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The voltage-sensing mechanism of the KvAP channel involves breaking of the S4 helix

Voltage-gated ion channels allow ion permeation upon changes of the membrane electrostatic potential (Vm). Each subunit of these tetrameric channels is composed of six transmembrane helices, of which the anti-parallel helix bundle S1-S4 constitutes the voltage-sensor domain (VSD) and S5-S6 forms the pore domain. Here, using molecular dynamics (MD) simulations, we report novel responses of the archaebacterial potassium channel KvAP to cell polarization. We show that the S4 helix, which is straight in the experimental crystal structure solved under depolarized conditions (Vm ∼ 0), breaks into two segments when the cell is polarized (Vm << 0), and reversibly forms a single straight helix following depolarization of the cell (Vm =0). The outermost segment of S4 translates along the normal to the membrane, bringing new perspective to previously paradoxical accessibility experiments that were initially thought to imply the displacement of the whole VSD across the membrane. Our simulations of KvAP reveal that the breaking of S4 under polarization is not a feature unique to hyperpolarization activated channel, as might be suggested by recent cryo-EM structures and MD simulations of the HCN channel.