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Nucleic Acids Research Advance Access originally published online on September 18, 2008
Nucleic Acids Research 2008 36(18):5910-5921; doi:10.1093/nar/gkn561
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Nucleic Acids Research, 2008, Vol. 36, No. 18 5910-5921
© 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.

Computational Biology

Dissociation of minor groove binders from DNA: insights from metadynamics simulations

Attilio Vittorio Vargiu1, Paolo Ruggerone1,*, Alessandra Magistrato2 and Paolo Carloni2

1CNR-INFM-SLACS and Department of Physics, University of Cagliari, I-09042 Cagliari and 2SISSA/ISAS and CNR-INFM-DEMOCRITOS, I-34014, Trieste, Italy

*To whom correspondence should be addressed. Tel: +39 070 6754922; Fax: +39 070 510171; Email: paolo.ruggerone{at}dsf.unica.it

Received June 5, 2008. Revised August 19, 2008. Accepted August 19, 2008.

We have used metadynamics to investigate the mechanism of noncovalent dissociation from DNA by two representatives of alkylating and noncovalent minor groove (MG) binders. The compounds are anthramycin in its anhydrous form (IMI) and distamycin A (DST), which differ in mode of binding, size, flexibility and net charge. This choice enables to evaluate the influence of such factors on the mechanism of dissociation. Dissociation of IMI requires an activation free energy of ~12 kcal/mol and occurs via local widening of the MG and loss of contacts between the drug and one DNA strand, along with the insertion of waters in between. The detachment of DST occurs at a larger free energy cost, ~16.5 or ~18 kcal/mol depending on the binding mode. These values compare well with that of 16.6 kcal/mol extracted from stopped-flow experiments. In contrast to IMI, an intermediate is found in which the ligand is anchored to the DNA through its amidinium tail. From this conformation, binding and unbinding occur almost at the same rate. Comparison between DST and with kinetic models for the dissociation of Hoechst 33258 from DNA uncovers common characteristics across different classes of noncovalent MG ligands.


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