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A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant. Article by: Garn F. Holman, Maha Zewail-Foote, Amy Rhoden Smith, Kenneth A. Johnson, and Brent L. Iverson Presentation by: Maggie Palmer and Joy Uyanwune.

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  1. A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant Article by: Garn F. Holman, Maha Zewail-Foote, Amy Rhoden Smith, Kenneth A. Johnson, and Brent L. Iverson Presentation by: Maggie Palmer and Joy Uyanwune

  2. “If you think of DNA as a spiral staircase imagine sliding something between the steps. That’s what our molecule does. It can be visualized as binding to DNA in the same way a snake might climb a ladder.” ~Brent L. Iverson Photo/quote source: http://web5.cns.utexas.edu/news/2012/02/dna-wranglers/

  3. What is a threading Intercalator? • A molecule that is capable of binding and inserting itself into a DNA sequence. • Sequence specific binding • 5’ – GATAAGTACTTATC – 3’ http://sketchfu.com/drawing/1919089-snake-and-ladder-

  4. Why is this important? Molecules that can bind to DNA can interfere and possibly control transcription, repair and replication. Possible cure for chronic diseases Photo source: http://www.nature.com/nchem/journal/v3/n11/full/nchem.1173.html

  5. Tetra-intercalator 3 • Designed with a minor-major-minor groove binding linkers • Tetra-intercalator 3 was designed using studies done previously on 1 and 2. • -βAla3-Lys- is the minor groove binding linker taken from bisintercalator 2. • Adipic acid with 2 L-Lysine residues are part of the major groove binding linker. • Causes C2 symmetry that simplifies the NMF • 14 Basepair binding site. • Pieced together by connecting together NDI units

  6. How to make a tetra-intercalator http://io9.com/5885072/dna+tangling-molecule-could-revolutionize-treatments-for-cancer-and-hiv Naphthalenetetracarboxylic diimide (NDI) molecules are chained together with resin beads. Reactions are ran directly on the resin beads until the molecule is large enough to cleave. “The larger molecule is composed of little pieces that bind to short segments of DNA, kind of life the way Legos fit together” ~Amy Rhoden-Smith

  7. Napthalenetetracarboxylic diimide • NDI units can be pieced together in different ways • The different arrangements then must be scanned in order to find the sequences the new arrangements will select for http://www.chemspider.com/Chemical-Structure.24771033.html

  8. Picture source: Lee et.al

  9. Slowed Dissociation Rate 3 will have a slow dissociation from its preferred DNA binding site. In order for 3 to fully dissociate from DNA it the individual units will have to dissociate in an ordered fashion before rebinding occurs. Photo source: http://mysam.net/wiki/index.php/%ED%8A%B9%EC%88%98%EA%B8%B0%EB%8A%A5:NatureNews?reply=4&page=1

  10. Experiment Section

  11. Threading bisintercalators 1&2 • figure 1a picture here • figure 1b picture here.

  12. Tetra-Intercalator 3 Figure 1c

  13. Threading Polyintercalator of 3 Show extremely slow dissociation from its preferred DNA sequence. Association is suspected to be rapid result of electrostatic interactions.

  14. DNase/Footprinting Figure 2

  15. Dissociation Kinetics

  16. Nonspecific Dissociation Kinetic Stopped Flow Method

  17. Association rate measurements 1H NMR spectroscopy, Gel mobility shift assay and stopped-flow ultraviolet–visible spectroscopy.

  18. Stopped Flow Ultraviolet-visible Spectroscopy Figure 5

  19. Conclusion Tetra-intercalator 3 has a slow dissociation rate. The half life of tetra-intercalator 3 was found to be16 days. Tetra-intercalator 3 also shows a rapid association rate to its target specific sequence driven by electrostatic attraction. Suspected to have the same threading topology on long pieces of DNA.

  20. Work Cited Holman, Garen G., Zewail-Foote, Maha; Smith, Amy Rhoden; Johnson, Kenneth A.; & Iverson, Brent L. 2001. A Sequence-specific threading teta-intercalator with an extremely slow dissociation rate constant. Nature Chemistry. 3; 875-881 Lee, J.; Guelev, V.; Sorey, S.;Hoffman, D.W. &Iverson, B.L.2004 NMR Structural analysis of a modular threading tetraintercalator bound to DNA. J. Am. Chem. Soc, 126; 14036-14042

  21. Work Cited Cont. Oppenheimer, Daniel. 2012 DNA- Targeting Molecule has Potential to Help Treat Genetic Disease and HIV. Online at. http://web5.cns.utexas.edu/news/2012/02/dna-wranglers

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