The A beta(5-x) peptides (x = 38, 40, 42) are minor A beta species in normal brains but elevated upon the application of inhibitors of A beta 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 A beta(5-x) peptide models comprising the metal binding site: A beta(5-9), A beta(5-12), A beta(5-12)Y10F, and A beta(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 x 10(12) M-1 at pH 7.4 for A beta(5-9) and A beta(5-12). This affinity was elevated 3-fold in A beta(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 A beta(5-9) and A beta(5-12) by adding appropriate amounts of the external imidazole ligand. The 3N Cu-A beta(5-x) 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 A beta(5-x) peptides, which bind Cu(II) ions much more strongly than A beta(1-x) peptides and only slightly weaker than A beta(4-x) peptides could interfere with Cu(II) handling by these peptides, adding to copper dyshomeostasis in Alzheimer brains.