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Prediction of Secondary Ionization of the Phosphate Group in Phosphotyrosine Peptides

M. Wojciechowski^*, T. Grycuk^*, J. M. Antosiewicz^* and B. Lesyng^*,

^* Department of Biophysics, Warsaw University, wirki i Wigury 93, 02-089 Warsaw, Poland, and the Interdisciplinary Center for Mathematical and Computational Modelling, Warsaw University, Pawiskiego 5A, 02-106 Warsaw, Poland

Correspondence: Address reprint requests to Bogdan Lesyng, Warsaw University, Pawiskiego 5A, Warsaw, Poland 02-106. Tel.: +48-22-874-9100; Fax: +48-22-874-9115; E-mail: lesyng{at}icm.edu.pl.

A computational approach, based on a continuum molecular electrostatics model, for the calculation of the pK_a values of secondary ionization of the phosphate group in phenyl phosphate derivatives is described. The method uses the ESP atomic charges of the mono-anionic and di-anionic forms of the ionizable phosphate group, computed with the use of the density functional method, and applies a new concept of the model group, being the reference state for the pK_a calculations. Both conformational flexibility and tautomeric degrees of freedom are taken into account in the calculations. The method was parameterized using experimentally available pK_a values of four derivatives of phenyl phosphates, and phosphotyrosine. Subsequently this parameterization was used to predict pK_a of the phosphate group in a short peptide Gly-Gly-Tyr(P)-Ala, and in a longer peptide consisting of 12 residues, the latter in water, and in a complex with a protein—phospholipase. The agreement between the computed and the experimental pK_a values is better than ±0.3 pH units for the optimized solute dielectric constant of 11–13. This approach is promising and its extension to other phospho-amino acids is in progress.