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 is sensitive to the sense and strength of screw‐sense induction by each N‐terminal residue, a conformational preference that is relayed along the 1‐nanometer‐long helical foldamer. Chloride binding is weaker when the screw‐sense preference of the chiral N‐terminal residue matches that of the C‐terminal binding site, whereas mismatches in screw‐sense preferences give stronger chloride binding. X‐ray crystallography and computational modeling provide a simple model for this relationship between chloride affinity and the screw‐sense preferences of both terminal groups. Chloride binding allows these foldamers to act as ion carriers in the bulk phase, but in bilayers, the length of each foldamer is more important for activity. The use of a helical relay to remotely control the binding of an achiral anion may offer pathways toward the remote allosteric control of chloride binding by macromolecules.