Tubular Unimolecular Transmembrane Channels: Construction Strategy and Transport Activities

Abstract

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(+).

Pillar-Shaped Macrocyclic Hosts Pillar[n]arenes: New Key Players for Supramolecular Chemistry

“…287 Their chemistry started from the crystal structure of pillar [5]arene with 10 ethyl ester moieties 44 [5] (Figure 77a). The decaester molecules Chem.…”

Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry

“…Lariat ethers 101 and their ilk were used to pioneer this area of supramolecular chemistry, but more recently the range of strategies has diversified considerably. 102 Simulations for discrimination of Na + and K + in membrane channels have been performed by the physical community, 103 but there is considerable opportunity for collaborative efforts to understand cation selectivity as well as ion-pairing cooperativity (which can be exploited to transport uphill using co-transport or counter-transport strategies). For transporter design, there is some information available from modeling studies using U-tube experiments.…”

Polymeric Tubular Aromatic Amide Helices

“…To address this possibility, we prepared both polymer P23 and oligomers 24a‐c , which all bear phenylalanine (Phe) tripeptide side chains. This short peptide chain has been demonstrated by Hou and co‐workers to remarkably promote the insertion of pillararene‐derived single molecular tubes into lipid bilayers . The molecular weight of polymer P23 was determined to be 15.8 KD by GPC, which corresponds to a polymerization degree of about 10 and 3.5 helix turns.…”