Accuratede novodesign of a voltage-gated anion channel

SUMMARY Ion channels gated by environmental cues play key roles in fundamental biological processes. Designing ion channels with tailored gating mechanisms remains a significant challenge due to the complexities involved in designing conformational changes in proteins. Here we report the accurate de novo design of a voltage-gated anion channel, namely VGAC. VGAC adopts a 15-helix pentameric structure featuring a constriction composed of five arginine residues within the transmembrane span. In patch-clamp experiments, VGAC showed strictly voltage-dependent currents and demonstrated selectivity for chloride anions over iodide anions. Our data suggests that the arginine constriction undergoes voltage-induced conformational changes, serving as both the voltage sensor and selectivity filter. A 2.9-Å-resolution cryo-electron microscopy structure of VGAC closely aligns with the design model. The ability to design ion channels with custom-designed conformational changes provides new insights into our understanding of the fundamental principles of membrane biophysics and unveils a wide range of potential applications.