[gmx-users] pKa calculations using gromacs

[Anton Feenstra]

The forcefields (all of them, as far as I'm aware) were never parametrized
to describe this kind of phenomena, making the results essentially random.
Besides, it seems to me this is a quantum-chemical process by nature, which
probably is badly described by any forcefield approach. But, it may just be
possible to include it during parameterization and get it right. (Lot of work, though...)

sameer varma wrote:

> 
> 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 126(13):4167-80.
> 
> 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
>> http://md.chem.rug.nl/education/Free-Energy_Course/)
>>
>> 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
>>
>>
>>
>> -- 
>> -----------www= http://www.iki.fi/markus.kaukonen---------------
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>> Helsinki Bioenergetics Group   \_______  02600 Espoo, Finland
>> Institute of Biotechnology             \ tel:+358-(0)9-5127122/h
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> 
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-- 
Groetjes,

Anton
  _____________ _______________________________________________________
|             |                                                       |
|  _   _  ___,| K. Anton Feenstra                                     |
| / \ / \'| | | Dept. of Pharmacochem. - Vrije Universiteit Amsterdam |
|(   |   )| | | De Boelelaan 1083 - 1081 HV Amsterdam - Netherlands   |
| \_/ \_/ | | | Tel: +31 20 44 47608 - Fax: +31 20 44 47610           |
|             | Feenstra at few.vu.nl - www.few.vu.nl/~feenstra/         |
|             | "If You See Me Getting High, Knock Me Down" (RHCP)    |
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