Water and a Proton Shift between a Tyrosine and a Glutamate are Two Keys to Gating in Kv1.2; A Hypothesis Based on Quantum Calculations: The Sensor is Dynamic, Based on Hydrogen Bond Rearrangements, Principally in Water Rotational Degrees of Freedom, Plus a Proton Pathway

Abstract

An apparent proton pathway in the Kv1.2 K+ channel exists starting with a tyrosine (Y266, 3Lut pdb numbering) and continuing through a glutamate (E226); amino acids that would constitute several more steps can be identified, on to the H310 at the intracellular end of S4. Quantum calculations to date include four cases in which a proton shifts between Y266 and E226, the first step in the pathway, depending on electric field,. Energy differences with H+ transfer are small, ≈5 kT (open), 2 kT (closed). The calculations are, so far, approximate, but good enough to show that H+ transfer is possible, and the proton may “flicker” between the two positions. We hypothesize that proton transfer proceeds intracellularly on closing, down to H310 (the complete proposed pathway, with distances between groups in the path, can be identified); H310 affects the PVPV gate such that, with the proton at the intracellular end of this path, the gate closes. The proposed proton pathway structure resembles that in bacteriorhodopsin, where the proton transfer has been established. The water movement discussed in our other abstract appears to push a water molecule into position to assist in the first step transfer, based on calculations completed so far.