ABB  Vol.2 No.5 , October 2011
MD Simulations of the P53 oncoprotein structure: the effect of the Arg273→His mutation on the DNA binding domain
ABSTRACT
A comparative molecular dynamics (MD) simulation study was performed on the p53 oncoprotein to investigate the effect of the Arg273His (R273H) mutation on the p53→DNA Binding Domain (DBD). The two p53 dimer structures of the wild-type and mutant Arg273His (R273H) were simulated with the same thermodynamic and environmental parameters. The obtained results demonstrate that the induced Arg273His mutation has a considerable effect on the p53→DNA close contact interaction and changes the picture of hydrogen formation. The Arg273His mutation, in some cases, destroys the existing native hydrogen bond, but, in other cases, forms a strong p53→DNA hydrogen bond, which is not proper for the native protein. The MD simulation results illustrate some molecular mechanism of the conformational changes of the Arg273His key amino acid residue in the p53→DNA binding domain, which might be important for the understanding of the physiological functioning of the p53 protein and the origin of cancer.

Cite this paper
nullKholmurodov, K. , Dushanov, E. and Yasuoka, K. (2011) MD Simulations of the P53 oncoprotein structure: the effect of the Arg273→His mutation on the DNA binding domain. Advances in Bioscience and Biotechnology, 2, 330-335. doi: 10.4236/abb.2011.25048.
References
[1]   Kern S.E., Kinzler K.W., Bruskin A., Jarosz D., Friedman P., Prives C., Vogelstein B., “Identification of p53 as a sequence-specific DNA-binding protein”. Science, 252, 1991, (5013): 170811.

[2]   Maltzman W., Czyzyk L., “UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells”. Mol. Cell. Biol., 4, 1984, (9): 168994.

[3]   Chumakov P.M., Iotsova V.S., Georgiev G.P., “Isolation of a plasmid clone containing the mRNA sequence for mouse nonviral Tantigen” (in Russian). Dokl. Akad. Nauk SSSR, 267, 1982, (5): 12725.

[4]   Vinall R.L, Tepper C.G., Shi X.-B., Xue L.A., Gandour- Edwards R. and de Vere White R.W., “The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7”. Oncogene, 25, 2006, 2082- 2093.

[5]   Joerger A.C., Fersht A.R., “Structural biology of the tumor suppressor p53”. Annu. Rev. Biochem., 77, 2008, 557-582.

[6]   Ma B. and Levine A.J., “Probing potential binding modes of the p53 tetramer to DNA based on the symmetries encoded in p53 response elements”. Nucleic Acids Res., 35, 2007; (22): 7733-7747.

[7]   Song H., Hollstein M. and Xu Y., “p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM”. Nature Cell Biology, 9, 2007, 573-580.

[8]   Pan Y. and Nussinov R., “Structural Basis for p53 Binding- induced DNA Bending”. The Journal of Biological Chemistry, 282, 2007, 691-699.

[9]   Lu Q., Tan Yu.-H., and Luo R., “Molecular Dynamics Simulations of p53 DNA-Binding Domain”. J. Phys. Chem. B, 111, 2007, 11538-11545.

[10]   Zhou Z., Li Y. “Molecular dynamics simulation of S100B protein to explore ligand blockage of the interaction with p53 protein”. J. Comput. Aided Mol. Des., 23, 2009; (10): 705-714.

[11]   Wang J., Cao Z. and Li S., “Molecular Dynamics Simulations of Intrinsically Disordered Proteins in Human Diseases”. Current Computer-Aided Drug Design, 5, 2009, 280-287.

[12]   van Dieck J., Brandt T., Teufel D.P., Veprintsev D.B., Joerger A.C., Fersht A.R., “Molecular basis of S100 proteins interacting with the p53 homologs p63 and p73”. Oncogene, 8, 2010, 29(14): 2024-35.

[13]   Ang H.C., Joerger A.C., Mayer S., Fersht A.R., “Effects of common cancer mutations on stability and DNA binding of full-length p53 compared with isolated core domains”. J. Biol. Chem., 281, 2006, (31): 21934-41.

