Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Department of Biochemistry and Biomedicine, University of Barcelona, Barcelona, Spain.
J Mol Biol. 2019 Sep 6;431(19):3845-3859. doi: 10.1016/j.jmb.2019.07.021. Epub 2019 Jul 17.
The rules governing sequence-specific DNA-protein recognition are under a long-standing debate regarding the prevalence of base versus shape readout mechanisms to explain sequence specificity and of the conformational selection versus induced fit binding paradigms to explain binding-related conformational changes in DNA. Using a combination of atomistic simulations on a subset of representative sequences and mesoscopic simulations at the protein-DNA interactome level, we demonstrate the prevalence of the shape readout model in determining sequence-specificity and of the conformational selection paradigm in defining the general mechanism for binding-related conformational changes in DNA. Our results suggest that the DNA uses a double mechanism to adapt its structure to the protein: it moves along the easiest deformation modes to approach the bioactive conformation, while final adjustments require localized rearrangements at the base-pair step and backbone level. Our study highlights the large impact of B-DNA dynamics in modulating DNA-protein binding.
关于序列特异性 DNA-蛋白质识别的规则，长期以来一直存在着关于碱基与形状读取机制的争论，以解释序列特异性，以及构象选择与诱导契合结合范例，以解释 DNA 结合相关构象变化。本研究使用一组代表性序列的原子模拟和蛋白质-DNA 相互作用组水平的介观模拟的组合，证明了形状读取模型在确定序列特异性方面的普遍性，以及构象选择范例在定义 DNA 结合相关构象变化的一般机制方面的普遍性。我们的结果表明，DNA 使用双重机制来使自身结构适应蛋白质：它沿着最容易的变形模式移动，以接近生物活性构象，而最终的调整需要在碱基对步骤和骨架水平上进行局部重排。我们的研究强调了 B-DNA 动力学在调节 DNA-蛋白质结合中的重要作用。
