Nucleic Acids Research Advance Access originally published online on December 17, 2007
Nucleic Acids Research 2008 36(3):897-904; doi:10.1093/nar/gkm1110
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Nucleic Acids Research, 2008, Vol. 36, No. 3 897-904
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
What drives the binding of minor groove-directed ligands to DNA hairpins?
University of Ljubljana, Faculty of Chemistry and Chemical Technology, Askerceva 5, 1000 Ljubljana, Slovenia
*To whom correspondence should be addressed. Tel: +381 1 2419 414; Fax: +386 1 2419 425; Email: jurij.lah{at}fkkt.uni-lj.si
Received August 27, 2007. Revised November 28, 2007. Accepted November 28, 2007.
Understanding the molecular basis of ligand–DNA-binding events, and its application to the rational design of novel drugs, requires knowledge of the structural features and forces that drive the corresponding recognition processes. Existing structural evidence on DNA complexation with classical minor groove-directed ligands and the corresponding studies of binding energetics have suggested that this type of binding can be described as a rigid-body association. In contrast, we show here that the binding-coupled conformational changes may be crucial for the interpretation of DNA (hairpin) association with a classical minor groove binder (netropsin). We found that, although the hairpin form is the only accessible state of ligand-free DNA, its association with the ligand may lead to its transition into a duplex conformation. It appears that formation of the fully ligated duplex from the ligand-free hairpin, occurring via two pathways, is enthalpically driven and accompanied by a significant contribution of the hydrophobic effect. Our thermodynamic and structure-based analysis, together with corresponding theoretical studies, shows that none of the predicted binding steps can be considered as a rigid-body association. In this light we anticipate our thermodynamic approach to be the basis of more sophisticated nucleic acid recognition mechanisms, which take into account the dynamic nature of both the nucleic acid and the ligand molecule.