Conformationally constrained α‐helical peptide models for protein ion channels

Abstract

Recently we described the design, synthesis, and characterization of some simple amphiphilic α-helical models for protein ion channels. These peptides, composed of only Leu and Ser residues, are hypothesized to form helical bundles capable of passing ions across phospholipid bilayers. In an effort to demonstrate that the peptides are, in fact, helical in their active ion-conducting state, the conformationally constrained amino acid, C^α, C^α-dimethylglycine (α-aminoisobutyric acid, Aib), was introduced simulataneously at three positions into one of the model peptides, H₂N-(Leu-Ser-Leu-Leu-Leu-Ser-Leu)₃-CONH₂, giving H₂N-(Leu-Ser-Leu-Aib-Leu-Ser-Leu)₃-CONH₂. Examination of a tetrameric model for the channel suggested that this substitution should have a minimal effect on conductance. CD spectroscopy of the Aib-modified and original peptide in phospholipid vesicles indicated that both were highly α-helical. Furthermore, the Aib-containing peptide formed proton channels nearly identical in conductance to the original peptide.