β-Peptidic Secondary Structures Fortified and Enforced by Zn2+ Complexation – On the Way toβ-Peptidic Zinc Fingers?

Abstract

The correlation between β2-, β3-, and β2,3-amino acid-residue configuration and stability of helix and hairpin-turn secondary structures of peptides consisting of homologated proteinogenic amino acids is analyzed (Figs. 1–3). To test the power of Zn2+ ions in fortifying and/or enforcing secondary structures of β-peptides, a β-decapeptide, 1, four β-octapeptides, 2–5, and a β-hexadecapeptide, 10, have been devised and synthesized. The design was such that the peptides would a) fold to a 14-helix (1 and 3) or a hairpin turn (2 and 4), or form neither of these two secondary structures (i.e., 5), and b) carry the side chains of cysteine and histidine in positions, which will allow Zn2+ ions to use their extraordinary affinity for RS− and the imidazole N-atoms for stabilizing or destabilizing the intrinsic secondary structures of the peptides. The β-hexadecapeptide 10 was designed to a) fold to a turn, to which a 14-helical structure is attached through a β-dipeptide spacer, and b) contain two cysteine and two histidine side chains for Zn complexation, in order to possibly mimic a Zn-finger motif. While CD spectra (Figs. 6–8 and 17) and ESI mass spectra (Figs. 9 and 18) are compatible with the expected effects of Zn2+ ions in all cases, it was shown by detailed NMR analyses of three of the peptides, i.e., 2, 3, 5, in the absence and presence of ZnCl2, that i) β-peptide 2 forms a hairpin turn in H2O, even without Zn complexation to the terminal β3hHis and β3hCys side chains (Fig. 11), ii) β-peptide 3, which is present as a 14-helix in MeOH, is forced to a hairpin-turn structure by Zn complexation in H2O (Fig. 12), and iii) β-peptide 5 is poorly ordered in CD3OH (Fig. 13) and in H2O (Fig. 14), with far-remote β3hCys and β3hHis residues, and has a distorted turn structure in the presence of Zn2+ ions in H2O, with proximate terminal Cys and His side chains (Fig. 15).