[14]   Joerger A.C., Ang H.C., Veprintsev D.B., Blair C.M., Fersht A.R., “Structures of p53 cancer mutants and mechanism of rescue by second-site suppressor mutations”. J. Biol. Chem., 280, 2005, (16): 16030-16037.

[15]   Branden C. and Tooze J., “Introduction to Protein Science, Second Edition”. Garland Publishing, New York, 1999.; http://en.wikipedia.org/wiki/Essential_amino_acid

[16]   Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.R., Cheatham, T.E., DeBolt, S., Ferguson, D., Seibel, G., Kollman, P., “AMBER, a computer program for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to elucidate the structures and energies of molecules”. Comp. Phys. Commun., 91, 1995, 1-41.

[17]   Case D.C., Pearlman D.A., Caldwell J.W., Cheatham III T.E., Ross W.S., Simmerling C.L., Darden T.A., Merz K.M., Stanton R.V., Cheng A.L., Vincent J.J., Crowley M., Ferguson D.M., Radmer R.J., Seibel G.L., Singh U.C., Weiner P.K., Kollman P.A., AMBER, 2010.

[18]   Essmann U., Perera L., Berkowitz M.L., Darden T., Lee H. and Pedersen L.G., J. Chem. Phys., 103, 1995, 8577- 8592.

[19]   Narumi T., Susukita R., Ebisuzaki T., McNiven G. and Elmergreen B., “Molecular Dynamics Machine: Special- purpose Computer for Molecular Dynamics Simulations”. Molecular Simulation, 21, 1999, 401-408.; Narumi T., Susukita R., Furusawa H., Yasuoka K., Kawai A., Koishi T., Ebisuzaki T., MDM version of AMBER, 2000.; Narumi, T., Susukita, R., Furusawa, H., Ebisuzaki, T., “46 Tflops Special-purpose Computer for Molecular Dynamics Simulations: (WINE-2)”. Proc. 5th Int. Conf. on Signal Processing. Beijing., 2000,

[20]   Ponder, J.W., Case, D.A.,”Force fields for protein simulations”. Adv. Prot. Chem., 66, 2003, 27-85.

[21]   Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, Jr.K.M., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W., Kollman, P.A., “A second Generation forth field for the simulation of Proteins and Nucleic Acids”. J. Am. Chem. Soc., 117, 1995, 5179-5197.

[22]   Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., “Comparison of simple potential functions for simulating liquid water”. J. Chem. Phys., 79, 1983, 926-935.

[23]   Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F., DiNola, A., Haak, J.R., “Molecular dynamics with coupling to an external bath”. J. Chem. Phys., 81, 1984, 3684- 3690.

[24]   Ryckaert, J.P., Ciccotti, G., Berendsen, H.J.C., “Numerical integration of the Cartesian equations of proteins and nucleic acids”. J. Comput. Phys., 23, 1997, 327-341.

[25]   Sayle, R.A., Milner-White, E.J., “RasMol: Biomolecular graphics for all”. Trends in Biochem. Sci., 20, 1995, 374- 376.

[26]   Koradi, R., Billeter, M., Wuthrich, K., “MOLMOL: a program for display and analysis of macromolecular structure”. J. Mol. Graphics, 4, 1996, 51-55.

[27]   Humphrey, W., Dalke, A. and Schulten, K., “VMD – Visual Molecular Dynamics”. J. Molec. Graphics, 14, 1996, 33-38.

[28]   Kholmirzo Kholmurodov (Ed.), “Molecular Dynamics of Nanobistructures”, Nova Science Publishers Ltd., 2011, 230p., ISBN: 978-1-61324-320-6.

[29]   Kholmurodov, K.T., Hirano, Y., Ebisuzaki, T., “MD Simulations on the Influence of Disease-Related Amino Acid Mutations in the Human Prion Protein”. Chem-Bio Informatics Journal, 3, No. 2, 2003, 86-95.

[30]   K. Kholmurodov, W. Smith, K. Yasuoka, T. Darden and T. Ebisuzaki, J. Comput. Chem., 21, 2000, 1187.3.

 
 
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