I want to perform an MD simulation of a protein under acidic solvent conditions. A quick literature search seems to indicate that people are more interested in the protonation of protein side chains (which is important, of course), but seem to ignore the abundance of $\ce{H+}$ ions (i.e. $\ce{H3O+})$ in water surrounding the protein.

Is there a standard practice for performing MD simulations of proteins in acidic environments? Should I account for $\ce{H+}$ at low pH?

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    $\begingroup$ I may just be making a silly mistake in a back of the envelope calculation, but wouldn't the concentration of water around the protein dwarf the concentration of $\ce{H3O+}$ by several orders of magnitude? A pH of 1 (very acidic for a biological setting) would correspond to an $\ce{H3O+}$ concentration of 0.1 M. Pure water has a concentration of 55 M. While this concentration would be reduced somewhat in an acidic solution, it still suggests that there is on the order of 100 times more waters than $\ce{H3O+}$. This ratio gets an order of magnitude larger when you increase the pH by 1 unit. $\endgroup$ – Tyberius Dec 22 '20 at 21:13
  • $\begingroup$ I think you're onto something. Just continuing in your train of thought, at pH = 1, an area of 10 angstrom^3, would just have 0.06 H3O+ molecules. At 100 angstrom ^3 (still pH = 1), you get 60 H3O+ molecules, which might become non-negligible. But rarely, do biomolecules function at pH=1. At pH = ~6, the number of H3O+ is still negligible at 100 angstrom^3. I wonder if the effects of H3O+ in biology (and hence simulation) would have a large effect, despite its small number... $\endgroup$ – Astronomer Dec 22 '20 at 22:03
  • $\begingroup$ @Mithoron but that's my point. The concentration of H3O+ is probably never large enough where one would actually need to alter the solvent itself for the simulation. I would think this would only be necessary in a solution that was so concentrated (e.g. negative pH) that H3O+ ions made up a significant portion of the solvent. $\endgroup$ – Tyberius Dec 23 '20 at 2:46
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    $\begingroup$ I think you have largely answered the question yourself, and it's not an entirely trivial answer, it depends on what you are probing and the conditions you are trying to simulate and the size of your simulation. If you are interested in the fate of the hydronium ions diffusing about a protein, then it is obviously a good idea to introduce them into the system. You would not need to even replicate the nominal concentration, but obviously have at least one ion. If you are interested in the effect of counterions in general at physiological pH then you may want to skip this. $\endgroup$ – Buck Thorn Dec 23 '20 at 14:00

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