Molecular interactions between estrogen receptor and its ligand studied by the ab initio fragment molecular orbital method
Molecular interactions between estrogen receptor and its ligand studied by the ab initio fragment molecular orbital method
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DOI：
10.1021/jp060770i
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发表时间：
2006-08-17
影响因子：
3.3
通讯作者：
Nakano, Tatsuya
中科院分区：
文献类型：
--
作者：
Fukuzawa, Kaori;Mochizuki, Yuji;Nakano, Tatsuya
对整个雌激素受体 (ER) 配体结合结构域与天然配体 17 ss-雌二醇 (EST) 的分子相互作用进行从头开始片段分子轨道计算。使用具有多个基组的 HF 和 MP2 方法计算配体在残基水平的相互作用能。还基于片段相互作用的构型分析来分析电荷转移（CT）相互作用。在 EST 和周围带电/极化残基、Glu353、Arg394、His524 和 Thr347 之间观察到强静电相互作用。在 EST 和许多周围的疏水残基之间观察到弱静电和显着的范德华色散相互作用。结合实验解释，两种相互作用对总结合能的贡献相等，并且发现包含电子相关性对于获得相互作用的适当图像至关重要。在 Glu353 和 EST 之间观察到最强的相互作用能，并且发现从 Glu353 的羰基氧的孤对轨道到 EST 的羟基的 α*(OH) 轨道的 CT 相互作用很重要。还观察到从EST的孤对轨道到Arg394的α*(NH)以及从EST的孤对轨道到His524的α*(NH)的CT相互作用。这些 CT 相互作用通过 ER 和 EST 之间的氢键网络发生。因此，从 ER 到 EST 的电子捐赠和从 EST 到 ER 的电子回赠是 ER-配体结合的特征。我们的方法提供了一个强大的工具来理解量子力学水平上详细的分子相互作用。
The ab initio fragment molecular orbital calculations were performed for molecular interactions of the whole estrogen receptor (ER) ligand-binding domain with a natural ligand, 17 ss-estradiol (EST). The interaction energies of the ligand at the residue level were calculated using HF and MP2 methods with several basis sets. The charge-transfer (CT) interactions were also analyzed based on configuration analysis for fragment interaction. Strong electrostatic interactions were observed between the EST and surrounding charged/polarized residues, Glu353, Arg394, His524, and Thr347. Weak electrostatic and significant van der Waals dispersion interactions were observed between the EST and the many surrounding hydrophobic residues. Together with the experimental interpretations, both interactions equally contributed to the total binding energies, and it was found that the inclusion of electron correlation was essential to obtain an appropriate picture of the interaction. The strongest interaction energy was observed between Glu353 and the EST, and the CT interactions from the lone- pair orbital of the carbonyl oxygen of Glu353 to the alpha*(OH) orbital of the hydroxyl group of EST were found to be important. The CT interactions from the lone- pair orbital of EST to the alpha*(NH) of Arg394 and from the lone- pair orbital of EST to the alpha*(NH) of His524 were also observed. These CT interactions occurred through the hydrogen-bond networks between the ER and EST. Therefore, electron donations from the ER to the EST and electron back-donations from EST to the ER were characteristic of ER-ligand binding. Our approach provides a powerful tool to understanding detailed molecular interactions at the quantum mechanical level.