Triply Responsive Control of Anion/Cation Transport with an Artificial Ion Channel Responsive to Multiple Stimuli

Ion channels are ubiquitous in Nature, performing complex and essential tasks in our bodies. Synthetic chemists have begun to understand how to form artificial channels, which hold great promise as components in artificial cells, and in synthetic biology more widely. Future generations of these systems will be critical in the treatment of channelopathies; diseases where ion channels malfunction, and which are challenging to treat with current modalities. Despite advances in the design of synthetic ion transporters, the current generation cannot approach the selectivity and controllability of the biological ion channels they seek to emulate, and multimodal control over activity remains hard to achieve. Herein, we present a synthetic ion channel whose activity can be controlled by three orthogonal stimuli (light, pH, guest/ligand). The channel is formed from a pillar[5]arene functionalized with photoswitchable tetrafluoroazobenzene moieties. We demonstrate excellent control over E:Z switching across ten incorporated photoswitches (E to Z 87%, Z to E quant.). We show that the most active isomer – the Z-isomer – forms dimeric ion channels in membranes, with selectivity for M+/Cl− symport. Single molecule planar bilayer conductance studies show distinct high and low conductance states dependent on irradiation wavelength. Finally, we demonstrate that this activity can be modulated over 170-fold by controlling pH, irradiation, and guest addition, creating a powerful addition to the canon of synthetic ion channels.