Imidazole‐Peptide Foldamers: Parabolic Dependence of the Folding Process on the Water Content of the Solvent

Abstract

Oligomers of azole peptides have been isolated from a multitude of marine organisms. Up to now, these azole-containing dipeptide-analogue oligomers have only been found as cyclic n-mers (mostly tri- and tetramers) in nature. Herein, we show that imidazole-containing pseudopeptides form helixlike secondary structures in different solvents. The screw sense of the helix can be determined by attaching a single chiral imidazole unit to the N terminus of the oligomer. Investigation by means of circular dichroism (CD) spectroscopy showed that the folding process of the helix depends on the water content of the solvent in a parabolic way. In a pure organic medium, the helix is stabilized by hydrogen bonds between the hydrogen atoms of the amide groups and the nitrogen atoms of the azole ring. In aqueous solution, the formation of the helix is driven by dispersion interactions. The formation of the helix is more pronounced in aqueous solution than in organic solvents.

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“…Based on the concentration-independent 1 H NMR spectra, it can be definitively excluded that these observations are caused by intermolecular processes like aggregation. 28 Variable temperature 1 H NMR measurements of the oligomers in CDCl 3 and C 2 D 2 Cl 4 show that the secondary structures collapse at higher temperatures. In the case of the heptamer 11, the hydrogen bonds are broken even at 50 °C resulting in a shift of the amide protons to the range of 7.6 ppm (Supporting Information).…”

“…This decamer is known to form a canonical helix in solution. 28 While the amide signals are found at 7.6−8.5 ppm for the short oligomers (up to the tetramer 10a), these are shifted to lower field for the higher oligomers (heptamer 11 and decamer 13a). The NH resonances are found at values of up to 10.2 ppm.…”

“…The extent of the hydrogen bond formation is comparable to that of the decamer 23 showing a canonical helix. 28 The 1 H NMR coupling constants of the amide protons in 13a ranges in the area from 6.9 to 8.5 Hz, which corresponds to dihedral angles θ(H−N2−C3−H) with absolute values from 140°to 153°. 42 An interesting aspect in 1 H NMR spectra of the linear oligomers is the broadening of the signals and thus the dynamic of the systems.…”

“…This is a known effect and represents that in aqueous solutions the folding is caused by dispersion interactions. 28 A comparison of the CD spectrum of decamer 13a with the CD spectrum of 23, which folds into a canonical P helix in solution and shows a positive Cotton effect at 260 nm, 28 reveals two differences. First, the CD spectrum of 13a exhibits a negative Cotton effect at 260 nm.…”

“…36−38 The helices formed by oligomers of this imidazole δ-amino acids are stabilized by both hydrogen bonds and dispersion interactions. 28 It is interesting to note that in these helices hydrogen bonds are arranged almost orthogonally to the axis of the helix. In naturally occurring helices of α-amino acids, the hydrogen bonds are arranged parallel to the axis of the helix.…”