Wen Si

Selective Artificial Transmembrane Channels for Protons by Formation of Water Wires

Lined up water molecules: Artificial transmembrane channels from pillar[5]arene monomeric and dimeric derivatives have been prepared. Single-channel conductance measurements and isotope effect experiments under acidic conditions showed selective proton transport through the channels, which were mediated by water wires formed in the pillar[5]arene backbones (see picture).

Chiral Selective Transmembrane Transport of Amino Acids through Artificial Channels

Peptide-appended pillar[n]arene (n = 5, 6) derivatives have been synthesized. (1)H NMR and IR studies revealed that the molecules adopt a tubular conformation in solution and lipid bilayer membranes. Kinetic measurements using the fluorescent labeling method with lipid vesicles revealed that these molecules can efficiently mediate the transport of amino acids across lipid membranes at a very low channel-to-lipid ratio (EC(50) = 0.002 mol %). In several cases, chiral selectivity for amino acid enantiomers was achieved, which is one of the key functions of natural amino acid channels.

Tubular Unimolecular Transmembrane Channels: Construction Strategy and Transport Activities

Lipid bilayer membranes separate living cells from their environment. Membrane proteins are responsible for the processing of ion and molecular inputs and exports, sensing stimuli and signals across the bilayers, which may operate in a channel or carrier mechanism. Inspired by these wide-ranging functions of membrane proteins, chemists have made great efforts in constructing synthetic mimics in order to understand the transport mechanisms, create materials for separation, and develop therapeutic agents. Since the report of an alkylated cyclodextrin for transporting Cu(2+) and Co(2+) by Tabushi and co-workers in 1982, chemists have constructed a variety of artificial transmembrane channels by making use of either the multimolecular self-assembly or unimolecular strategy. In the context of the design of unimolecular channels, important advances have been made, including, among others, the tethering of natural gramicidin A or alamethicin and the modification of various macrocycles such as crown ethers, cyclodextrins, calixarenes, and cucurbiturils. Many of these unimolecular channels exhibit high transport ability for metal ions, particularly K(+) and Na(+). Concerning the development of artificial channels based on macrocyclic frameworks, one straightforward and efficient approach is to introduce discrete chains to reinforce their capability to insert into bilayers. Currently, this approach has found the widest applications in the systems of crown ethers and calixarenes. We envisioned that for macrocycle-based unimolecular channels, control of the arrangement of the appended chains in the upward and/or downward direction would favor the insertion of the molecular systems into bilayers, while the introduction of additional interactions among the chains would further stabilize a tubular conformation. Both factors should be helpful for the formation of new efficient channels. In this Account, we discuss our efforts in designing new unimolecular artificial channels from tubular pillar[n]arenes by extending their lengths with various ester, hydrazide, and short peptide chains. We have utilized well-defined pillar[5]arene and pillar[6]arene as rigid frameworks that allow the appended chains to afford extended tubular structures. We demonstrate that the hydrazide and peptide chains form intramolecular N-H···O═C hydrogen bonds that enhance the tubular conformation of the whole molecule. The new pillar[n]arene derivatives have been successfully applied as unimolecular channels for the selective transport of protons, water, and amino acids and the voltage-gated transport of K(+). We also show that aromatic hydrazide helices and macrocycles appended with peptide chains are able to mediate the selective transport of NH4(+).

Voltage-driven reversible insertion into and leaving from a lipid bilayer: tuning transmembrane transport of artificial channels.

Three new artificial transmembrane channel molecules have been designed and synthesized by attaching positively charged Arg-incorporated tripeptide chains to pillar[5]arene. Fluorescent and patch-clamp experiments revealed that voltage can drive the molecules to insert into and leave from a lipid bilayer and thus switch on and off the transport of K(+) ions. One of the molecules was found to display antimicrobial activity toward Bacillus subtilis with half maximal inhibitory concentration (IC50 ) of 10 μM which is comparable to that of natural channel-forming peptide alamethicin.

Directional Potassium Transport through a Unimolecular Peptide Channel

Three unimolecular peptide channels have been designed and prepared by using the β-helical conformation of gramicidin A (gA). The new peptides bear one to three NH3+ groups at the N-end and one to three CO2- groups at the C-end. These zwitterionic peptides were inserted into lipid bilayers in an orientation-selective manner. Conductance experiments on planar lipid bilayers showed that this orientation bias could lead to observable directional K+ transport under multi-channel conditions. This directional transport behavior can further cause the generation of a current across a planar bilayer without applying a voltage. More importantly, in vesicles with identical external and internal KCl concentrations, the channels can pump K+ across the lipid bilayer and cause a membrane potential.