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

 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 (bashford -8 at 8- scripps.edu)
   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 pka -8 at 8-
 cumbnd.bioc.columbia.edu
 or windemut -8 at 8- cumbnd.bioc.columbia.edu 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
 ---
 | Stefan Grzybek   email: grzybek -8 at 8- ruf.uni-freiburg.de           |
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