Please join Yale Chemistry for a Silliman Seminar in theory chemistry with Prof. Benoît Roux, Amgen Professor of Biochemistry and Molecular Biology and Professor of Neuroscience Institute, from the University of Chicago.
Abstract: Voltage-gated potassium (Kv) channels play an essential role in cellular excitability and the propagation of nerve impulses. Despite tremendous advances in structural determination, achieving a fundamental, atomic-level understanding of ion channel function—encompassing permeation, selectivity, activation, inactivation, and regulation—remains a formidable biophysical challenge. Fast and selective ion conduction through K⁺ channels is governed by a delicate balance of strong electrostatic interactions among partially dehydrated ions translocating along a narrow pore. Voltage activation of Kv channels involves large and complex conformational rearrangements mediated by the voltage-sensing domain (VSD), which opens the intracellular gate of the channel in response to changes in the transmembrane potential. C-type inactivation arises from conformational alterations of the pore that drive it toward a non-conducting state. Classical molecular dynamics (MD) simulations based on accurate atomic models provide a powerful framework for elucidating the mechanisms underlying these complex biomolecular systems. Here, we examine and delineate the microscopic conditions governing classical multi-ion conduction via the “knock-on” mechanism in K⁺ channels. We find that the occupancy of the narrow pore by ions and water molecules is extremely sensitive to small (~kBT) variations in the interaction between ion, water, and backbone carbonyls. To probe the electromechanical coupling mechanism, we used single-particle cryo-EM to determine the structure of the ILT mutant of the voltage-gated Shaker channel known to exhibit a long-lived closed intermediate state during activation. The results, integrating experimental structure together with computational modeling and MD simulations, provide unprecedented mechanistic insight into how structural rearrangements underpin voltage activation in Kv channels. Lastly, to investigate the molecular basis of C-type inactivation, simulations were performed based on the high-resolution structure of a strongly inactivated triple-mutant channel of Kv1.2–Kv2.1–3, which revealed a novel conformation of the selectivity filter dilated at its outer end—distinct from the well-characterized conductive state. Remarkably, the dilated filter is found to be conductive, and a secondary gate is required to block ionic current.
Benoît Roux was born in Montréal, Canada, in 1958. In 1981, he received a B.Sc. in Physics from the University of Montréal, followed by a M.Sc. in Biophysics in 1985 under the supervision of Rémy Sauvé. In 1990, he obtained a Ph.D. in Biophysics from Harvard University under the direction of Martin Karplus. In the last decade, he has held positions at the University of Montréal and the Weill Medical College of Cornell University. Since 2005, he is Professor in the Department of Biochemistry and Molecular Biology at the University of Chicago with a joint appointment as Senior Computational Biologist at Argonne National Laboratory. For more information on the Roux Lab’s research: Research | Roux Lab
Hosted by Graduate Student Jinchan Liu and Prof. Tianyu Zhu.
Trainee Research Talk: SCL 111, 3:00 pm
Jinchan Liu, Batista Lab
