Molecular design and synthesis of artificial ion channels based on cyclic peptides containing unnatural amino acids

A series of novel cyclic. peptides composed of 3 to 5 dipeptide units with alternating natural-unnatural amino acid units, have been designed and synt hesized, employing 5-(N-alkanoylamino)-3-aminobenzoic acid with a long alka noyl chain as the unnatural amino acid. All cyclic peptides with systematic ally varying pore size, shape, and lipophilicity are found to form ion chan nels with a conductance of ca. 9 pS in aqueous KCl (500 mM) upon examinatio n by the voltage clamp method. These peptide channels are cation selective with the permeability ratio PCl-/PK+ of around 0.17. The ion channels forme d by the neutral, cationic, and anionic cyclic peptides containing L-alanin e, L-lysine, and L-aspartate, respectively, show the monovalent cation sele ctivity with the permeability ratio PNa+,/PK+ of ca. 0.39. On the basis of structural information provided by voltage-dependent blockade of the single channel current of all the tested peptides by Ca2+, we inferred that each channel is formed from a dimer of the peptide with its peptide ring constru cting the channel entrance and its alkanoyl chains lining across the membra ne to build up the channel pore. The experimental results are consistent wi th an idea that the rate of ion conduction is determined by the nature of t he hydrophobic alkanoyl chain region, which is common to all the channels.