Remote Conformational Control of a Chloride-Binding Site

Peptide foldamers, each with a stereogenic C-terminal bis(squaramide) separated from an N-terminal amino acid “controller” by an α-aminoisobutyric acid (Aib) tetramer, have been shown to bind chloride. Chloride affinity was sensitive to the sense and strength of screw-sense induction by each N-terminal residue, a
conformational preference that was relayed along the 1 nanometre long helical foldamer. Chloride binding was weaker when the screw-sense preference of the chiral N-terminal residue matched that of the C-terminal binding site, whereas mismatched screw-sense preferences gave stronger chloride binding. X-ray crystallography and computational modelling provided a simple model for this relationship between chloride affinity and the screw-sense preferences of both terminal groups. Chloride binding allowed these foldamers to act as ion carriers in the bulk phase, but in bilayers the length of each foldamer was more important for activity. The use of a helical relay to remotely control of the binding of an achiral anion may offer pathways towards the remote allosteric control of
chloride binding by macromolecules.