Extreme stability of helices formed by water‐soluble poly‐N‐substituted glycines (polypeptoids) with α‐chiral side chains

Abstract

Poly‐N‐substituted glycines or “peptoids” are protease‐stable peptide mimics. Although the peptoid backbone is achiral and lacks hydrogen‐bond donors, substitution with α‐chiral side chains can drive the formation of stable helices that give rise to intense CD spectra. To systematically study the solution properties and stability of water‐soluble peptoid helices with α‐chiral side chains, we have synthesized and characterized an amphipathic, 36‐residue N‐substituted glycine oligomer. CD was used to investigate effects of concentration and solvent environment on this helical peptoid. We saw no significant dependence of helical structure on concentration. Intense, “α‐helix‐like” CD spectra were observed for the 36‐mer in aqueous, 2,2,2‐trifluorethanol (TFE), and methanol solution, proving a relative insensitivity of peptoid helical structure to solvent environment. While CD spectra taken in these different solvents were fundamentally similar in shape, we did observe some interesting differences in the intensities of particular CD bands in the various solvents. For example, the addition of TFE to an aqueous solvent increases the degree of peptoid helicity, as is observed for polypeptide α‐helices. Moreover, the helical structure of peptoids appears to be virtually unaffected by heat, even in an aqueous buffer containing 8 M urea. The extraordinary resistance of these peptoid helices to denaturation is consistent with a dominant role of steric forces in their structural stabilization. The structured polypeptoids studied here may have potential as robust mimics of helical polypeptides of therapeutic interest. © 2002 John Wiley & Sons, Inc. Biopolymers 63: 12–20, 2002