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Nucleic Acids Research Advance Access originally published online on April 16, 2007
Nucleic Acids Research 2007 35(9):3032-3038; doi:10.1093/nar/gkm199
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Nucleic Acids Research, 2007, Vol. 35, No. 9 3032-3038
© 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.

Structural Biology

The open state of human topoisomerase I as probed by molecular dynamics simulation

Giovanni Chillemi1, Alessandro Bruselles2, Paola Fiorani2, Susana Bueno1 and Alessandro Desideri2,*

1CASPUR Inter-University Consortium for the Application of Super-Computing for Universities and Research, Via dei Tizii 6, Rome 00185, Italy and 2INFM National Institute for the Physics of Matter, interdisciplinary Centre of Bioinformatics and Biostatistics and Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, Rome 00133, Italy

*To whom correspondence should be addressed. Tel: +39 0672594376; Fax: +39 062022798; Email: desideri{at}uniroma2.it

Received February 23, 2007. Revised March 20, 2007. Accepted March 21, 2007.

The open state of human topoisomerase I has been probed by molecular dynamics simulation, starting from the coordinates of the closed structure of the protein complexed with DNA, after elimination of the 22-bp DNA duplex oligonucleotide. A repulsion force between the two lips of the protein has been introduced for a short time to induce destabilization of the local minimum, after which an unperturbed simulation has been carried out for 10 ns. The simulation shows that the protein undergoes a large conformational change due to rearrangements in the orientation of the protein domains, which however move as a coherent unit, fully maintaining their secondary and tertiary structures. Despite movements between the domains as large as 80–90 Å, the catalytic pentad remains preassembled, the largest deviation of the active site backbone atoms from the starting crystallographic structure being only 1.7 Å. Electrostatic calculation of the open protein structure shows that the protein displays a vast positive region with the active site residues located nearly at its center, in a conformation perfectly suited to interact with the negatively charged supercoiled DNA substrate.


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G. Chillemi, I. D'Annessa, P. Fiorani, C. Losasso, P. Benedetti, and A. Desideri
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[Abstract] [Full Text] [PDF]


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