Membrane-Active Molecular Machines

Abstract

Conspectus Both biological and artificial membrane transporters mediate passive transmembrane ion flux predominantly via either channel or carrier mechanisms, tightly regulating the transport of materials entering and exiting the cell. One early elegant example unclassifiable as carriers or channels was reported by Smith who derivatized a phospholipid molecule into an anion transporter, facilitating membrane transport via a two-station relay mechanism (Smith et al. J. Am. Chem. Soc. 2008, 130, 17274–17275). Our journey toward blurring or even breaking the boundaries defined by the carrier and channel mechanisms starts in January of 2018 when seeing a child swinging on the swing at the playground park. Since then, I have been wondering whether we could build a nanoscale-sized molecular swing able to perform the swing function at the molecular level to induce transmembrane ion flux. Such research journey culminates in several membrane-active artificial molecular machines, including molecular swings, ion fishers, ion swimmers, rotors, tetrapuses and dodecapuses that permeabilize the membrane via swinging, ion-fishing, swimming, rotating, or swing-relaying actions, respectively. Except for molecular ion swimmers, these unconventional membrane transporters in their most stable states readily span across the entire membrane in a way akin to channels. With built-in flexible arms that can swing or bend in the dynamic membrane environment, they transport ions via constantly changing ion permeation pathways that are more defined than carriers but less defined than channels. Applying the same benzo-crown ether groups as the sole ion-binding and -transporting units, these transporters however differ immensely in ion transport property. While the maximal K+ transport activity is achieved by the molecular swing also termed “motional channel” that displays an EC50 value of 0.021 mol % relative to lipid and transports K+ ions at rate 27% faster than gramicidin A, the highest K+/Na+ selectivity of 18.3 is attained by the molecular ion fisher, with the highest Na+/K+ selectivity of 13.7 by the molecular dodecapus. Having EC50 values of 0.49–1.60 mol % and K+/Na+ values of 1.1–6.3, molecular rotors and tetrapuses are found to be generally active but weakly to moderately K+-selective. For molecular ion swimmers that contain 10 to 14 carbon atom alkyl linkers, they all turn out to be highly active (EC50 = 0.18–0.41 mol %) and highly selective (R K +/R Na + = 7.0–9.5) transporters. Of special note are crown ether-appended molecular dodecapuses that establish the C60-fullerene core as an excellent platform to allow for a direct translation of solution binding affinity to transmembrane ion transport selectivity, providing a de novo basis for rationally designing artificial ion transporters with high transport selectivity. Considering remarkable cytotoxic activities displayed by molecular swings and ion swimmers, the varied types of existing and emerging unconventional membrane transporters with enhanced activities and selectivities even...

Molecular Complementarity of Proteomimetic Materials for Target‐Specific Recognition and Recognition‐Mediated Complex Functions

“…By mimicking diverse macroscopic functions at the molecular level, various molecular machineries such as molecular swings, ion fishers, rotors, shuttles, swimmers, tetrapuses, and dodecapuses have been developed to perform binding‐induced nanomechanical motions. [ 261 ] For instance, the ion fishers developed by Zeng's group adopted both the design and mechanisms of fishing rods comprising rod, line, and bait/hook; [ 262 ] the hydroxyl‐rich cholesterol group and the alkyl chain served as a rigid lipid‐anchoring rod and a flexible fishing line across the membrane, respectively, while a terminal crown ether was used to catch and release metal cations as a bait/hook underneath the membrane. When the ions were trapped by the bait/hook, the fishing line curled up and the trapped ions were subsequently released across the membrane as programmed actions.…”

Molecular Machines For The Control Of Transmembrane Transport

“…In recent years, the scope of transporters has been broadened beyond the archetypal classification of either a mobile carrier or membrane-spanning channel. , These new transporters can be described as “ anchored ion carriers ”: operating via molecular machine-inspired nanomechanical motion within the bilayer, but without the entire construct translocating through the membrane (as for mobile carriers). These are entirely abiotic mechanisms, distinct from their biological counterparts.…”

Engineering Bio‐inspired Self‐assembled Nanochannels for Smart Ion Transport

“…In this regard, crown ethers and their derivatives have been widely used in the construction of ion channels because of their customizable ion affinities, especially of alkali-metal ions. [20] Zeng and co-workers developed an amidated monopeptide scaffold that includes an integrated hydrogen-bonding capacity through the directional assembly of crown ethers (Figure 3a). [20d] A 160 % enhancement of the ion transport activity could be achieved by tuning the electron density around the crown ether units.…”