[gmx-users] pKa calculations using gromacs

Markus O Kaukonen mokaukon at cc.helsinki.fi
Thu Sep 9 09:15:31 CEST 2004

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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