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Nucleic Acids Research Advance Access published online on November 26, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm892
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© 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.

Computational Biology

Indirect readout in drug-DNA recognition: role of sequence-dependent DNA conformation

Marcos J. Araúzo-Bravo and Akinori Sarai*

Department of Biosciences and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka, 820-8502, Japan

*To whom correspondence should be addressed. Tel: +(81) 0948-29-7811; Fax: +(81) 0948-29-7841; Email: sarai{at}bio.kyutech.ac.jp

Received July 6, 2007. Revised September 22, 2007. Accepted October 3, 2007.

DNA-binding drugs have numerous applications in the engineered gene regulation. However, the drug-DNA recognition mechanism is poorly understood. Drugs can recognize specific DNA sequences not only through direct contacts but also indirectly through sequence-dependent conformation, in a similar manner to the indirect readout mechanism in protein-DNA recognition. We used a knowledge-based technique that takes advantage of known DNA structures to evaluate the conformational energies. We built a dataset of non-redundant free B-DNA crystal structures to calculate the distributions of adjacent base-step and base-pair conformations, and estimated the effective harmonic potentials of mean force (PMF). These PMFs were used to calculate the conformational energy of drug-DNA complexes, and the Z-score as a measure of the binding specificity. Comparing the Z-scores for drug-DNA complexes with those for free DNA structures with the same sequence, we observed that in several cases the Z-scores became more negative upon drug binding. Furthermore, the specificity is position-dependent within the drug-bound region of DNA. These results suggest that DNA conformation plays an important role in the drug-DNA recognition. The presented method provides a tool for the analysis of drug-DNA recognition and can facilitate the development of drugs for targeting a specific DNA sequence.


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