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

The temperature dependence is potentially the most serious objection to quantum calculations that give 0 K energy minima, creating one possible advantage of MD calculations. The minima are local minima; they show proton positions that are steps in the path that the protons take, and are metastable. There is no relevant global energy minimum. If the system fell into such a minimum, it is hard to see how it could go forward. There appears to be no way for the system to reach such a minimum, however; also, during gating the voltage keeps changing, so the states are necessarily transient; if they were not, there could be no proton current. We can in principle estimate the lifetime from the activation energy that it would take to get from one state to another, but we cannot yet get enough states to fix all the activation . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 energies with sufficient accuracy, and the pre-exponential terms are also hard to estimate. The apparent activation energy of the system fits reasonably well with the results to date. PRESSURE: There are pressure sensitive channels (e.g., MscS, MscL) that are stretch activated. However, for the channels we are considering here, relatively little work has been done on pressure effects. More has been done on sodium than potassium channels, but in all probability the effects should be quite similar. Heinemann et al found hydrostatic pressure slowed gating, with an activation volume of 33, and then 39, Ã… 3 for two cases (148) . There has been more work on osmotic pressure, which might be expected to behave quite differently, as hydrostatic pressure increases the free energy of the water, while the water free energy drops in case of hyperosmolarity. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 are relevant to gating have been proposed. We omit discussion of these in this paper; while these are a very likely useful way to obtain information as to gating mechanisms, the interpretations are not entirely obvious, and it would take a considerable amount of discussion to consider exactly how these results accord with the various possible gating models; we have not discussed conduction in detail, and some toxins interfere with conduction rather than gating. While potentially valuable, this information does not yet seem to allow a specific interpretation at the level we are considering.