Published online 4 July 2006
© 2006 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-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Information-driven protein–DNA docking using HADDOCK: it is a matter of flexibility
NMR Spectroscopy Research Group, Bijvoet Center for Biomolecular Research, Faculty of Sciences, Utrecht University The Netherlands 1 Department of Biochemistry and Biophysics, Oregon State University Corvallis, USA
*To whom correspondence may be addressed. Tel: +31 30 2533859; Fax: +31 30 2537623; Email: a.m.j.j.bonvin{at}chem.uu.nl
Received April 27, 2006. Revised May 16, 2006. Accepted May 18, 2006.
Intrinsic flexibility of DNA has hampered the development of efficient protein–DNA docking methods. In this study we extend HADDOCK (High Ambiguity Driven DOCKing) [C. Dominguez, R. Boelens and A. M. J. J. Bonvin (2003) J. Am. Chem. Soc. 125, 1731–1737] to explicitly deal with DNA flexibility. HADDOCK uses non-structural experimental data to drive the docking during a rigid-body energy minimization, and semi-flexible and water refinement stages. The latter allow for flexibility of all DNA nucleotides and the residues of the protein at the predicted interface. We evaluated our approach on the monomeric repressor–DNA complexes formed by bacteriophage 434 Cro, the Escherichia coli Lac headpiece and bacteriophage P22 Arc. Starting from unbound proteins and canonical B-DNA we correctly predict the correct spatial disposition of the complexes and the specific conformation of the DNA in the published complexes. This information is subsequently used to generate a library of pre-bent and twisted DNA structures that served as input for a second docking round. The resulting top ranking solutions exhibit high similarity to the published complexes in terms of root mean square deviations, intermolecular contacts and DNA conformation. Our two-stage docking method is thus able to successfully predict protein–DNA complexes from unbound constituents using non-structural experimental data to drive the docking.
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