Computational Modeling of DNA Binding Molecules

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Computational Modeling of DNA Binding Molecules

• Charles Brian Kelly
• Department of Chemistry and Biochemistry
• University of North Carolina Wilmington
• Wilmington, NC 28403

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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

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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.)

• 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)
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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 Varadarajan
• Dr. Libero Bartolotti ( East Carolina University)
• Dr. Ned Martin
• Heather Hill

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