A Calculated Proton Path in KV1.2 from the Voltage Sensing Domain S4 Segment Toward the Gate, with a Hypothesis as to the Remainder of the Path

Abstract

Quantum calculations on a 976 atom section of the voltage sensing domain (VSD) of the KV1.2 channel (published in J.Phys.Chem B: 123,7984 (2019) DOI:10.1021/acs.jpcb.9b05448) showed a proton path through the section. We now extend this calculation to an 1180 atom section containing much of the original section, plus an extension to the intracellular surface of the membrane. This determines a proton path that turns from the end of the S4 segment towards the gate, showing how the proton can move towards completing the path necessary to allow protons to operate the gate. This calculation suggests a hypothesis for a probable proton path for the section still to be calculated. The part that is complete shows how the proton can make the necessary turn from S4 towards the gate, and how the path that has been calculated connects to the intracellular surface section of the path. In the remaining section, water becomes important. There is one intracellular triad of amino acids like that shown in the earlier VSD calculation to facilitate proton transport. The T1 intracellular section is part of the path. While the hypothesis gives a reasonable path for proton transmission to the gate, it remains to be shown that the postulated proton positions for the closed and open gate correspond to the proton positions calculated for the VSD with and without voltage applied. In this intracellular region, the proton positions differ in the open and closed states, but there is no significant external voltage drop, nor major conformational change.