Abstract
We applied the fragment molecular orbital (FMO) method, which enables total electronic calculations of large molecules at ab initio level, to the evaluation of binding affinities between the human progesterone receptor ligand-binding domain (PR LBD) and various steroidal ligands. The FMO calculations were performed on the entire structure of the PR LBD, which is composed of ∼4,100 atoms. Our computational binding energies of PR LBD/ligand complexes agreed well with experimental binding affinities (r = 0.909). Interaction energies between each ligand and specific amino acid residues were also obtained from the FMO calculations. The principal residues involved in the interactions with these ligands were Arg766 and Asn719, with some additional contribution by Gln725. The main factor determining differences in binding affinity of the various ligands was not interactions with particular residues, but with the binding-site residues closest to the ligand. The interfragment interaction energy analysis is proving to be a useful method for gaining detailed information on ligand binding.
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References
Bergink EW, van Meel F, Turpijn EW, van der Vies J (1983) Binding of progestagens to receptor proteins in MCF-7 cells. J Steroid Biochem 19:1563–1570
Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE (2002) Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110:93–105
Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature 375:377–382
Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:187–217
Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Ohman L, Greene GL, Gustafsson JÅ, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758
Cramer RD III, Patterson DE, Bunce JD (1998) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967
Fedorov DG, Ishida T, Uebayasi M, Kitaura K (2007) The fragment molecular orbital method for geometry optimizations of polypeptides and proteins. J Phys Chem A 111:2722–2732
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery Jr. JA,Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nkai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C,Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Forcsman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2003) Gaussian 03. Gaussian Inc, Pittsburgh
Fukuzawa K, Kitaura K, Uebayasi M, Nakata K, Kaminuma T, Nakano T (2005) Ab initio quantum mechanical study of the binding energies of human estrogen receptor α with its ligands: an application of fragment molecular orbital method. J Comp Chem 26:1–10
Gantchev TG, Ali H, van Lier JE (1994) Quantitative structure–activity relationships/comparative molecular field analysis (QSAR/CoMFA) for receptor-binding properties of halogenated estradiol derivatives. J Med Chem 37:4164–4176
Grill HJ, Manz B, Elger W, Pollow K (1985) 3H-cyproterone acetate: binding characteristics to human uterine progestagen receptors. J Endocrinol Investig 8:135–141
Gu Y, Kar T, Scheiner S (1999) Fundamental properties of the CH···O interaction: is it a true hydrogen bond? J Am Chem Soc 121:9411–9422
Hammond GL, Rabe T, Wagner JD (2001) Preclinical profiles of progestins used in formulations of oral contraceptives and hormone replacement therapy. Am J Obstet Gynecol 185:S24–S31
Insight II (1998) Molecular Simulations Inc, San Diego, CA
Jiang L, Lai L (2002) CH···O Hydrogen bonds at protein–protein interfaces. J Biol Chem 277:37732–37740
Kauppi B, Jakob C, Färnegårdh M, Yang J, Ahola H, Alarcon M, Calles K, Engström O, Harlan J, Muchmore S, Ramqvist A-K, Thorell S, Öhman L, Greer J, Gustafsson J-Å, Carlstedt-Duke J, Carlquist M (2003) The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J Biol Chem 278:22748–22754
Kitaura K, Ikeo E, Asada T, Nakano T, Uebayasi M (1999a) Fragment molecular orbital method: an approximate computational method for large molecule. Chem Phys Lett 313:701–706
Kitaura K, Sawai T, Asada T, Nakano T, Uebayasi M (1999b) Pair interaction molecular orbital method: an approximate computational method for molecular interactions. Chem Phys Lett 312:319–324
Kitaura K, Sugiki S, Nakano T, Komeiji Y, Uebayasi M (2001) Fragment molecular orbital method: analytical energy gradients. Chem Phys Lett 336:163–170
Klaholz BP, Moras D (2002) C-H···O hydrogen bonds in the nuclear receptor RARγ—a potential tool for drug selectivity. Structure 10:1197–1204
Komeiji Y, Ishida T, Fedorov DG, Kitaura K (2007) Change in a protein's electronic structure induced by an explicit solvent: an ab initio fragment molecular orbital study of ubiquitin. J Comp Chem 28:1750–1762
Le Questel J-Y, Boquet G, Berthelot M, Laurence C (2000) Hydrogen bonding of progesterone: a combined theoretical, spectroscopic, thermodynamic, and crystallographic database study. J Phys Chem B 104:11816–11823
Letz M, Bringmann P, Mann M, Mueller-Fahrnow A, Reipert D, Scholz P, Wurtz J-M, Egner U (1999) Investigation of the binding interactions of progesterone using muteins of the human progesterone receptor ligand binding domain designed on the basis of a three-dimensional protein model. Biochim Biophys Acta 1429:391–400
Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, Otto N, Joschko S, Scholz P, Wegg A, Bäsler S, Schäfer M, Egner U, Carrondo MA (2000) Structural evidence for ligand specificity in the binding domain of the human androgen receptor: implications for pathogenic gene mutations. J Biol Chem 275:26164–26171
Mordasini T, Curioni A, Bursi R, Andreoni W (2003) The binding mode of progesterone to its receptor deduced from molecular dynamics simulations. ChemBioChem 4:155–161
Morizono D, Yamagishi K, Shimizu M, Nomura K, Iwashita T, Tokiwa H, DeLuca H F, Yamada S (2007) 19F NMR Study of Fluorovitamin D Compounds Complexed with Vitamin D Receptor: Probing the Conformation of Vitamin D Ligands Accommodated in the Receptor. Cell Chem & Bio (submitted)
Nakanishi I, Fedorov DG, Kitaura K (2007) Molecular recognition mechanism of FK506 binding protein: an all-electron fragment molecular orbital study. Proteins: Structure, Functions, and Bioinformatics 68:145–158
Nakano T, Kaminuma T, Sato T, Akiyama Y, Uebayasi M, Kitaura K (2000) Fragment molecular orbital method: application to polypeptides. Chem Phys Lett 318:614–618
Nakano T, Kaminuma T, Sato T, Fukuzawa K, Akiyama Y, Uebayasi M, Kitaura K (2002) Fragment molecular orbital method: use of approximate electrostatic potential. Chem Phys Lett 351:475–480
Oostenbrink BC, Pitera JW, van Lipzig MMH, Meerman JHN, van Gunsteren WF (2001) Simulations of the estrogen receptor ligand-binding domain: affinity of natural ligands and xenoestrogens. J Med Chem 43:4594–4605 (Published erratum appears in J. Med. Chem. 2001, 44, 1124.)
Pasqualini JR, Paris J, Sitruk-Ware R, Chetrite G, Botella J (1998) Progestins and breast cancer. J Steroid Biochem Mol Biol 65:225–235
Renaud JP, Moras D (2000) Structural studies on nuclear receptors. Cell Mol Life Sci 57:1748–1769
Sadler BR, Cho SJ, Ishaq KS, Chae K, Korach KS (1998) Three-dimensional quantitative structure–activity relationship study of nonsteroidal estrogen receptor ligands using the comparative molecular field analysis/cross-validated r2-guided region selection approach. J Med Chem 41:2261–2267
Scheiner S, Kar T, Gu Y (2001) Strength of the CαH··O hydrogen bond of amino acid residues. J Biol Chem 276:9832–9837
Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95:927–937
Steinmetz ACU, Renaud JP, Moras D (2001) Binding of ligands and activation of transcription by nuclear receptors. Annu Rev Biophys Biomol Struct 30:329–359
Tanenbaum DM, Wang Y, Williams SP, Sigler PB (1998) Crystallographic comparison of the estrogen and progesterone receptors’ ligand binding domains. Proc Natl Acad Sci U S A 95:5998–6003
Tong W, Perkins R, Xing L, Welsh WJ, Sheehan DM (1997) QSAR Models for binding of estrogenic compounds to estrogen receptor α and β subtypes. Endocrinology 138:4022–4025
Waller CL, Juma BW, Gray LE Jr, Kelce WR (1996) Three-dimensional quantitative structure–activity relationships for androgen receptor ligands. Toxicol Appl Pharmacol 137:219–227
Williams SP, Sigler PB (1998) Atomic structure of progesterone complexed with its receptor. Nature 393:392–396
Wurtz J-M, Egner U, Heinrich N, Moras D, Mueller-Fahrnow A (1998) Three-dimensional models of estrogen receptor ligand binding domain complexes, based on related crystal structures and mutational and structure–activity relationship data. J Med Chem 41:1803–1814
Yamagishi K, Yamamoto K, Yamada S, Tokiwa H (2006) Function of key residues in the ligand-binding pocket of vitamin D receptor: fragment molecular orbital–interfragment interaction energy analysis. Chem Phys Lett 420:465–468
Yamagishi K, Yamamoto K, Mochizuki Y, Nakano T, Yamada S, Tokiwa H (2007) Flexible ligand recognition of peroxisome proliferators-activated receptor-γ(PPAR-γ). Bioch Biophys Res Comm: submitted
Yamamoto K, Abe D, Yoshimoto N, Choi M, Yamagishi K, Tokiwa H, Shimizu M, Makishima M, Yamada S (2006) Vitamin D receptor: ligand recognition and allosteric network. J Med Chem 46:1313–1324
Acknowledgment
The authors thank Prof. Shizuo Yamada (University of Shizuoka) for his kind encouragement. The work reported here was supported primarily by Frontier Project “Adaptation and Evolution of Extremophile” from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was also partially supported by the “Revolutionary Simulation Software for 21st Century” (RSS21) project operated by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and the CREST project operated by the Japan Science and Technology Agency (JST).
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Harada, T., Yamagishi, K., Nakano, T. et al. Ab initio fragment molecular orbital study of ligand binding to human progesterone receptor ligand-binding domain. Naunyn-Schmied Arch Pharmacol 377, 607–615 (2008). https://doi.org/10.1007/s00210-008-0268-9
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DOI: https://doi.org/10.1007/s00210-008-0268-9