> On Feb 28, 2019, at 12:14 PM, Brian Radak <brian.radak.gmail.com> wrote:
>
> Just my 2 cents:
>
> I don't have much firsthand experience with the specific constant-pH MD
> code in AMBER, but this is something I also had to grapple with while
> implementing a similar approach in NAMD. Our paper, as well as another from
> the GROMACS community, deals with the nuances in excruciating detail. The
> even older work from Shen and Brooks probably also addresses this, but I
> haven't looked at it recently.
>
> Jason (I believe) is speaking to the issue of microscopic versus
> macroscopic values.
Yes, I was.
> For identical sites (like carboxylates)
> the "extra entropy" is exactly the log ratio of identical species on either
> side of the transition (1 deprotonated state versus 4 protonated states, so
> the shift is roughly log(4))
It’s actually closer to log 2, since the anti-positions are significantly higher in energy. But yes, Mongans original derivation of the reference energies just took the TI energy and subtracted our log(2 + 2exp(-Eanti/kT)).
Setting all of the protonates states to the same reference energy level ensured that the syn- and anti- positions were appropriately populated during the simulation (that no further correction was needed was reflective of the force field getting that detail correct on its own).
> . Any deviations from the sites not being
> equivalent are then completely predicted by the force field. For the
> carboxylate syn/anti ratio this is probably a good approximation, since you
> are essentially asking that the PMF of proton rotation be "correct". For
> histidine, this is probably a horrible approximation, because the force
> field probably doesn't accurately account for the different bond energies
> of HID vs HIE, which is why the separate values of 6.5 and 7.1 are used.
Exactly. If you have some way of estimating populations of the delta and epsilon protonations experimentally, you can find microscopic pKa values that give the correct macroscopic pKa for Histidine as well as correctly reproduce the experimental populations of the two protonation sites.
I’ve forgotten the details of why those two microscopic pkas were originally chosen, though.
Good to hear from you, Brian.
All the best,
Jason
--
Jason M. Swails
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Received on Sat Mar 02 2019 - 07:00:03 PST
