A much higher boost of affinity could be achieved in Aβ_5-9 and Aβ_5-12 by adding appropriate amounts of the external imidazole ligand. The 3N Cu-Aβ_5- complexes could be irreversibly reduced to Cu(I) at about -0.6 V vs Ag/AgCl and oxidized to Cu(III) at about 1.2 V vs Ag/AgCl. The internal or external imidazole coordination to the 3N core resulted in a slight destabilization of the Cu(I) state and stabilization of the Cu(III) state. Taken together these results indicate that Aβ_5- peptides, which bind Cu(II) ions much more strongly than Aβ_1- peptides and only slightly weaker than Aβ_4- peptides could interfere with Cu(II) handling by these peptides, adding to copper dyshomeostasis in Alzheimer brains.