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Structural Basis of DNA Recognition by Synthetic Ligands


Kielkopf, Clara Louise (2000) Structural Basis of DNA Recognition by Synthetic Ligands. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/73K1-K290.


The DNA double helix presents functional groups in the major and minor grooves that can be used by ligands for readout of the base pair sequence. The overall flexibility and shape also distinguishes various sequences. Although the information displayed in the major groove is more diverse, small DNA-binding polyamides predictably distinguish all four base pairs in the minor groove. In this work, the structural basis of this recognition has been studied using x-ray crystallographic techniques, and is described for G•C (Chapter 2) and T•A base pairs (Chapter 3-4). The polyamides directly read the DNA sequence using a combination of specific hydrogen bonds and shape selection. A second class of ligands called intercalators bind to DNA via the major groove by slipping a planar aromatic ligand between the bases. Although this shape-selective DNA binding is relatively nonspecific, the substitution of the ancillary ligands on octahedral metallointercalators allows specific sequences to be recognized in the major groove. The high resolution crystal structure of a designed metal complex bound to its target site reveals the nature of these specific contacts, as well as the precise stacking of the ligand between the bases. A detailed understanding of specific DNA recognition by small molecules is important for their further development as tools for molecular biology and medicine. These structures reveal how synthetic ligands can distinguish all four base pairs in both the major and the minor grooves of DNA.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Biology, DNA structure, polyamide, DNA binding, minor groove
Degree Grantor:California Institute of Technology
Major Option:Biology
Minor Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Rees, Douglas C.
Thesis Committee:
  • Dervan, Peter B. (chair)
  • Barton, Jacqueline K.
  • Roberts, Richard W.
  • Bjorkman, Pamela J.
Defense Date:17 August 1999
Record Number:CaltechTHESIS:03302018-093456214
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10783
Deposited By: Bianca Rios
Deposited On:30 Mar 2018 16:54
Last Modified:04 Oct 2019 00:20

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