Aromatic Interaction‐Driven Adaptive Transformation of Macrocyclic Unimolecular Chloride Channels Into Nanopores

Biological ion channels and pores frequently exhibit dynamic, concentration-dependent adaptive assembly, yet synthetic systems that faithfully replicate this intriguing behavior remain rare. In this study, we present a novel class of tripeptide-appended macrocyclic ion channels that undergo aromatic interaction-driven adaptive transformation from unimolecular chloride channels into higher-order nanopores. At low concentrations, analogues with aromatic tripeptide-functionalized macrocycles (MC-F and MC-W) function as discrete and efficient chloride channels. Upon increasing the concentration, cooperative aromatic interactions among the tripeptide side chains promote their lateral self-assembly into stable nanopores, enabling efficient transmembrane transport of small molecules, including carboxyfluorescein and glucose. In contrast, the aliphatic analogues (MC-A, MC-L, and MC-I) remain restricted to unimolecular chloride channels. Single-channel measurements combined with theoretical calculations further substantiate the structural stability and energetic preference of tetrameric and pentameric assemblies within lipid bilayers. Collectively, this work establishes cooperative aromatic interactions as a versatile and robust design principle for engineering adaptive artificial channels, thereby narrowing the functional gap between synthetic systems and the dynamic regulatory behavior of natural channels.