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eE-Motif Structures in DNA

eE-Motif Structures in DNA. Kathryn Iverson USC Health Sciences Center and School of Pharmacy SoCalBSI 2007. Outline. E-motif structure Project objectives Methods Working results. G. C. C. G. C. C. 5’. CGCCGCCG CCGCCGCC G C C GCCGCCG. CCGCCGCCG. C. G. GGCGGCGGC. C.

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eE-Motif Structures in DNA

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  1. eE-Motif Structures in DNA Kathryn Iverson USC Health Sciences Center and School of Pharmacy SoCalBSI 2007

  2. Outline • E-motif structure • Project objectives • Methods • Working results

  3. G C C G C C 5’ CGCCGCCG CCGCCGCC G C CGCCGCCG CCGCCGCCG C G GGCGGCGGC C GGCG G GCGGCGGCGGCGGCGG CGGCGGC 5’ C G C C G G C G G C G G G C Hairpins formed by GCC repeats

  4. 5’ C GC CG GC CG C 5’ C C

  5. E-motif Structure • Extra-helical cytosines • Extra-helical cytosines from first GCC and third GCC repeats are interacting • Stacking between G-C

  6. Fragile X • Is the most common forms of inherited mental retardation. 1 in 2000 boys and 1 in 4000 girls are afflicted and 1 in 260 women are carriers1 • July 22, National Fragile X Awareness Day • Characterized by the expansion of GCC repeat in the 5’ untranslated region of the FMR1 gene 1. http://www.conquerfragilex.org/about.php

  7. Objectives of Project • Accurate model of eE-motif structure • Knowledge of extra-helical cytosine structures • Insight into Fragile X syndrome • Therapeutic targets

  8. Methods • Generate NASDAC input files • Run energy minimization on the structures using AMBER • Molecular dynamics modeling with restraints in AMBER

  9. Generation of pdb files • User enters how many GCC repeats • Option to protonate one of cytosines • What parameter to vary and within what range • Create data.in file, run NASDAC and produce .pdb file

  10. Minimization Without Restraints • G-C base pairs no longer close enough to hydrogen bond • Stacking of extra-helical cytosines

  11. Restraints • Hydrogen bonding distance between G and C base pairs • Distance between N2 atoms in G-C base pairs • Torsion angle for G-C base pairs • Distance between extra-helical cytosines

  12. eE-Motif with Restraints • Extra-helical cytosines are in the same plane • Hydrogen bonding

  13. Acknowledgements • Thank you to Dr. Ian Haworth and Dr. Rebecca Romero for their guidance and advice throughout the project • USC Health Sciences Center and School of Pharmacy • Program leaders and faculty of SoCalBSI • SoCalBSI participants • Cal State LA

  14. Questions?

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