The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

Alisher M Kariev; Michael E Green

3) There are other proteins that have some sections of their internal structures very similar to those of the VSD, and that are known to transmit protons, including cytochrome c(66-68), bacteriorhodopsin (69) (70) (71) , and the M2 channel of the flu virus (72, 73) . Of the latter cases, some have water, unlike the VSD amino acid triad that can transmit a proton without water. (74) showed that S3, which has negative charges, appears to move in the same direction as S4 when the standard cysteine mutation plus MTS experiment is done; this would indicate that this experiment measures in situ availability of the residues, but the authors found an explanation consistent with the standard model. The possible motion looks a little like the MacKinnon paddle model in which half of S3 moves together with S4(75, 76); a number of objections have been raised to this model, and it would take too long to discuss them all here; this model at present does not seem to be a probable candidate for gating. 5) Naranjo and coworkers found that making a mutation of either sign(77) appears to have the same effect on gating charge; if S4 moves outward to open the channel, a positive (base) mutation should add to gating charge, while an acid, if ionized, hence negative, should subtract, but both subtracted. If S4 motion has nothing to do with gating current, this is easily understandable, but the authors found an interpretation that appeared consistent with the standard models; it is less clear that the interpretation was consistent with other experiments in which S4 would have to make somewhat different motions. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/371914 doi: bioRxiv preprint 6) It has been shown that the first step in gating is a very small and very fast component of gating current (about 1% of gating current, and faster than the RC time constant of the membrane, hence too fast to measure, <2µs rise time), the "piquito" (78, 79) . For a standard model interpretation one must assume that it is some sort of side chain rearrangement in an energy landscape; however, the nature of this energy landscape remains to be fully defined (80) . An alternate interpretation is as a first step in a proton cascade, in which a proton tunnels to a neighboring residue, with the voltage change making this possible by matching energy levels. Such a component of gating current makes little sense in the standard models.