Molecular dynamics of a kappaB DNA element: base flipping via cross-strand intercalative stacking in a microsecond-scale simulation.

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 'kappaB' family of genetic regulatory elements in particular, we performed molecular dynamics simulations of a 20-bp DNA encompassing a cognate kappaB site recognized by the proto-oncogenic 'c-Rel' subfamily of NF-kappaB transcription factors. Simulations of the kappaB 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 approximately 0.7 micros and characterized by cross-strand intercalative stacking of nucleotides within a longitudinally sheared base pair, followed (at approximately 1 micros) 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-kappaB recognition motif, and are amenable to testing and further exploration via specific experimental approaches that are suggested herein.