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

 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

Molecules being prepared in our laboratory

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

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

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

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

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

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