Voltage-Gated Potassium Ion Channels are Frustrated

Abstract

It has been suggested for some time that prolines allow the S6 helices of voltage-gated potassium ion channels to move between straight and kinked conformations thereby gating the channel. The kinked conformation was subsequently observed in the x-ray crystallographic structures of Kv1.2 and the paddle chimera, both of which are open. Although closed structures of potassium ion channels with straight inner helices have been observed, none of these have the characteristic PVPV motif. When the voltage sensor moves in response to changes in transmembrane potential, it pulls on the S4-S5 linker, moving this also, which in turn presses on the S6 helix and closes the channel. What remains unclear in this mechanical model is how the channel then opens. We shall show using free energy calculations that the S6 helices of the paddle chimera prefer to be kinked and that conformations corresponding to a closed channel are not favoured. Our results suggest that when the channel is open the S6 helices adopt similar conformations to those observed in the x-ray crystallographic structures. These calculations include the pore region of the paddle chimera, a lipid bilayer and explicit water and therefore include the steric and cooperative effects introduced by moving all four S6 helices simultaneously. We conclude that the closed state of the paddle chimera is frustrated; the S6 helices are only straight because the voltage sensor, via the S4-S5 linker, is held in the down position by the transmembrane voltage. This has important consequences for efforts to try and crystallize a voltage-gated potassium channel in the closed state.