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Nucleic Acids Research 2005 33(2):725-733; doi:10.1093/nar/gki195
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Published online 1 February 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site

Jozica Dolenc, Chris Oostenbrink1, Joze Koller and Wilfred F. van Gunsteren1,*

Faculty of Chemistry and Chemical Technology, University of Ljubljana Askerceva 5, SI-1000 Ljubljana, Slovenia 1 Laboratory of Physical Chemistry, Swiss Federal Institute of Technology ETH-Hönggerberg, CH-8093 Zurich, Switzerland

*To whom correspondence should be addressed. Tel: +41 1632 5501; Fax: +41 1632 1039; Email: wfvgn{at}igc.phys.chem.ethz.ch

Received September 30, 2004. Revised December 24, 2004. Accepted December 24, 2004.

Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG)·d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration. It is shown that even though distamycin is less hydrated than netropsin, the loss of ligand–solvent interactions is very similar for both ligands. The relative mobilities of the ligands in their bound and free forms indicate a larger entropic penalty for distamycin when binding to the minor groove compared with netropsin, partially explaining the lower binding affinity of the distamycin molecule. The detailed structural and energetic insights obtained from the molecular dynamics simulations allow for a better understanding of the factors determining ligand–DNA binding.


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