Hydrophobicity and helicity of membrane-interactive peptides containing peptoid residues

Peptoid (N-alkylglycyl) residues in peptides have been studied in a variety of applications, but their behavior in membrane environments has not been systematically investigated. We have synthesized a series of membrane-interactive peptides of prototypic structure KKAAAXAAAAAXAAWAAXAAAKKKK-amide, where X corresponds to the peptoid residues Nala (= sarcosine), Nval, Nile, Nleu, Nphe, and Ntrp. Investigation of their relative hydrophobic character by high-performance liquid chromatography indicated an order of hydrophobicity Ntrp > Nphe > Nleu > Nile > Nval > Nala-largely parallel to the relative scale for these side-chains in natural amino acids, although all values were significantly more "hydrophilic" than their amino acid correspondents. Conformations of peptoid-containing peptides measured by circular dichroism spectroscopy were unordered in the presence of SDS micelles but helical for peptides with X = the corresponding amino acids, suggesting a general helix-breaking tendency for the peptoid residues. However, peptides were able to form helical structures in the solvent n-butanol, indicating that this conformation is possible if peptides became inserted into micellar phases. The latter notion was confirmed by increasing hydrophobic content of the peptides by embedding peptoid Nala residues in Leu-rich rather than Ala-rich sequences, which promoted peptide insertion and helical structure in micelles. The overall results suggest that judicious interspersing of amino acid and peptoid residues in peptide sequences can produce hydrophobic water-soluble materials with membrane-partitioning capacity.