Quantum Calculations on the Transport of Protons in the Voltage Sensing Domain of the Kv1.2 Potassium Channel: Multiple Paths, Charged Groups, and a Switch

Abstract

The upper part of the voltage sensing domain (VSD) of the Kv1.2 potassium channel resembles the upper part of the Hv1 proton channel, suggesting that transport of protons in the VSD is possible. Our calculations have shown how two sets of amino acids, each with two acid and three basic residues, hence with net one positive charge each, plus three polar but uncharged residues, and a limited number of water molecules, are critical elements of the proton pathway. The upper group consists of (numbering from the 3Lut pdb structure) R297:T184:E183:R300:Y266:R303:E226:S176; the lower section includes D259:K306:R309:R240:E236:W232:H310:S169, in each case, plus water. F233 is an additional critical residue: rotating it facilitates the motion of a proton through what would otherwise seem a hydrophobic block; in effect it acts as a switch. An electric field starts the proton cascade from the upper section, which drives protons through the lower section; the cascade continues, in a nearly field-free environment, along the cytoplasmic surface of the membrane, to the gate. A mutation within the VSD, F233W, left shifts the gating current curve (MacKinnon and coworkers). In addition to finding the path through the VSD, our calculations explain this left shift by lower activation energy of proton transfer from K306 to D259, then on to H310; we also explain the right shift found with F233E. The calculations show minimal shifts in structure with the field, of the order of 1 Å, but these are enough to produce electrostatic effects that lower the barrier to the proton's progress. Calculations with the protons in several positions have shown the relative energy, and the barriers, to proton transitions along the path.