Fluorofoldamer-Based Salt- and Proton-Rejecting Artificial Water Channels for Ultrafast Water Transport.

Here, we report on a novel class of fluorofoldamer-based artificial water channels (AWCs) that combines excellent water transport rate and selectivity with structural simplicity and robustness. Produced by a facile one-pot copolymerization reaction under mild conditions, the best-performing channel (AWC 1) is an n-C8H17-decorated foldamer nanotube with an average channel length of 2.8 nm and a pore diameter of 5.2 Å. AWC 1 demonstrates an ultrafast water conduction rate of 1.4 × 1010 H2O/s per channel, outperforming the archetypal biological water channel, aquaporin 1, while excluding salts (i.e., NaCl and KCl) and protons. Unique to this class of channels, the inwardly facing C(sp2)-F atoms being the most electronegative in the periodic table are proposed as being critical to enabling the ultrafast and superselective water transport properties by decreasing the channel's cavity and enhancing the channel wall smoothness via reducing intermolecular forces with water molecules or hydrated ions.

Small Molecule-Based Highly Active and Selective K+ Transporters with Potent Anticancer Activities.

We report here a novel class of cation transporters with extreme simplicity, opening a whole new dimension of scientific research for finding small molecule-based cation transporters for therapeutic applications. Comprising three modular components (a headgroup, a flexible alkyl chain-derived body, and a crown ether-derived foot for ion binding), these transporters efficiently (EC50 = 0.18-0.41 mol % relative to lipid) and selectively (K+/Na+ selectivity = 7.0-9.5) move K+ ions across the membrane. Importantly, the most active (EC50 = 0.18-0.22 mol %) and highly selective series of transporters A12, B12, and C12 concurrently possess potent anticancer activities with IC50 values as low as 4.35 ± 0.91 and 6.00 ± 0.13 µM toward HeLa and PC3 cells, respectively. Notably, a mere replacement of the 18-crown-6 unit in the structure with 12-crown-4 or 15-crown-5 units completely annihilates the cation-transporting ability.

Hybrid Pyridine-Pyridone Foldamer Channels as M2-Like Artificial Proton Channels.

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 Šin 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.

Crystal Packing-Guided Construction of Hetero-Oligomeric Peptidic Ensembles as Synthetic 3-in-1 Transporters.

Strategies to generate heteromeric peptidic ensembles via a social self-sorting process are limited. Herein, we report a crystal packing-inspired social self-sorting strategy broadly applicable to diverse types of H-bonded peptidic frameworks. Specifically, a crystal structure of H-bonded alkyl chain-appended monopeptides reveals an inter-chain separation distance of 4.8 Šdictated by the H-bonded amide groups, which is larger than 4.1 Šseparation distance desired by the tightly packed straight alkyl chains. This incompatibility results in loosely packed alkyl chains, prompting us to investigate and validate the feasibility of applying bulky tert-butyl groups, modified with an anion-binding group, to alternatively interpenetrate the straight alkyl chains, modified with a crown ether group. Structurally, this social self-sorting approach generates highly stable hetero-oligomeric ensembles, having alternated anion- and cation-binding units vertically aligned to the same side. Functionally, these hetero-oligomeric ensembles promote transmembrane transport of cations, anions and more interestingly zwitterionic species such as amino acids.

Aquafoldmer-Based Aquaporin-like Synthetic Water Channel.

Synthetic water channels were developed with an aim to replace aquaporins for possible uses in water purification, while concurrently retaining aquaporins' ability to conduct highly selective superfast water transport. Among the currently available synthetic water channel systems, none possesses water transport properties that parallel those of aquaporins. In this report, we present the first synthetic water channel system with intriguing aquaproin-like features. Employing a "sticky end"-mediated molecular strategy for constructing abiotic water channels, we demonstrate that a 20% enlargement in angstrom-scale pore volume could effect a remarkable enhancement in macroscopic water transport profile by 15 folds. This gives rise to a powerful synthetic water channel able to transport water at a speed of ∼3 × 109 H2O s-1 channel-1 with a high rejection of NaCl and KCl. This high water permeability, which is about 50% of aquaporin Z's capacity, makes channel 1 the fastest among the existing synthetic water channels with high selectivity.

Buckyball-Based Spherical Display of Crown Ethers for De Novo Custom Design of Ion Transport Selectivity.

