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

Area of Science:

• Supramolecular chemistry
• Biomimetic materials science
• Ion channel biophysics

Background:

• Potassium (K+) channels are crucial for cellular function.
• Dysfunction of K+ channels leads to channelopathies.
• Synthetic channels are needed to mimic biological K+ channel selectivity and transport.

Purpose of the Study:

• To design and synthesize biomimetic supramolecular K+ channels.
• To achieve high ion selectivity and transport efficiency.
• To investigate the role of channel scaffold and side chains in ion transport.

Main Methods:

• Foldamer synthesis with pyridine and oxadiazole backbones.
• Lipid-water partitioning studies using partition coefficient (log P).
• Ion transport assays using large unilamellar vesicles (LUVs) and bilayer lipid membranes (BLMs).

Main Results:

• Optimized partition coefficient (log P ~5.0) enhanced ion transport.
• M1 channel (isopropyl side chains) showed record EC50 of 1.1 nM.
• M1 channel achieved K+/Na+ permeability ratios (P K/Na) of 55.2 (1 M) and 138 (2 M), surpassing KcsA.
• Scaffold determined selectivity; side chains modulated transport activity.

Conclusions:

• Foldamer-based K+ channels can mimic biological channel function with high efficiency and selectivity.
• Side chain modification is key for tuning transport activity.
• Scaffold design dictates ion selectivity.
• These biomimetic channels hold promise for treating channelopathies.