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Nucleic Acids Research 2006 34(9):2550-2557; doi:10.1093/nar/gkl271
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Published online 12 May 2006

© The Author 2006. 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@oxfordjournals.org

Article

Strong physical constraints on sequence-specific target location by proteins on DNA molecules

Henrik Flyvbjerg2,3, Steven A. Keatch1 and David T.F. Dryden1,3,*

1 School of Chemistry, The King's Buildings, The University of Edinburgh Edinburgh, EH9 3JJ, UK 2 Risø National Laboratory, Biosystems Department and Danish Polymer Centre Building BIO-776, PO Box 49, Frederiksborgvej 399, DK-4000 Roskilde, Denmark 3 Isaac Newton Institute for Mathematical Sciences 20 Clarkson Road, Cambridge, CB3 0EH, UK

*To whom correspondence should be adressed. Tel: +0131 650 4735; Fax: +0131 650 6453; Email: David.Dryden{at}ed.ac.uk

Received January 31, 2006. Revised February 26, 2006. Accepted April 3, 2006.

Sequence-specific binding to DNA in the presence of competing non-sequence-specific ligands is a problem faced by proteins in all organisms. It is akin to the problem of parking a truck at a loading bay by the side of a road in the presence of cars parked at random along the road. Cars even partially covering the loading bay prevent correct parking of the truck. Similarly on DNA, non-specific ligands interfere with the binding and function of sequence-specific proteins. We derive a formula for the probability that the loading bay is free from parked cars. The probability depends on the size of the loading bay and allows an estimation of the size of the footprint on the DNA of the sequence-specific protein by assaying protein binding or function in the presence of increasing concentrations of non-specific ligand. Assaying for function gives an ‘activity footprint’; the minimum length of DNA required for function rather than the more commonly measured physical footprint. Assaying the complex type I restriction enzyme, EcoKI, gives an activity footprint of ~66 bp for ATP hydrolysis and 300 bp for the DNA cleavage function which is intimately linked with translocation of DNA by EcoKI. Furthermore, considering the coverage of chromosomal DNA by proteins in vivo, our theory shows that the search for a specific DNA sequence is very difficult; most sites are obscured by parked cars. This effectively rules out any significant role in target location for mechanisms invoking one-dimensional, linear diffusion along DNA.

Present address: Steven A. Keatch Stirling Medical Innovations, Unit 10, Scion House, Stirling University Innovation Park, Stirling, FK9 4NF, UK


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