[gmx-users] pKa calculations using gromacs

sameer varma varma1 at uiuc.edu
Thu Sep 9 21:44:10 CEST 2004

Although linear response theories using MD free energies have now been used 
for quite a while to predict amino-acid pka's, it definitely is NOT a 
completely reliable method. You can find some of the pros and cons of this 
method discussed in a recently published journal article:

Simonson, T., J. Carlsson, D.A. Case. 2004. Proton binding to proteins: 
pK(a) calculations with explicit and implicit solvent models. J Am Chem Soc 

You would find that different force-fields produce different directions of 
pKa shifts!
But is it really just a force-field related issue? I think not.

cheers - Sameer

At 10:15 AM 9/9/2004 +0300, Markus O Kaukonen wrote:
>Dear All,
>Did some literature search and could not find any hit with
>'pKa AND Gromacs'. Maybe there is a reason for this?
>I wonder does somebody know about calculting of gibbs free energy of
>AH(p) + H2O(aq) -> A-(p) + H3O+(aq)
>A   : titrable residue in protein,(p) : in protein, (aq): in bulk water
>using Gromacs?
>Based on this deltaG one gets pKa estimate of the residue
>assuming a given protonation state of the rest of the protein
>(see for example Schuurmann J.Phys.ChemA v102, pp6706-6712-y1998,
>                  Sham J.Phys.ChemB v101, pp4458-4472-y1997 ).
>So to the question:
>I guess in the actual calculation one must use periodic boundary
>condition and this requires the simulation box to be neutral.
>The only way I was able to fullfill this requirement is simply
>to make a big water box containing the protein and putting Na+
>atoms to water part to make simulation box neutral.
>In AH(p) + H2O(aq) state the H2O(aq) is 'far away' from the protein in water
>(state X).
>In A-(p) + H3O+(aq) state the H3O+(aq) is 'far away' from the protein in water
>(state Y)
>Then thermodynamic integration between states X and Y to get deltaG
>(and pKa). (See excellent examples in
>Is there some serious flaw in this procedure because I could not find this
>in the literature?  (Like pH of the water in A-(p) + H3O+(aq) would be -3,
>no force field parameters for H3O+...). Partial charges for A- and AH one
>gets from QM.
>Terveisin Markus
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