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Copper(II) complexes of the N‐terminal peptide fragments of tau protein have been studied by potentiometric and various spectroscopic techniques (UV‐vis, CD, ESR and ESI‐MS). The octapeptide Tau(9‐16) (Ac−EVMEDHAG−NH2) contains the H14 residue of the native protein, while Tau(26‐33) (Ac−QGGYTMHQ−NH2) and its mutants Tau(Q26K‐Q33K) (Ac−KGGYTMHK−NH2) and Tau(Q26K‐Y29A‐Q33K) (Ac−KGGATMHK−NH2) include the H32 residue. To compare the binding ability of H14 and H32 in a single molecule the decapeptide Ac−EDHAGTMHQD−NH2 (Tau(12‐16)(30‐34)) has also been synthesized and studied. The histidyl residue is the primary metal binding site for metal ions in all the peptide models studied. In the case of Tau(9‐16) the side chain carboxylate functions enhance the stability of the M−Nim coordinated complexes compared to Tau(26‐33) (logK(Cu−Nim)=5.04 and 3.78, respectively). Deprotonation and metal ion coordination of amide groups occur around the physiological pH range for copper(II). The formation of the imidazole‐ and amide‐coordinated species changes the metal ion preference and the complexes formed with the peptides containing the H32 residue predominate over those of H14 at physiological pH values (90 %–10 %) and in alkaline samples (96 %–4 %).

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The hexa-and hepta-peptides CSSACS-NH2 and ACSSACS-NH2 have been synthesized by solid phase peptide synthesis and their zinc(II) and cadmium(II) complexes studied by potentiometric, NMR spectroscopic and ESI MS techniques. Both peptides have outstanding zinc(II) and cadmium(II) binding affinity but their coordination chemistry is different. In the case of the hexapeptide, the amino terminus is the primary metal binding site in the form of a stable (NH2,S -) 5-membered chelate supported by macrochelation via the distant cysteinyl residue. The heptapeptide ACSSACS-NH2 is a slightly less effective metal binder but its coordination chemistry is more versatile. The thiolate groups are the primary binding sites for both metal ions and an 18-membered (S -,S -) macrochelate is the favored coordination mode of the peptide. In slightly basic samples the deprotonated amino group can also contribute to metal binding. Moreover, the interaction of the terminal amino-N and the thiolate-Sof Cys(2) moiety can promote the deprotonation and metal ion coordination of the amide group between these residues. This reaction results in the formation of the (NH2,N -,S -) fused chelates supported by the thiolate of the distant cysteinyl residue. Zinc(II) induced deprotonation and coordination of amide groups have already been described in various peptides of histidine, but in the case of cadmium(II) this is the first example for the formation of a Cd-N(peptide amide) bond. Potentiometric measurementsThe pH-potentiometric titrations were performed in 3 mL samples at 2 mM ligand concentration with the use of carbonate-free stock solution (0.2 M) of potassium hydroxide. The metal ion to ligand ratios were selected as 1:1, 1:2 and 1:3. During the titration, argon was bubbled through the samples to ensure the absence of oxygen and carbon dioxide. The samples were stirred by a VELP Scientific magnetic stirrer. All pH-potentiometric measurements were carried out at 298 K. The ionic strength was adjusted to 0.2 M with KCl in the case The novel synthesized cysteine peptides form stable zinc(II) and cadmium(II) complexes; the specific sequence makes possible metal induced amide deprotonation.