Supramolecular Transmembrane Ion Channels Formed by Multiblock Amphiphiles

Abstract

Conspectus Transmembrane proteins located within biological membranes play a crucial role in a variety of important cellular processes, such as energy conversion and signal transduction. Among them, ion channel proteins that can transport specific ions across the biological membranes are particularly important for achieving precise control over those processes. Strikingly, approximately 20% of currently approved drugs are targeted to ion channel proteins within membranes. Thus, synthetic molecules that can mimic the functions of natural ion channel proteins would possess great potential in the sensing and manipulation of biologically important processes, as well as in the purification of key industrial materials. Inspired by the sophisticated structures and functions of natural ion channel proteins, our research group developed a series of multiblock amphiphiles (MAs) composed of a repetitive sequence of flexible hydrophilic oligo­(ethylene glycol) chains and rigid hydrophobic oligo­(phenylene–ethynylene) units. These MAs can be effectively incorporated into the hydrophobic layer of lipid bilayer membranes and adopt folded conformations, with their hydrophobic units stacked in a face-to-face configuration. Moreover, the folded MAs can self-assemble within the membranes and form supramolecular nanopores that can transport ions across the membranes. In these studies, we focused on the structural flexibility of the MAs and decided to design new molecules able to respond to various external stimuli in order to control their transmembrane ion transport properties. For this purpose, we developed new MAs incorporating sterically bulky groups within their hydrophobic units and demonstrated that their transmembrane ion transport properties could be controlled via mechanical forces applied to the membranes. Moreover, we developed MAs incorporating phosphate ester groups that functioned as ligand-binding sites at the boundary between hydrophilic and hydrophobic units and found that these MAs exhibited transmembrane ion transport properties upon binding with aromatic amine ligands, even within the biological membranes of living cells. We further modified the hydrophobic units of the MAs with fluorine atoms and demonstrated their voltage-responsive transmembrane ion transport properties. These molecular design principles were extended to the development of a transmembrane anion transporter whose transport mechanism was studied by all-atom molecular dynamics simulations. This Account describes the basic principles of the molecular designs of MAs, the characterization of their self-assembled structures within a lipid bilayer, and their transmembrane ion transport properties, including their responsiveness to stimuli. Finally, we discuss future perspectives on the manipulation of biological processes based on the characteristic features of MAs.

Supramolecular Mechanosensitive Potassium Channel Formed by Fluorinated Amphiphilic Cyclophane

“…Over the last decade, our research group has developed a series of linear-shaped multiblock amphiphiles that can self-assemble within the lipid bilayer membranes to form supramolecular ion channels. 46 We also demonstrated that appropriate chemical modifications enabled these ion channels to be responsive to ligand molecules, 32,33,47 membrane potential, 33 and mechanical forces applied to the membranes. 44 The multiblock structures are particularly attractive for their combination of rigid aromatic units and flexible oligo(ethylene glycol) chains reminiscent of the structure of natural multipass transmembrane proteins, contributing to their stimuli-responsive ion transport properties.…”

Protein‐Mimicking Nanoparticles in Biosystems

“…Inspired by this structural feature, researchers have used a variety of multiblock amphiphiles to construct folded scaffolds that imitate the conformation and function of supramolecular transmembrane channels. [ 192–194 ] Muraoka et al. reported the construction of a three‐transmembrane ion channel through the folding of multiblock amphiphiles.…”

“…Inspired by this structural feature, researchers have used a variety of multiblock amphiphiles to construct folded scaffolds that imitate the conformation and function of supramolecular transmembrane channels. [192][193][194] Muraoka et al reported the construction of a three-transmembrane ion channel through the folding of multiblock amphiphiles. The multiblock amphiphiles were composed of alternatively connected oligoethylene glycol (oligoEG) chains and rigid 3,3′-dimethyl-5,5′-dis(phenylethynyl)-2,2′-bipyridine (BPBP) units as the hydrophilic and hydrophobic moieties, respectively.…”

Dense and Acidic Organelle-Targeted Visualization in Living Cells using a Viscosity-Responsive Fluorescent Probe Independent of the Twisted Intramolecular Charge Transfer Process

“…We previously reported multiblock amphiphilic compounds consisting of aromatic hydrophobic units and hydrophilic oligo(ethylene glycol) chains that have high affinity to lipid bilayer membranes. 44 Some of these molecules also work as trans-membrane transporters. 45 Since oligo(ethylene glycol) units are biocompatible, 46 we designed the multiblock molecule AnP2-OEG by combining a diaminoanthracene unit with octa(ethylene glycol) (OEG) chains to allow high membrane permeability while maintaining low cytotoxicity (Figure 1).…”