1.D.210.  The Polyhydrazide-based Organic Nanotube Iodide Channel (PH-ICh) Family 

Roy et al. 2020 studied polymers that form unimolecular anion channels (see the figure below). Taking inspiration from similar cation channels (Xin et al. 2014), the authors switched out phenylalanines for alkyl sidechains to give a new family of foldamers. They screened coupling agents and conditions to prepare 53 polymers from a resorcinol-based dihydrazide (unit A) and an isophthalate (unit B). “One-pot” synthesis gave 60–80% yields of foldamers of Mw 5–70 kDa. Six of those polymers stood out as anion transporters in POPC vesicles. The authors concluded that a proper balance of water solubility vs. lipophilicity and the appropriate length were both critical for ion transport. The paper focused on polymer 54 (Mw 18.4 kDa), which contains 24 units of the A and B building blocks. Models of 54 indicated it has a pore diameter of 6.5 Å and a helical length of 3.6 nm, ideal for a unimolecular channel.


(a) Structure and (b) molecular models of foldamer 54. (c) Computational model of the channel formed by foldamer 54 in a bilayer.  Copyright 2020, Wiley.

The authors found that 54 was selective for anion transport in vesicles and planar bilayers (conductance γCl−/K+ = 13). Polymer 54 was efficient (EC50 = 0.042 μM) and selective (kI/kCl = 42) for iodide transport in liposomes. Current measurements in planar bilayers showed single channels with specific conductance of γCl− = 1.19 pS. More support for channel formation by 54 came from controls with an analogue modified with terminal benzyl groups. That polymer was inactive in transport assays in liposomes, consistent with the pore being blocked by the benzyl sidechains (Davis et al. 2020).

Insight was provided by computation. MD simulations revealed key features about the foldamer's iodide-selectivity: (1) 54 maintains its helical structure in the bilayer; (2) water fills the pore; (3) the channel's electrostatic potential is positive due to methoxy carbons in the lumen; (4) energetic barriers to cross the channel are much lower for anions than for cations; (5) I− sheds waters of solvation more readily than Cl− as it enters the channel, and (6) the partially hydrated I− forms fewer hydrogen bonds with the walls of 54 than does Cl−, allowing I− to move faster thru the pore. The combination of experiment and computation gave a better understanding of the foldamer's anion-selectivity. The authors emphasise that their modular synthesis enables one to make foldamers of varying dimensions, useful for new applications.


 

References:

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]
Roy, A., H. Joshi, R. Ye, J. Shen, F. Chen, A. Aksimentiev, and H. Zeng. (2020). Polyhydrazide-Based Organic Nanotubes as Efficient and Selective Artificial Iodide Channels. Angew Chem Int Ed Engl 59: 4806-4813.
Xin, P., P. Zhu, P. Su, J.L. Hou, and Z.T. Li. (2014). Hydrogen-bonded helical hydrazide oligomers and polymer that mimic the ion transport of gramicidin A. J. Am. Chem. Soc. 136: 13078-13081.