在拉伸、扭转约束的DNA中序列依赖性结构基序的出现
The emergence of sequence-dependent structural motifs in stretched, torsionally constrained DNA
摘要：
DNA的双螺旋结构是由典型的碱基配对和堆积相互作用产生的。然而，从稳态构象的变化导致细胞中的机械扰动。这些不同的拓扑结构具有生理相关性，但它们对序列的依赖性仍不清楚。在这里，我们使用分子动力学模拟表明，序列差异导致显着不同的结构基序后，生理扭曲和拉伸。我们在四种不同的DNA序列（（AA）12，（AT）12，（GG）12和（GC）12）上模拟过延伸，超螺旋密度在生理范围内。我们发现，DNA变性在大多数拉伸模拟，令人惊讶的是，包括那些过度扭曲的DNA。观察到富含GC的序列比富含AT的序列更稳定，特异性反应依赖于碱基对排序。此外，我们发现，（AT）12形成稳定的周期性结构与非典型的氢键在某些区域和非典型的堆叠在其他地区，而（GC）12形成一个堆叠基序的四个碱基对的超螺旋密度无关。我们的研究结果表明，20-30%的DNA延伸足以打破B-DNA周围和显着高于细胞超螺旋，DNA序列是理解机械应力下的结构变化至关重要。我们的发现对所有细胞中与DNA相互作用的蛋白质机制的活动具有重要意义。
英文摘要：
The double-helical structure of DNA results from canonical base pairing and stacking interactions. However, variations from steady-state conformations result from mechanical perturbations in cells. These different topologies have physiological relevance but their dependence on sequence remains unclear. Here, we use molecular dynamics simulations to show that sequence differences result in markedly different structural motifs upon physiological twisting and stretching. We simulated overextension on four different sequences of DNA ((AA)12, (AT)12, (GG)12 and (GC)12) with supercoiling densities within the physiological range. We found that DNA denatures in the majority of stretching simulations, surprisingly including those with overtwisted DNA. GC-rich sequences were observed to be more stable than AT-rich, with the specific response dependent on base pair ordering. Furthermore, we found that (AT)12 forms stable periodic structures with non-canonical hydrogen bonds in some regions and non-canonical stacking in others, whereas (GC)12 forms a stacking motif of four base pairs independent of supercoiling density. Our results demonstrate that 20-30% DNA extension is sufficient for breaking B-DNA around and significantly above cellular supercoiling, and that the DNA sequence is crucial for understanding structural changes under mechanical stress. Our findings have important implications for the activities of protein machinery interacting with DNA in all cells.
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