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 synthesized, employing 5-(N-alkanoylamino)-3-aminobenzoic acid with a long alkanoyl chain as the unnatural amino acid. All cyclic peptides with systematically varying pore size, shape, and lipophilicity are found to form ion channels with a conductance of ca. 9 pS in aqueous KCl (500 mM) upon examination by the voltage clamp method. These peptide channels are cation selective with the permeability ratio PCl−/PK+ of around 0.17. The ion channels formed by the neutral, cationic, and anionic cyclic peptides containing l-alanine, l-lysine, and l-aspartate, respectively, show the monovalent cation selectivity 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 w...