Combinatorial Evolution of Fast-Conducting Highly Selective K⁺-Channels via Modularly Tunable Directional Assembly of Crown Ethers

We describe here a modularly tunable molecular strategy for construction and combinatorial optimization of highly efficient K⁺-selective channels. In our strategy, a highly robust supramolecular H-bonded 1D ensemble was used to order the appended crown ethers in such a way that they roughly stack on top of each other to form a channel for facilitated ion transport across the membrane. Among 15 channels that all prefer K⁺ over Na⁺ ions, channel molecule 5F8 shows the most pronounced optimum for K⁺ while disfavoring all other biologically important cations (e.g., Na⁺, Ca²⁺ and Mg²⁺). With a K⁺/Na⁺ selectivity of 9.8 and an EC₅₀ value of 6.2 μM for K⁺ ion, 5F8 is clearly among the best synthetic potassium channels developed over the past decades.