Summary: How and why phosphotyrosine-containing peptides bind to the
SH2 and PTB domains
Yingyao Zhou and Ruben Abagyan
Background: Specific recognition of phosphotyrosine-containing protein
segments by Src homology 2 (SH2) and phosphotyrosine-binding (PTB)
domains plays an important role in intracellular signal transduction. Although
many SH2/PTB-domain-containing receptorpeptide 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
peptideprotein pair is an extremely important problem.
Results: A procedure to predict binding energies of phosphotyrosine-
containing peptides with SH2/PTB domains was developed. The average
deviation between experimentally measured binding energies and theoretical
evaluations was 1.8 kcal/mol. Binding states of unphosphorylated peptides
were also predicted reasonably well. Ab initio predictions of binding geometry
of fully flexible peptides correctly identified conformations of two pentapeptides
and a hexapeptide complexed with a v-Src SH2 domain receptor with root
mean square deviations (rmsds) of 0.3 Ĺ, 1.2 Ĺ and 1.5 Ĺ, respectively.
Conclusions: The binding energies of phosphotyrosine-containing complexes
can be effectively predicted using the procedure developed here. It was also