Effects of the Hydroxyl Group on Phenyl Based Ligand/ERR纬 Protein Binding

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• 作者：Oleg N. Starovoytov ; Yalin Liu ; Liuxi Tan ; Shizhong Yang
• 刊名：Chemical Research in Toxicology
• 出版年：2014
• 出版时间：August 18, 2014
• 年：2014
• 卷：27
• 期：8
• 页码：1371-1379
• 全文大小：396K
• ISSN：1520-5010

文摘

Bisphenol-A (4,4鈥?dihydroxy-2,2-diphenylpropane, BPA, or BPA-A) and its derivatives, when exposed to humans, may affect functions of multiple organs by specific binding to the human estrogen-related receptor 纬 (ERR纬). We carried out atomistic molecular dynamics (MD) simulations of three ligand compounds including BPA-A, 4-伪-cumylphenol (BPA-C), and 2,2-diphenylpropane (BPA-D) binding to the ligand binding domain (LBD) of a human ERR纬 to study the structures and energies associated with the binding. We used the implicit Molecular Mechanics/Poisson鈥揃oltzmann Surface Area (MM/PBSA) method to estimate the free energies of binding for the phenyl based compound/ERR纬 systems. The addition of hydroxyl groups to the aromatic ring had only a minor effect on binding structures and a significant effect on ligand/protein binding energy in an aqueous solution. Free binding energies of BPA-D to the ERR纬 were found to be considerably less than those of BPA-A and BPA-C to the ERR纬. These results are well correlated with those from experiments where no binding affinities were determined in the BPA-D/ERR纬 complex. No conformational change was observed for the helix 12 (H-12) of ERR纬 upon binding of these compounds preserving an active transcriptional conformation state.