Anion-Selective Channels Formed by Synthetic 13-Mer Chimeric α -Peptide-Oligourea Foldamers

Attempts to design transmembrane channels with selective transport properties using advanced chemistry and computational tools have had limited success. Previously, we characterized 15-mer α-peptide-oligourea chimeric foldamers that form anion channels with high Cl^- selectivity. Here, we report the design and synthesis of four 13-mer α-peptide-oligourea chimeric foldamers (HPU-EK, HPU-QQ, HPU-AA, and HPU-RH) as part of our attempts to generate new foldamers with distinct hydrophobic and hydrophilic surfaces in their helices. They consist of an 8-mer peptide with varied sequences at the N-terminal of a shorter oligourea segment (5-mer). They self-assemble into supramolecular channels. A 6.5 Å cryo-EM structure of HPU-AA revealed nanofibers with distinct dimensions and diverse modes of molecular assembly. Functional assays of the four chimeras demonstrated varying anion transport activities across lipid bilayer membranes. Enhanced ion transport activity was achieved by selective mutations within the foldamer sequences. HPU-AA, which has extended hydrophobic and narrower hydrophilic surfaces, showed the highest ion transport activity among the four foldamers. It exhibits distinct anion selectivity (I^->SCN^->NO₃ ^- = Cl^->Br^->OAc^->F^-), with ∼3-fold higher conductance value for I^- than Cl^-. These studies help us understand the self-assembly of these chimeric foldamers and offer opportunities for designing novel channels for various biomedical applications.