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Nucleic Acids Research 2005 33(20):6621-6634; doi:10.1093/nar/gki935
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Published online 27 November 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}oxfordjournals.org

Article

Rotation of DNA around intact strand in human topoisomerase I implies distinct mechanisms for positive and negative supercoil relaxation

Levent Sari and Ioan Andricioaei*

Department of Chemistry and The Program in Bioinformatics, University of Michigan Ann Arbor, MI 48109, USA

*To whom correspondence should be addressed. Tel: +1 734 763 8013; Fax: +1 734 615 6553; Email: andricio{at}umich.edu

Received June 9, 2005. Revised August 1, 2005. Accepted October 12, 2005.

Topoisomerases are enzymes of quintessence to the upkeep of superhelical DNA, and are vital for replication, transcription and recombination. An atomic-resolution model for human topoisomerase I in covalent complex with DNA is simulated using molecular dynamics with external potentials that mimic torque and bias the DNA duplex downstream of a single-strand cut to rotate around the intact strand, according to the prevailing enzymatic mechanism. The simulations reveal the first dynamical picture of how topoisomerase accommodates large-scale motion of DNA as it changes its supercoiling state, and indicate that relaxation of positive and negative supercoils are fundamentally different. To relax positive supercoils, two separate domains (the ‘lips’) of the protein open up by about 10–14 Å, whereas to relax negative supercoils, a continuous loop connecting the upper and lower parts (and which was a hinge for opening the lips) stretches about 12 Å while the lips remain unseparated. Normal mode analysis is additionally used to characterize the functional flexibility of the protein. Remarkably, the same combination of low-frequency eigenvectors exhibit the dominant contribution for both rotation mechanisms through a see-saw motion. The simulated mechanisms suggest mutations to control the relaxation of either type of supercoiling selectively and advance a hypothesis for the debated role of the N-terminal domain in supercoil relaxation.


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