Subject: Re: CCL:How to calculate pKa values in large proteins?...

From: Stefan Grzybek <[email-masked]>
Date: Wed, 7 May 1997 09:19:01 +0200 (MDT)

On Tue, 6 May 1997, Vladislav Vassiliev wrote:
> Dear Netters:
> 
> Let's imagine I have coordinates of a real protein (for example, from
> PDB) and now I would like to know the pKa values of all the residues
> (Asp's, Glu's, Lys's, Arg's, His's) at a given pH. What kind of programs
> could predict these pKa values?
> 
> I would also be interested in any references concerning the approaches of
> this kind of prediction.
> 
> Thanks in advance,
> Dr. V.Vassiliev 

There are different approaches available for this kind of calculation. The
main differences are how the electrostatic potentials and interaction energies
are calculated and how the interacting charges are treated to calculate
ionization states.

To the first point: It is possible to calculate the electrostatic
interactions simply using Coulomb's law with an appropriately choosen
dielectric constant or to use solutions of the Poisson-Boltzmann equation
to calculate interaction energies. The most programs I know of, use
solutions to the Poisson-Boltzmann equation for calculating interaction
energies.

The second point: First is possible to use the Tanford-Roxby approximation
to solve the problem of interactiong ionization states; however this breaks
down if there are strongly interacting residues present. Better is to
consider the real statistical mechanical average over all possible ionization
states. This however has the drawback that calculating the ionization states
of a small protein with only about 25 to 30 ionizable residues already becomes
problematic. Therefore people have invented the 'reduced site' approximation,
monte carlo methods or mixed tanford-roxby/statistical mechanics methods.

Recent developments in this field focus on the incorporation of protein dynamics
or sidechain flexibility into the treatment of pK-calculations.

Some programs I know of:
MacroDox by Scott H. Northrup (uses the Tanford-Roxby approximation)
  http://pirn.chem.tntech.edu/macrodox.html

MEAD by Donald Bashford ([email-masked])
  ftp://ftp.scripps.edu/pub/electrostatics/

There has also been developed a pk-calculation program suite in the
lab of Barry Honig by Andreas Windemuth. Mail to [email-masked]
or [email-masked] for further information.

Since there is a large amount of literature in this field, I don't append a
list here. If you are interested, please contact me directly.

Hope this helps,
Stefan Grzybek
---
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