Nucleic Acids Research Advance Access originally published online on July 25, 2008
Nucleic Acids Research 2008 36(15):5000-5012; doi:10.1093/nar/gkn392
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Nucleic Acids Research, 2008, Vol. 36, No. 15 5000-5012
© 2008 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.
Structural Biology |
Selective recognition of pyrimidine–pyrimidine DNA mismatches by distance-constrained macrocyclic bis-intercalators
1Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany, 2Department of Chemistry, Mass Spectrometry Laboratory, University of Liège, B-4000 Liège, Belgium and 3Institut Curie, UMR176 CNRS, Centre Universitaire, F-91405 Orsay, France
*To whom correspondence should be addressed. Tel: +33 169 86 30 86; +33 169 07 53 81; Email: marie-paule.teulade-fichou{at}curie.fr
Correspondence may also be addressed to Elmar Weinhold. Email: elmar.weinhold{at}oc.rwth-aachen.de
Received April 28, 2008. Revised May 30, 2008. Accepted June 4, 2008.
Binding of three macrocyclic bis-intercalators, derivatives of acridine and naphthalene, and two acyclic model compounds to mismatch-containing and matched duplex oligodeoxynucleotides was analyzed by thermal denaturation experiments, electrospray ionization mass spectrometry studies (ESI-MS) and fluorescent intercalator displacement (FID) titrations. The macrocyclic bis-intercalators bind to duplexes containing mismatched thymine bases with high selectivity over the fully matched ones, whereas the acyclic model compounds are much less selective and strongly bind to the matched DNA. Moreover, the results from thermal denaturation experiments are in very good agreement with the binding affinities obtained by ESI-MS and FID measurements. The FID results also demonstrate that the macrocyclic naphthalene derivative BisNP preferentially binds to pyrimidine–pyrimidine mismatches compared to all other possible base mismatches. This ligand also efficiently competes with a DNA enzyme (M.TaqI) for binding to a duplex with a TT-mismatch, as shown by competitive fluorescence titrations. Altogether, our results demonstrate that macrocyclic distance-constrained bis-intercalators are efficient and selective mismatch-binding ligands that can interfere with mismatch-binding enzymes.