kB DNA单元的分子动力学：微秒尺度模拟中跨链插入堆积引起的碱基翻转
Molecular Dynamics of a kB DNA Element: Base Flipping via Cross-strand Intercalative Stacking in a Microsecond-scale Simulation
摘要：
DNA的序列依赖性结构变异性和构象动力学在许多生物学环境中起关键作用，例如在转录因子与靶调控元件的位点特异性结合中。为了更好地理解DNA的结构、功能和动力学，特别是“kB”家族遗传调控元件中的蛋白质-DNA识别，我们对20个碱基对的DNA进行了分子动力学模拟，该DNA包含由NF-kB转录因子的原癌基因“c-Rel”亚家族识别的同源kB位点。在明确的水kB DNA的模拟扩展到微秒的持续时间，提供了一个广泛的，原子详细的一瞥到双螺旋DNA的结构和动力学行为在许多时间尺度。特别值得注意的是，新的（和结构上合理的）构象的DNA开发只有在长时间的采样在这个模拟-包括一个特殊的状态出现在约0.7 us，其特征是跨链插入堆叠的核苷酸内的一个剪切的碱基对，随后（约1 us）由一个相邻的胸腺嘧啶内的A-丰富的双链自发碱基翻转。从美国规模的模拟的结果和预测包括动态NF-κ B识别基序的影响，并通过本文建议的具体实验方法进行测试和进一步探索。
英文摘要：
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.
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