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

. CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 Y266(0), R300(0), E183(0)), exchange plus correlation energy summed to 96.0 kJ above the lowest energy state (total energy was much larger), while for the lowest energy open state (Y266(-),R300(+),E183(0)), it was only 25.2 kJ. The much larger electrostatic and kinetic energy terms more than made up for the differences, but if these relatively small differences in XC terms were neglected, the states would still be placed out of order. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 tyrosine that has to ionize to make that pathway work. It appears that mutating this to a phenylalanine must interrupt this path, and make it more difficult to open the channel. The experiment has been carried out by Dr. Carlos Bassetto and Professor Francisco Bezanilla, and it showed approximately a 1.7 fold drop in slope of the gating current -voltage curve, showing that eliminating the possibility of ionizing this residue did interfere with gating, as predicted. In the standard models, one might expect, if anything, that given the slightly smaller volume of phenylalanine, a Y266F mutation might increase the probability of gating, rather than decreasing it, because it would be easier for S4 to slide up. Since the E226 path remains, the channel still functions, but not as well. This evidence supports the model we propose, and tends to refute the standard model. There must be a gating charge, so that there must be a shift in the center of charge. For the 976 atom case, we used NBO to find the charges on all the atoms. Then, by dividing the system into 11 3 Ã… slices, and adding all the charges on the atoms in each slice, we determined the center of charge in the two cases of low energy (-70 mV, Y266=R300=E183=0 nominal charge, 0 mV Y266 negative, R300 positive, E183 zero nominal charge). For the -70 mV case, the center of charge was at 19.6 Ã…, for the 0 mV case, at 8.3 Ã…, for a shift of 11.3 Ã…. This is very nearly just what it should be, but it must be taken with caution, as the error bar on this value may be several Angstroms. The total charge on the system is always +2.