Department of Chemistry, Seoul National University, Seoul 08826, Korea.
J Chem Theory Comput. 2021 Mar 9;17(3):1308-1317. doi: 10.1021/acs.jctc.0c01116. Epub 2021 Feb 11.
Kink formation is essential in highly bent DNA complexed with gene regulatory proteins such as histones to release the bending stress stored within the DNA duplex. Local opening of the double-stranded DNA creates a sharp turn along the specific sequence, which leads to the global bending of the DNA strand. Despite the critical role of kink formation, it is still challenging to predict the position of kink formation for a given DNA sequence. In this study, we propose a theoretical model and perform molecular dynamics simulations to quantify the sequence-dependent kink probability of a strongly bent DNA. By incorporating the elastic bending energy and the sequence-specific thermodynamic parameters, we investigate the importance of the DNA sequence on kink formation. We find that the sequence with TA dinucleotide repeats flanked by GC steps increases the kink propensity by more than an order of magnitude under the same bending stress. The number of base pairs involved in the local opening is found to be coupled with the sequence-specific bubble formation free energy. Our study elucidates the molecular origin of the sequence heterogeneity on kink formation, which is fundamental to understanding protein-DNA recognition.
扭结形成对于高度弯曲的 DNA 与基因调控蛋白（如组蛋白）复合物至关重要，它可以释放 DNA 双螺旋中储存的弯曲应力。双链 DNA 的局部打开会在特定序列上产生急剧的转角，从而导致 DNA 链的整体弯曲。尽管扭结形成具有重要作用，但预测给定 DNA 序列的扭结形成位置仍然具有挑战性。在这项研究中，我们提出了一个理论模型，并进行了分子动力学模拟，以定量研究强弯曲 DNA 的序列依赖性扭结概率。通过结合弹性弯曲能量和序列特异性热力学参数，我们研究了 DNA 序列对扭结形成的重要性。我们发现，在相同的弯曲应力下，由 TA 二核苷酸重复序列侧翼 GC 步组成的序列会使扭结倾向增加一个数量级以上。局部开口涉及的碱基对数量与序列特异性泡形成自由能相关。我们的研究阐明了扭结形成中序列异质性的分子起源，这对于理解蛋白质-DNA 识别至关重要。
