Protons in gating the Kv1,2 channel: a calculated conformational change in response to addition of a proton, and a proposed path from voltage sensing domain to gate

Abstract

We have in the past proposed that protons constitute the gating current in the potassium channel Kv1.2. Here we present a quantum calculation of a protonation change in a 311 atom section of intracellular S4-S5 linker, together with part of the T1 intracellular moiety of the channel. This proton shift leads to a hinge rotation in the linker, which in turn produces a separation of two amino acids, K312 and R326 (using the numbering of the 3Lut pdb structure). Two complete proton wires can then be proposed that would fully account for the gating mechanism with protons; the proton wires have as yet not been completely calculated. However, the path seems reasonably evident, based on the amino acids in the S4-S5 linker, which connects to the pore transmembrane S6 segment as well, and the T1 moiety of the channel, which is part of one proton path. This therefore also accounts for the T1 effect on gating. We had earlier shown how a proton could be generated from the VSD. Taken together the paths from the VSD to the gate show how the VSD can couple to the gating mechanism by having protons move between the VSD and the gate, closing the channel by both producing the hinge rotation and providing electrostatic repulsion to an incoming K+ ion. The protons move under the influence of membrane polarization/depolarization. Taken together, this makes our previous model much more detailed, specifying the role of particular amino acids.