Molecular Dynamics of a kB DNA Element: Base Flipping via Cross-strand Intercalative Stacking in a Microsecond-scale Simulation

TL;DR

This study uses microsecond-scale molecular dynamics simulations to reveal novel DNA conformations, including base flipping and intercalative stacking, providing insights into DNA dynamics relevant for protein recognition.

Contribution

The paper presents the first microsecond-scale simulations of a kB DNA element, uncovering new conformational states and dynamic behaviors relevant to transcription factor binding.

Findings

Identification of a novel cross-strand intercalative stacking conformation.

Observation of spontaneous base flipping within the DNA duplex.

Implications for NF-kB recognition mechanisms.

Abstract

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 'kB' family of genetic regulatory elements in particular, we performed molecular dynamics simulations of a 20-base pair DNA encompassing a cognate kB site recognized by the proto-oncogenic 'c-Rel' subfamily of NF-kB transcription factors. Simulations of the kB 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 ~ 0.7 us and characterized by cross-strand intercalative stacking of nucleotides within a longitudinally-sheared base pair, followed (at ~ 1 us) by spontaneous base flipping of a neighboring thymine within the A-rich duplex. Results and predictions from the us-scale simulation include implications for a dynamical NF-kB recognition motif, and are amenable to testing and further exploration via specific experimental approaches that are suggested herein.