Dataset Information

Prediction of secondary ionization of the phosphate group in phosphotyrosine peptides.

ABSTRACT: 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.

SUBMITTER: Wojciechowski M

PROVIDER: S-EPMC1302655 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Prediction of secondary ionization of the phosphate group in phosphotyrosine peptides.

Wojciechowski M M Grycuk T T Antosiewicz J M JM Lesyng B B

Biophysical journal 20030201 2 Pt 1

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 conformationa ...[more]

PMID: 12547759

Similar Datasets

Project description:Acute myeloid leukemia (AML) is a clonal disorder arising from hematopoietic myeloid progenitors. Aberrantly activated tyrosine kinases (TK) are involved in leukemogenesis and are associated with poor treatment outcome. Kinase inhibitor (KI) treatment has shown promise in improving patient outcome in AML. However, inhibitor selection for patients is suboptimal.In a preclinical effort to address KI selection, we analyzed a panel of 16 AML cell lines using phosphotyrosine (pY) enrichment-based, label-free phosphoproteomics. The Integrative Inferred Kinase Activity (INKA) algorithm was used to identify hyperphosphorylated, active kinases as candidates for KI treatment, and efficacy of selected KIs was tested.Heterogeneous signaling was observed with between 241 and 2764 phosphopeptides detected per cell line. Of 4853 identified phosphopeptides with 4229 phosphosites, 4459 phosphopeptides (4430 pY) were linked to 3605 class I sites (3525 pY). INKA analysis in single cell lines successfully pinpointed driver kinases (PDGFRA, JAK2, KIT and FLT3) corresponding with activating mutations present in these cell lines. Furthermore, potential receptor tyrosine kinase (RTK) drivers, undetected by standard molecular analyses, were identified in four cell lines (FGFR1 in KG-1 and KG-1a, PDGFRA in Kasumi-3, and FLT3 in MM6). These cell lines proved highly sensitive to specific KIs. Six AML cell lines without a clear RTK driver showed evidence of MAPK1/3 activation, indicative of the presence of activating upstream RAS mutations. Importantly, FLT3 phosphorylation was demonstrated in two clinical AML samples with a FLT3 internal tandem duplication (ITD) mutation.Our data show the potential of pY-phosphoproteomics and INKA analysis to provide insight in AML TK signaling and identify hyperactive kinases as potential targets for treatment in AML cell lines. These results warrant future investigation of clinical samples to further our understanding of TK phosphorylation in relation to clinical response in the individual patient.

Dataset Information

Prediction of secondary ionization of the phosphate group in phosphotyrosine peptides.

Publications

Prediction of secondary ionization of the phosphate group in phosphotyrosine peptides.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure