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1.D.211.  The Phenylalanine-based Peptide Cation Channel (PAP-CCh) Family

 Macrocycle 55 has 6 phenylalanine-based peptide chains that help it insert into the membrane (see the figure below; Xin et al. 2017). The peptides terminate with carboxyl groups that presumably sit at the channel's portals. The macrocycle features three amino groups pointing toward the channel interior. Based on I/V measurements in planar bilayers, the authors established that macrocycle 55 is a cation-selective ion channel.

Schematic for the ion channel formed by macrocycle 55 in lipid bilayer. The channel becomes a better anion transporter at acidic pH, consistent with protonation of the internal amino groups. Reproduced from ref. 59. Copyright 2017, Royal Society of Chemistry.

The authors hypothesised that because of the ionisable carboxyl and amino groups that pH should influence the channel's ion selectivity. This was the case, as the K+/Cl selectivity of channel 55 decreased from 7.4 at pH 10, to 3.7 at pH 7, to 2.3 at pH 4. The authors reasoned that at pH 10.0, anionic carboxylates at the channel's mouth attract K+ but reject Cl. As the solution becomes more acidic, protonation of carboxylates and the inward-pointing amines increase the channel's affinity for Cl. This research shows how ion selectivity can be tuned by using chemical synthesis to functionalise the interior of a conducting channel (Davis et al. 2020).


References associated with 1.D.211 family:

Davis, J.T., P.A. Gale, and R. Quesada. (2020). Advances in anion transport and supramolecular medicinal chemistry. Chem Soc Rev. [Epub: Ahead of Print] 32692794
Xin, P., S. Tan, Y. Wang, Y. Sun, Y. Wang, Y. Xu, and C.P. Chen. (2017). Functionalized hydrazide macrocycle ion channels showing pH-sensitive ion selectivities. Chem Commun (Camb) 53: 625-628. 27982142