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Computational Modeling of DNA Binding Molecules

Computational Modeling of DNA Binding Molecules. Charles Brian Kelly Department of Chemistry and Biochemistry University of North Carolina Wilmington Wilmington, NC 28403. Me-Lex: A DNA damaging agent. Me-Lex binds in the minor groove of DNA

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Computational Modeling of DNA Binding Molecules

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  1. Computational Modeling of DNA Binding Molecules Charles Brian Kelly Department of Chemistry and Biochemistry University of North Carolina Wilmington Wilmington, NC 28403

  2. Me-Lex: A DNA damaging agent • Me-Lex binds in the minor groove of DNA • Me-Lex causes specific DNA damage resulting in the death of the cell without any mutations • Me-Lex has potential application in cancer chemotherapy

  3. Molecules being prepared in our laboratory

  4. Objectives • Develop Computational Method of Analysis • Identify Linkers which are favorable for DNA Binding • Identify Linkers which do not favor DNA Binding • Identify what compounds are good candidates for synthesis in the laboratory

  5. Methods • Import structure from protein data bank into computational program (Insight II) • Modify structure to represent compounds for project Crystal structure imported from Brookhaven protein data bank

  6. Methods (cont.) • Subject modified structure to molecular dynamics calculations (AMBER) • Calculations indicate whether new structure energetically favorable or not • Calculations are being conducted in collaboration with Dr. Lee Bartolotti (ECU) using SGI Origin 350 High Performance Computer Me-Lex with attached linker and glucose ring (modified in INSIGHT II)

  7. Preliminary Work • 14 different modified structures have been created using INSIGHTII • Parameters have been defined for Me-Lex • Molecular dynamics calculations have been initiated on one compound

  8. ACKNOWLEDGEMENTS: • Dr. Sridhar Varadarajan • Dr. Libero Bartolotti ( East Carolina University) • Dr. Ned Martin • Heather Hill

  9. REFERENCES • Zhang, Y., Chen, F.-X., Mehta, P., and Gold, B., Biochemistry32, 7954-7965. 1993. • Varadarajan, S., Dharini, S., Dande, P., Settles, S., Chen, F.-X., Gilberto, F., and Gold, B., Biochemistry42, 14318-14327, 2003. • Henry-Amar, M., and Dietrich, P. Y., Eds., W. B. Saunders Hematology/Oncology Clinics of North America, Therapy-Related Second Malignancies, 7, Philadelphia, 1993. • Ferguson, A. T., Lapidus, R. G., Davidson, N. E., The regulation of estrogen receptor expression and function in human breast cancer, Cancer treatment and research,94 255- 278, 1998. • Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.R., Cheatham III,, T.E., DeBolt, S.Ferguson, D., Seibel, G., and 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, 1-41, 1995. • Tsui, V., and Case, D.A., Theory and applications of the generalized Born solvation model in macromolecular simulations. Biopolymers (Nucl. Acid. Sci.)56, 275-291, 2001. • Onufriev, Alexey, Bashford, D., and Case, D.A., “Exploring native states and large-scale conformational changes with a modified Generalized Born model.”, Proteins, 55, 383-394, 2004.

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