光谱及分子模拟法对HSA和BSA与酪氨酸激酶抑制剂Imatinib相互作用的比较分析

研究一种酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)伊马替尼(imatinib,IMA)与人血清清蛋白(HSA)及牛血清清蛋白(BSA)的相互作用,比较分析HSA和BSA与IMA相互作用机制的差异.模拟生理条件下,计算机模拟技术结合荧光光谱和紫外光谱法,研究IMA与蛋白质的作用机制.分子模建IMA与血清清蛋白的结合模型,表明伊马替尼与蛋白质的相互作用力为疏水作用力,兼有氢键作用.光谱结果表明,IMA与HSA和BSA的相互作用表现为静态结合过程,结合强度较强,IMA与HSA和BSA分子的结合距离r值较小,说明发生了能量转移现象.IMA对HSA和BSA的结构域微区构象产生影响,使结合位域的疏水性发生改变.荧光相图技术解析出IMA与HSA和BSA反应构象型态的变迁为"二态"模型.HSA与IMA相互作用的热力学参数表明,IMA与HSA之间是以疏水作用为主的分子间作用,而IMA与BSA之间的作用力为氢键和范德华力,兼有少量的疏水作用力.光谱实验与计算机模拟结果基本一致,可为研究IMA与HSA和BSA相互作用本质提供一定参考.

Comparing the Interactions of Tyrosine Kinase Inhibitor Imatinib with HSA or BSA by Spectroscopy and Molecular Modeling

The interactions between tyrosine kinase inhibitor imatinib (IMA) with HSA or BSA were investigated. Following physiological stimulations, the IMA binding with HSA or BSA were simulated by computer software and referred to fluorescence spectrometry and ultraviolet spectrum. From the molecular modeling, hydrophobic forces and hydrogen bonds contributed to the binding. The spectroscopy results indicated that the interactions were static processes with strong bonding strength. The distances r between the IMA and HSA or BSA was small enough for energy transfer. IMA influenced the conformation of HSA or BSA and introduced changes in the hydrophobic binding domain. From the fluorescent phase diagram, the reaction conformational pattern of IMA-HSA and IMA-BSA fitted “two-state” models. The main force between IMA and HSA was hydrophobic force, whereas the forces to bridge IMA and BSA were hydrogen bonds and van der Waals force. These data demonstrated an example of joining spectrum experiment with computer simulation in protein structural analysis.