Quantum Calculations on a Voltage Sensing Domain of K V 1.2: H + Transfer and Gating Current

Quantum calculations on the voltage sensing domain (VSD) of the Kv1.2 potassium channel (pdb: 3Lut)have been carried out on a 904 atoms subset of the VSD, plus 24 water molecules. Side chains pointing away from the center of the VSD were truncated; S1,S2,S3 end atoms were were fixed (all calculations); S4 end atoms could be fixed or free. Open conformations (membrane potentials >= 0) closely match the known X-ray structure of the open state with salt bridges in the in the VSD not ionized (H+ on the acid) whether S4 end atoms were fixed or free (slightly closer fixed than free).The S4 segment backbone, free or not, moves less than 2.5 A for positive to negative membrane potential switches, not entirely in the expected direction, leaving H+ motion as the principal component of the gating current. Groups of 3 - 5 side chains are important for proton transport, based on the calculations. A proton transfers from tyrosine (Y266), through arginine (R300), to glutamate (E183), accounting for approximately 20 - 25% of the gating charge. Clusters of amino acids that can transfer protons (acids, bases, tyrosine, histidine) are the main paths for proton transport. A group of five amino acids, bounded by the conserved aromatic F233, appears to exchange a proton. Dipole rotations may also contribute. A proton path (calculations still in progress) is proposed for the remainder of the VSD, suggesting a hypothesis for a complete gating mechanism.