单/双磷酸化酪氨酸底物与蛋白酪氨酸磷酸酯酶1B相互作用分子动力学研究

摘要

目的:探索双磷酸化酪氨酸底物与蛋白酪氨酸磷酸酯酶1B(PTP1B)亲和能力比单磷酸化酪氨酸底物高的原因.方法:利用分子动力学模拟的方法来研究上述两种底物与PTP1B相互作用的差异.结果:双磷酸化酪氨酸底物和单磷酸化酪氨酸底物对PTP1B骨架运动影响模式相近.但双磷酸化酪氨酸底物可以增强底物与PTP1B的Asp48之间的形成氢键的概率.能量分解分析表明双磷酸化酪氨酸底物两个双磷酸化酪氨酸与PTP1B之间的强静电作用是导致双磷酸化酪氨酸底物与PTP1B相互作用能的主要原因.结论:双磷酸化酪氨酸底物与PTP1B比单磷酸化酪氨酸底物亲和力高的主要原因是双磷酸化酪氨酸底物与PTP1B中Asp48强氢键作用以及双磷酸化酪氨酸底物的两个双磷酸化酪氨酸与PTP1B之间的强静电作用.%Objective: To investigate the reason of greater affinity between bis-phosphotyrosine substrate and protein tyrosine phos-phatase IB (PTP1B). Methods: Molecular dynamics simulation methods were used to explore the difference in the interaction between PTP1B and mono-/bis-phosphotyrosine substrates. Results: Bis-phosphotyrosine substrate and mono-phosphotyrosine substrate had the same effect on the backbone movement of PTP1B. But bis-phosphotyrosine substrate could increase the hydrogen bond probability between substrate and Asp 48 in PTP1B. Energy decomposition analysis showed that the two phosphotyrosines of bis-phosphotyrosine substrate had higher electrostatic interactions with PTP1B, which could lead to the enhanced interaction energies between substrate and protein. Conclusion: The highter binding affinity between bis-phosphotyrosine substrate and PTP1B relative to mono-phosphotyrosine substrate could be contribute to the increased the hydrogen bond stability between substrate and Asp48 in PTP1B, as well as the increased interaction electrostatic attraction between two phosphotyrosines and PTP1B in bis-phosphotyrosine substrate.