Supramolecular Barrel-Stave Anion Channel With Hydroxyl-Rich Selectivity Filter

Abstract

In naturally occurring CLC channels, the hydroxyl groups of serine (Sercen) and tyrosine (Tyrcen) that orient toward the central region of the pore are important for Cl− selectivity. Herein, artificial anion channels with a hydroxyl-rich selectivity filter are reported based on the self-assembly of (R)-(−)-mandelic acid-based derivatives. It was envisaged that multiple monomers would self-assemble in a transmembrane orientation, stabilised by intermolecular hydrogen bonds between the hydroxyl and amide groups of the scaffold, thereby forming the half-channel. Further, the antiparallel, tail-to-tail assembly of two such units would form the channel. Among the derivatives tested, the octyl chain-containing compound 1c exhibited the highest transmembrane transport activity and chloride selectivity. This transport relies on channel-mediated antiport, featuring an average channel diameter of 3.9 ± 0.1 Å and a single-channel conductance of 16.0 ± 0.8 pS. The 1H NMR titration experiment confirmed the major involvement of hydroxyl protons (OH) in chloride binding. Geometry optimisation shows that 1c (17.553 Å) can span half the egg yolk phosphatidylcholine lipid bilayer. Further geometry optimisation confirmed that the pentameric assembly is best suited to form the hydroxyl-rich hydrogen-bonded selectivity filter and to recognise Cl− within the cavity.