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

Presumably this arginine would not move. This seems entirely reasonable, as it reaches into the headgroup section of the membrane. Arginine can complex with phosphate, and the headgroup region has a phosphate group for every lipid; not all lipids have net charge, although some negatively charged . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 lipids are needed (86, 87) . Furthermore, phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is needed to have a functioning channel (88) (89) (90) , and this adds negative charges. While evidence that PIP2 is involved in complexing arginine in channels has not been reported (yet), this would be consistent with the existence of phosphate-arginine complexes; so far a complete proof awaits further evidence. However, calculations (91, 92) and experiment (93, 94) both show that guanidinium and phosphate form complexes that are fairly stable. Therefore, the end arginine, which reaches into the headgroup region, would be complexed with phosphate, with high probability. It would be necessary to release this complex if the S4 were to move as a rigid body, or nearly so. With the first arginine anchored in the membrane, there remains the possibility that S4 could break. With a fraction moving down, while the extracellular section remains in place, the broken helix would have to re-form thousands of times with no mistakes at all, such as returning to a local minimum with a different set of hydrogen bonds and salt bridges; returning so many times without error seems very implausible. The reason the S4 helix would have to re-form without error thousands of times can be understood as follows: consider that the channel must open and close more than once per second in many nerve cells, some of which fire at rates of 50 Hz. Let us assume 10 Hz to be conservative. A minimum lifetime for the channel might be 10 minutes; even this is expensive, in terms of the energy the cell must expend, if the protein must be resynthesized that often, but let us say 10 minutes. Then the channel must open and close completely accurately 6000 times in its lifetime, and with four transmembrane domains, that means a total of 24,000 openings and closings before the protein is replaced. If the S4 really must re-fold exactly correctly that many times, it must somehow use the rest of the VSD as a chaperonin, something for which there is no evidence, nor does it seem clear how it could be possible. This supports the idea that S4 does not unfold. However, if it does not, then there must be some way for the first arginine to get out of the headgroup layer, something that also seems extremely unlikely.