Foldamer-based K+ channels with ion selectivity surpassing the KcsA channel

Abstract

This study presents biomimetic supramolecular K⁺ channels based on pore-containing foldamers with pyridine and oxadiazole backbones, aimed at high ion selectivity and transport efficiency. Modification of helical peripheral chains controlled their distribution in aqueous and lipid phases. LUV experiments demonstrated that a partition coefficient (log P) of ∼5.0 optimally balanced this distribution, significantly enhancing ion transport activity. The M1 channel with isopropyl side chains exhibited an EC₅₀ of 1.1 nM, the highest known activity for synthetic K⁺ channels, supporting the role of side chains in enhancing transport efficiency, as seen in natural K⁺ carriers. Bilayer lipid membrane (BLM) experiments revealed a potassium-to-sodium permeability ratio (P_K/Na) of 55.2 for the M1 channel under 1 M asymmetric salt conditions, setting a new record for bioinspired K⁺ channels. Under 2 M asymmetric salt conditions, P_K/Na increased to 138, surpassing the selectivity of the KcsA channel (80). BLM tests showed that M1 and M2 channels, with identical scaffolds, had similar selectivity and transport rates, indicating that the scaffold structure governs ion selectivity, while side chains primarily modulate transport activity. These findings offer key insights for bioinspired channel design and underscore the potential of biomimetic K⁺ channels in treating channelopathies.