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Frustrated, or nonoptimal, interactions have been proposed to be essential to a protein’s ability to display responsive behav-ior, such as allostery, conformational signaling, and signal transduction. However, the intentional incorporation of frustrated noncovalent interactions has not been explored as a design element in the field of dynamic foldamers. Here we report the design, synthesis, characterization, and MD simulations of the first dynamic water-soluble foldamer that, in response to a stimulus, exploits relief of frustration in its noncovalent network to structurally rearrange from a pleated to intercalated co-lumnar structure. Thus, relief of frustration provides the energetic driving force for structural rearrangement. This work repre-sents a previously unexplored design element for development of stimulus-responsive systems that has potential application to materials chemistry, synthetic biology, and molecular machines. 

Abstract Currently, completely abiotic channel systems that concurrently reproduce the high selectivity and high permeation rate of natural protein channels are rare. Here, we provide one such biomimetic channel system, i.e., a novel family of helically folded hybrid amide foldamers that can serve as powerful artificial proton channels to mimic key transport features of the exceptionally selective Matrix‐2 (M2) proton channels. Possessing an angstrom‐scale tubular pore 3 Å in diameter, these low water permeability artificial channels transport protons at a rate 1.22 and 11 times as fast as gramicidin A and M2 channels, respectively, with exceptionally high selectivity factors of 167.6, 122.7, and 81.5 over Cl⁻, Na⁺, and K⁺ions. Based on the experimental and computational findings, we propose a novel proton transport mechanism where a proton may create a channel‐spanning water chain from two or more short water chains to facilitate its own transmembrane flux via the Grotthuss mechanism.