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Nucleic Acids Research Advance Access published online on July 24, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn473
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© 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.

Structural Biology

Molecular dynamics of a {kappa}B DNA element: base flipping via cross-strand intercalative stacking in a microsecond-scale simulation

Cameron Mura1,* and J. Andrew McCammon1,2

1Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA 92093-0365 and 2Howard Hughes Medical Institute and Department of Pharmacology, University of California, San Diego; La Jolla, CA 92093-0636, USA

*To whom correspondence should be addressed: Tel: +1 434 924 7824; Fax: +1 434 924 3710; Email: cmura{at}virginia.edu

Received May 13, 2008. Revised July 3, 2008. Accepted July 7, 2008.

The sequence-dependent structural variability and conformational dynamics of DNA play pivotal roles in many biological milieus, such as in the site-specific binding of transcription factors to target regulatory elements. To better understand DNA structure, function, and dynamics in general, and protein···DNA recognition in the ‘{kappa}B’ family of genetic regulatory elements in particular, we performed molecular dynamics simulations of a 20-bp DNA encompassing a cognate {kappa}B site recognized by the proto-oncogenic ‘c-Rel’ subfamily of NF-{kappa}B transcription factors. Simulations of the {kappa}B DNA in explicit water were extended to microsecond duration, providing a broad, atomically detailed glimpse into the structural and dynamical behavior of double helical DNA over many timescales. Of particular note, novel (and structurally plausible) conformations of DNA developed only at the long times sampled in this simulation—including a peculiar state arising at {approx}0.7 µs and characterized by cross-strand intercalative stacking of nucleotides within a longitudinally sheared base pair, followed (at {approx}1 µs) by spontaneous base flipping of a neighboring thymine within the A-rich duplex. Results and predictions from the microsecond-scale simulation include implications for a dynamical NF-{kappa}B recognition motif, and are amenable to testing and further exploration via specific experimental approaches that are suggested herein.

Present address: Cameron Mura, Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319, USA


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