Searching for membrane-active synthetic analogues that are structurally simple yet functionally comparable to natural channel proteins has been of central research interest in the past four decades, yet custom design of the ion transport selectivity still remains a grand challenge. Here we report on a suite of buckyball-based molecular balls (MBs), enabling transmembrane ion transport selectivity to be custom designable. The modularly tunable MBm-Cn (m = 4-7; n = 6-12) structures consist of a C60-fullerene core, flexible alkyl linkers Cn (i.e., C6 for n-C6H12 group), and peripherally aligned benzo-3m-crown-m ethers (i.e., m = 4 for benzo-12-crown-4) as ion-transporting units. Screening a matrix of 16 such MBs, combinatorially derived from four different crown units and four different Cn linkers, intriguingly revealed that their transport selectivity well resembles the intrinsic ion binding affinity of the respective benzo-crown units present, making custom design of the transport selectivity possible. Specifically, MB4s, containing benzo-12-crown-4 units, all are Li+-selective in transmembrane ion transport, with the most active MB4-C10 exhibiting an EC50(Li+) value of 0.13 µM (corresponding to 0.13 mol % of the lipid present) while excluding all other monovalent alkali-metal ions. Likewise, the most Na+ selective MB5-C8 and K+ selective MB6-C8 demonstrate high Na+/K+ and K+/Na+ selectivity values of 13.7 and 7.8, respectively. For selectivity to Rb+ and Cs+ ions, the most active MB7-C8 displays exceptionally high transport efficiencies, with an EC50(Rb+) value of 105 nM (0.11 mol %) and an EC50(Cs+) value of 77 nM (0.079 mol %).

Polypyridine-Based Helical Amide Foldamer Channels: Rapid Transport of Water and Protons with High Ion Rejection.

Synthetic strategies that enable rapid construction of covalent organic nanotubes with an angstrom-scale tubular pore remain scarcely reported. Reported here is a remarkably simple and mild one-pot polymerization protocol, employing POCl3 as the polymerization agent. This protocol efficiently generates polypyridine amide foldamer-based covalent organic nanotubes with a 2.8 nm length at a yield of 50 %. Trapping single-file water chains in the 2.8 Štubular cavity, rich in hydrogen-bond donors and acceptors, these tubular polypyridine ensembles rapidly and selectively transport water at a rate of 1.6×109  H2 O⋅S-1 ⋅channel-1 and protons at a speed as fast as gramicidin A, with a high rejection of ions.

Polyhydrazide-Based Organic Nanotubes as Efficient and Selective Artificial Iodide Channels.

Reported herein is a series of pore-containing polymeric nanotubes based on a hydrogen-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of about a 6.5 Šdiameter, mediate highly efficient transport of diverse types of anions, rather than cations, across lipid membranes. The reported polymer channel, having an average molecular weight of 18.2 kDa and 3.6 nm in helical height, exhibits the highest anion-transport activities for iodide (EC50 =0.042 µm or 0.028 mol % relative to lipid), whcih is transported 10 times more efficiently than chlorides (EC50 =0.47 µm). Notably, even in cholesterol-rich environment, iodide transport activity remains high with an EC50 of 0.37 µm. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.

Pyridine/Oxadiazole-Based Helical Foldamer Ion Channels with Exceptionally High K+ /Na+ Selectivity.

Protein channels are characterized by high transport selectivity, which is essential for maintaining cellular function. Efforts to reproduce such high selectivity over the past four decades have not been very successful. We report a novel series of aromatic foldamer-based polymeric channels where the backbone is stabilized by differential electrostatic repulsions among heteroatoms helically arrayed along the helical backbone. Nanotubes averaging 2.3 and 2.7 nm in length mediate highly efficient transport of K+ ions as a consequence of hydrophilic electron-rich hollow cavities that are 3 Šin diameter. Exceptionally high K+ and Na+ selectivity values of 16.3 and 12.6, respectively, are achieved.

Molecular Ion Fishers as Highly Active and Exceptionally Selective K+ Transporters.

We report here a unique ion-fishing mechanism as an alternative to conventional carrier or channel mechanisms for mediating highly efficient and exceptionally selective transmembrane K+ flux. The molecular framework, underlying the fishing mechanism and comprising a fishing rod, a fishing line and a fishing bait/hook, is simple yet modularly modifiable. This feature enables rapid construction of a series of molecular ion fishers with distinctively different ion transport patterns. While more efficient ion transports are generally achieved by using 18-crown-6 as the fishing bait/hook, ion transport selectivity (K+/Na+) critically depends on the length of the fishing line, with the most selective MF6-C14 exhibiting exceptionally high selectivity (K+/Na+ = 18) and high activity ( EC50 = 1.1 mol % relative to lipid).