DNA and Estrogen Receptor Interaction Revealed by Fragment Molecular Orbital Calculations

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• 作者：Toshio Watanabe ; Yuichi Inadomi ; Kaori Fukuzawa ; Tatsuya Nakano ; Shigenori Tanaka ; Lennart Nilsson ; Umpei Nagashima
• 刊名：Journal of Physical Chemistry B
• 出版年：2007
• 出版时间：August 16, 2007
• 年：2007
• 卷：111
• 期：32
• 页码：9621 - 9627
• 全文大小：533K
• 年卷期：v.111,no.32(August 16, 2007)
• ISSN：1520-5207

文摘

Molecular orbital calculations of the complex between DNA-ERE (estrogen response element) and ER(estrogen receptor)-DBD (DNA-binding domain) were performed using the fragment molecular orbital (FMO)method, which enables large-scale MO (molecular orbital) calculations by reducing the computational costand by significantly increasing efficiency for parallel computation. Such a large system, which contains 3354atoms, is impractical via conventional MO methods due to the immense computational cost. Details of theinteraction between DNA-ERE and ER-DBD were revealed in this study as follows by using the FMOcalculations to analyze the interfragment interaction energies (IFIEs) and the electrostatic potentials (ESPs).An area with a high positive ESP is identified on the DNA-binding side of ER-DBD and is the main drivingforce behind access to the DNA. The position of the ER-DBD monomer can be fixed on a phosphate groupof DNA-ERE by the strong electrostatic interactions, whereas the rotation cannot be fixed. In contrast, boththe position and rotation of the ER-DBD dimer can be fixed and can therefore form the stable(ER-DBD)₂···DNA-ERE complex. Dimerization of the ER-DBD monomers, each of which have a chargeof +5, is mainly due to large attractive interaction energies of the second Zn fragments. The base pairs inthe consensus sequence of DNA-ERE interact only with the recognition helix located in the major groovedue to the large shielding effect of the phosphate groups of DNA. The recognition helix has weaker interactionswith the base pairs than the electrostatic interactions with the phosphate groups. Thus, the DNA-bindingmachinery of the ER-DBD dimer, which can secure the recognition helix in the major groove of DNA, iscrucial for interactions between the recognition helix and base pairs.