<html>
<br>
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: <br><br>
<font face="Arial, Helvetica">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 126(13):4167-80.<br><br>
</font>You would find that different force-fields produce different
directions of pKa shifts! <br>
But is it really just a force-field related issue? I think not.<br>
<br>
cheers - Sameer<br><br>
At 10:15 AM 9/9/2004 +0300, Markus O Kaukonen wrote:<br>
<blockquote type=cite class=cite cite>Dear All,<br><br>
Did some literature search and could not find any hit with<br>
'pKa AND Gromacs'. Maybe there is a reason for this?<br><br>
I wonder does somebody know about calculting of gibbs free energy
of<br>
AH(p) + H2O(aq) -> A-(p) + H3O+(aq)<br>
A : titrable residue in protein,(p) : in protein, (aq): in
bulk water<br>
using Gromacs?<br><br>
Based on this deltaG one gets pKa estimate of the residue<br>
assuming a given protonation state of the rest of the protein<br>
(see for example Schuurmann J.Phys.ChemA v102, pp6706-6712-y1998,<br>
Sham J.Phys.ChemB v101, pp4458-4472-y1997 ).<br><br>
So to the question:<br>
I guess in the actual calculation one must use periodic boundary<br>
condition and this requires the simulation box to be neutral.<br><br>
The only way I was able to fullfill this requirement is simply<br>
to make a big water box containing the protein and putting Na+<br>
atoms to water part to make simulation box neutral.<br><br>
In AH(p) + H2O(aq) state the H2O(aq) is 'far away' from the protein in
water<br>
(state X).<br>
In A-(p) + H3O+(aq) state the H3O+(aq) is 'far away' from the protein in
water<br>
(state Y)<br><br>
Then thermodynamic integration between states X and Y to get deltaG<br>
(and pKa). (See excellent examples in<br>
<a href="http://md.chem.rug.nl/education/Free-Energy_Course/" eudora="autourl">http://md.chem.rug.nl/education/Free-Energy_Course/</a>)<br><br>
Is there some serious flaw in this procedure because I could not find
this<br>
in the literature? (Like pH of the water in A-(p) + H3O+(aq) would
be -3,<br>
no force field parameters for H3O+...). Partial charges for A- and AH
one<br>
gets from QM.<br><br>
Terveisin Markus<br><br>
<br><br>
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