Computational Modeling of DNA Binding Molecules
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Transcript of Computational Modeling of DNA Binding Molecules
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Computational Modeling of DNA Binding Molecules
Charles Brian Kelly
Department of Chemistry and BiochemistryUniversity of North Carolina Wilmington
Wilmington, NC 28403
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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
Me-Lex: A DNA damaging agent
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Molecules being prepared in our laboratory
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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
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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
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Methods (cont.)
Me-Lex with attached linker and glucose ring (modified in INSIGHT II)
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
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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
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ACKNOWLEDGEMENTS:
Dr. Sridhar VaradarajanDr. Sridhar Varadarajan
Dr. Libero Bartolotti ( East Carolina Dr. Libero Bartolotti ( East Carolina University)University)
Dr. Ned MartinDr. Ned Martin
Heather HillHeather Hill
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REFERENCES
Zhang, Y., Chen, F.-X., Mehta, P., and Gold, B., Biochemistry 32, 7954-7965. 1993. Varadarajan, S., Dharini, S., Dande, P., Settles, S., Chen, F.-X., Gilberto, F., and
Gold, B., Biochemistry 42, 14318-14327, 2003. Henry-Amar, M., and Dietrich, P. Y., Eds., W. B. Saunders Hematology/Oncology
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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.