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Science 336 (6078): 229-233

Copyright © 2012 by the American Association for the Advancement of Science

Mechanism of Voltage Gating in Potassium Channels

Morten Ø. Jensen,1,* Vishwanath Jogini,1 David W. Borhani,1 Abba E. Leffler,1 Ron O. Dror,1 David E. Shaw1,2,*

Abstract: The mechanism of ion channel voltage gating—how channels open and close in response to voltage changes—has been debated since Hodgkin and Huxley’s seminal discovery that the crux of nerve conduction is ion flow across cellular membranes. Using all-atom molecular dynamics simulations, we show how a voltage-gated potassium channel (KV) switches between activated and deactivated states. On deactivation, pore hydrophobic collapse rapidly halts ion flow. Subsequent voltage-sensing domain (VSD) relaxation, including inward, 15-angstrom S4-helix motion, completes the transition. On activation, outward S4 motion tightens the VSD–pore linker, perturbing linker–S6-helix packing. Fluctuations allow water, then potassium ions, to reenter the pore; linker-S6 repacking stabilizes the open pore. We propose a mechanistic model for the sodium/potassium/calcium voltage-gated ion channel superfamily that reconciles apparently conflicting experimental data.

1 D. E. Shaw Research, New York, NY 10036, USA.
2 Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: morten.jensen{at} (M.Ø.J.);{at} (D.E.S.)

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