TY - JOUR
T1 - Ab initio quantum mechanical study of the binding energies of human estrogen receptor α with its ligands
T2 - An application of fragment molecular orbital method
AU - Fukuzawa, Kaori
AU - Kitaura, Kazuo
AU - Uebayasi, Masami
AU - Nakata, Kotoko
AU - Kaminuma, Tsuguchika
AU - Nakano, Tatsuya
PY - 2005/1/15
Y1 - 2005/1/15
N2 - We have theoretically examined the relative binding affinities (RBA) of typical ligands, 17β-estradiol (EST), 17α-estradiol (ESTA), genistein (GEN), raloxifene (RAL), 4-hydroxytamoxifen (OHT), tamoxifen (TAM), clomifene (CLO), 4-hydroxyclomifene (OHC), diethylstilbestrol (DES), bisphenol A (BISA), and bisphenol F (BISF), to the α-subtype of the human estrogen receptor ligand-binding domain (hERα LBD), by calculating their binding energies. The ab initio fragment molecular orbital (FMO) method, which we have recently proposed for the calculations of macromolecules such as proteins, was applied at the HF/STO-3G level. The receptor protein was primarily modeled by 50 amino acid residues surrounding the ligand. The number of atoms in these model complexes is about 850, including hydrogen atoms. For the complexes with EST, RAL, OHT, and DES, the binding energies were calculated again with the entire ERαLBD consisting of 241 residues or about 4000 atoms. No significant difference was found in the calculated binding energies between the model and the real protein complexes. This indicates that the binding between the protein and its ligands is well characterized by the model protein with the 50 residues. The calculated binding energies relative to EST were very well correlated with the experimental RBA (the correlation coefficient r = 0.837) for the ligands studied in this work. We also found that the charge transfer between ER and ligands is significant on ER-ligand binding. To our knowledge, this is the first achievement of ab initio quantum mechanical calculations of large molecules such as the entire ERαLBD protein.
AB - We have theoretically examined the relative binding affinities (RBA) of typical ligands, 17β-estradiol (EST), 17α-estradiol (ESTA), genistein (GEN), raloxifene (RAL), 4-hydroxytamoxifen (OHT), tamoxifen (TAM), clomifene (CLO), 4-hydroxyclomifene (OHC), diethylstilbestrol (DES), bisphenol A (BISA), and bisphenol F (BISF), to the α-subtype of the human estrogen receptor ligand-binding domain (hERα LBD), by calculating their binding energies. The ab initio fragment molecular orbital (FMO) method, which we have recently proposed for the calculations of macromolecules such as proteins, was applied at the HF/STO-3G level. The receptor protein was primarily modeled by 50 amino acid residues surrounding the ligand. The number of atoms in these model complexes is about 850, including hydrogen atoms. For the complexes with EST, RAL, OHT, and DES, the binding energies were calculated again with the entire ERαLBD consisting of 241 residues or about 4000 atoms. No significant difference was found in the calculated binding energies between the model and the real protein complexes. This indicates that the binding between the protein and its ligands is well characterized by the model protein with the 50 residues. The calculated binding energies relative to EST were very well correlated with the experimental RBA (the correlation coefficient r = 0.837) for the ligands studied in this work. We also found that the charge transfer between ER and ligands is significant on ER-ligand binding. To our knowledge, this is the first achievement of ab initio quantum mechanical calculations of large molecules such as the entire ERαLBD protein.
KW - Ab initio fragment molecular orbital (FMO) method
KW - Charge transfer
KW - Estrogen receptor α
KW - Ligand-binding domain; binding energy
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U2 - 10.1002/jcc.20130
DO - 10.1002/jcc.20130
M3 - Article
C2 - 15521089
AN - SCOPUS:11144282711
VL - 26
SP - 1
EP - 10
JO - Journal of Computational Chemistry
JF - Journal of Computational Chemistry
SN - 0192-8651
IS - 1
ER -