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  

Molecular dynamics simulations of the interactions between mono-/bis- phosphotyrosine substrate and protein tyrosine phosphatase 1B

作　　者：董振科[1] 刘梦源[1] 程先超[1] 王润玲[1] 

机构地区：[1]天津医科大学药学院天津市临床药物关键技术重点实验室,天津300070

出　　处：《天津医科大学学报》2011年第4期440-442,454,F0003,共5页Journal of Tianjin Medical University

基　　金：国家自然科学基金资助项目(20972112);教育部博士点基金资助项目(20091202110010);天津市自然科学基金重点项目(09JCZDJC21600)

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 phosphatase 1B （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-phospbotyrosine substrate could increase the hydrogen bond probability between substrate and Asp 48 in PTP1B. Energydecomposition 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 bighter 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.

关 键 词：蛋白酪氨酸磷酸酯酶1B 抑制剂 磷酸化酪氨酸底物 分子动力学 

分 类 号：R91[医药卫生—药学]