How and why phosphotyrosine-containing peptides bind to the SH2 and PTB domains

Background: Specific recognition of phosphotyrosine-containing protein segm ents by Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains play s an important role in intracellular signal transduction. Although many SH2 /PTB-domain-containing receptor-peptide complex structures have been solved , little has been done to study the problem computationally. Prediction of the binding geometry and the binding constant of any peptide-protein pair i s an extremely important problem. Results: A procedure to predict binding energies of phosphotyrosine-contain ing peptides with SH2/PTB domains was developed. The average deviation betw een experimentally measured binding energies and theoretical evaluations wa s 1.8 kcal/mol. Binding states of unphosphorylated peptides were also predi cted reasonably well. Ab initio predictions of binding geometry of fully fl exible peptides correctly identified conformations of two pentapeptides and a hexapeptide complexed with a v-Src SH2 domain receptor with root mean sq uare deviations (rmsds) of 0.3 Angstrom, 1.2 Angstrom and 1.5 Angstrom, res pectively. Conclusions: The binding energies of phosphotyrosine-containing complexes c an be effectively predicted using the procedure developed here. It was also possible to predict the bound conformations of flexible short peptides cor rectly from random starting conformations.