Published online 2 April 2004
Nucleic Acids Research, 2004, Vol. 32, No. 6 2000-2007
© 2004 Oxford University Press
Energetic basis for selective recognition of T·G mismatched base pairs in DNA by imidazole-rich polyamides
1 Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA, 2 Department of Chemistry, Furman University, Greenville, SC 29613, USA and 3 Department of Oncology, Royal Free and University College Medical School, University College London, London W1W 7BS, UK
*To whom correspondence should be addressed. Tel: +1 404 651 3903; Fax: +1 404 651 1416; Email: chewdw{at}panther.gsu.edu
Correspondence may also be addressed to Moses Lee. Tel: +1 864 294 3368; Fax: +1 864 294 3559; Email: moses.lee{at}furman.edu
Received January 8, 2004; Revised and Accepted March 9, 2004
To complement available structure and binding results and to develop a detailed understanding of the basis for selective molecular recognition of T·G mismatches in DNA by imidazole containing polyamides, a full thermodynamic profile for formation of the T·G–polyamide complex has been determined. The amide-linked heterocycles f-ImImIm and f-PyImIm (where f is formamido group, Im is imidazole and Py is pyrrole) were studied by using biosensor-surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) with a T·G mismatch containing DNA hairpin duplex and a similar DNA with only Watson–Crick base pairs. Large negative binding enthalpies for all of the polyamide–DNA complexes indicate that the interactions are enthalpically driven. SPR results show slower complex formation and stronger binding of f-ImImIm to the T·G than to the match site. The thermodynamic analysis indicates that the enhanced binding to the T·G site is the result of better entropic contributions. Negative heat capacity changes for the complex are correlated with calculated solvent accessible surface area changes and indicate hydrophobic contributions to complex formation. DNase I footprinting analysis in a long DNA sequence provided supporting evidence that f-ImImIm binds selectively to T·G mismatch sites.
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