Zhou Y, Abagyan R
Skirball Institute of Biomolecular Medicine, Structural Biology, New York University Medical Center, NY 10016, USA.
Fold Des. 1998;3(6):513-22. doi: 10.1016/S1359-0278(98)00067-4.
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 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 is an extremely important problem.
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 A, 1.2 A and 1.5 A, respectively.
The binding energies of phosphotyrosine-containing complexes can be effectively predicted using the procedure developed here. It was also possible to predict the bound conformations of flexible short peptides correctly from random starting conformations.
Src同源2（SH2）结构域和磷酸酪氨酸结合（PTB）结构域对含磷酸酪氨酸蛋白片段的特异性识别在细胞内信号转导中起重要作用。尽管已经解析了许多含SH2/PTB结构域的受体 - 肽复合物结构，但在计算研究该问题方面做得很少。预测任何肽 - 蛋白对的结合几何结构和结合常数是一个极其重要的问题。
开发了一种预测含磷酸酪氨酸肽与SH2/PTB结构域结合能的方法。实验测量的结合能与理论评估之间的平均偏差为1.8千卡/摩尔。未磷酸化肽的结合状态也得到了较好的预测。对完全柔性肽的结合几何结构进行从头预测，正确识别了与v-Src SH2结构域受体复合的两种五肽和一种六肽的构象，其均方根偏差（rmsds）分别为0.3埃、1.2埃和1.5埃。
使用此处开发的方法可以有效地预测含磷酸酪氨酸复合物的结合能。从随机起始构象正确预测柔性短肽的结合构象也是可能的。
