Effects of Point Mutations on the Binding Energies of Estrogen Receptor with Estradiol

Kousuke MAEDAa, Alexander SCHUGb, c, Hirofumi WATANABEb, c, Kaori FUKUZAWAc, d, Yuji MOCHIZUKIc, e, Tatsuya NAKANOc, f and Shigenori TANAKAa, b, c*

aDepartment of Science of Human Environment, Faculty of Human Development, Kobe University
3-11 Tsurukabuto, Nada-ku, Kobe 657-8501, Japan
bGraduate School of Science and Technology, Kobe University
1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan
cCREST, Japan Science and Technology Agency (JST)
4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
dDivision of Science and Technology, Mizuho Information & Research Institute, Inc.
2-3 Kanda Nishiki-cho, Chiyoda-ku, Tokyo 101-8443, Japan
eAdvancesoft and Institute of Industrial Science, Center for Collaborative Research, University of Tokyo
4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
fDivision of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences
1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

(Received: August 3, 2006; Accepted for publication: November 30, 2006; Published on Web: January 24, 2007)

We have studied the molecular mechanism for the binding between estrogen receptor and estradiol using ab initio methods. To examine the validity of in silico analysis of mutation effects, we made point mutations of receptor employed in experiments, and compared the calculated results for the binding energies with experimental data. We performed the calculations at the HF/STO-3G and MP2/STO-3G levels by using the Fragment Molecular Orbital (FMO) method. The calculated results for three of six mutants qualitatively agreed with experimental data. However, the other three examples failed to reproduce the experimental data. We discussed the reasons for these discrepancies.

Keywords: Estrogen receptor, Point mutation, Binding energy, Fragment Molecular Orbital method


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