Krajina Brad A, Spakowitz Andrew J
Department of Chemical Engineering, Stanford University, Stanford, California.
Department of Chemical Engineering, Stanford University, Stanford, California; Department of Applied Physics, Stanford University, Stanford, California; Department of Materials Science and Engineering, Stanford University, Stanford, California; Biophysics Program, Stanford University, Stanford, California.
Biophys J. 2016 Oct 4;111(7):1339-1349. doi: 10.1016/j.bpj.2016.07.045.
Topological constraints, such as those associated with DNA supercoiling, play an integral role in genomic regulation and organization in living systems. However, physical understanding of the principles that underlie DNA organization at biologically relevant length scales remains a formidable challenge. We develop a coarse-grained simulation approach for predicting equilibrium conformations of supercoiled DNA. Our methodology enables the study of supercoiled DNA molecules at greater length scales and supercoiling densities than previously explored by simulation. With this approach, we study the conformational transitions that arise due to supercoiling across the full range of supercoiling densities that are commonly explored by living systems. Simulations of ring DNA molecules with lengths at the scale of topological domains in the Escherichia coli chromosome (∼10 kilobases) reveal large-scale conformational transitions elicited by supercoiling. The conformational transitions result in three supercoiling conformational regimes that are governed by a competition among chiral coils, extended plectonemes, and branched hyper-supercoils. These results capture the nonmonotonic relationship of size versus degree of supercoiling observed in experimental sedimentation studies of supercoiled DNA, and our results provide a physical explanation of the conformational transitions underlying this behavior. The length scales and supercoiling regimes investigated here coincide with those relevant to transcription-coupled remodeling of supercoiled topological domains, and we discuss possible implications of these findings in terms of the interplay between transcription and topology in bacterial chromosome organization.
拓扑约束，例如与DNA超螺旋相关的那些约束，在生命系统的基因组调控和组织中起着不可或缺的作用。然而，对生物相关长度尺度下DNA组织背后原理的物理理解仍然是一项艰巨的挑战。我们开发了一种粗粒度模拟方法来预测超螺旋DNA的平衡构象。我们的方法能够在比以前模拟探索的更大长度尺度和超螺旋密度下研究超螺旋DNA分子。通过这种方法，我们研究了在生命系统通常探索的整个超螺旋密度范围内由于超螺旋引起的构象转变。对大肠杆菌染色体中拓扑结构域尺度长度（约10千碱基）的环状DNA分子的模拟揭示了由超螺旋引发的大规模构象转变。这些构象转变导致了三种超螺旋构象状态，它们由手性螺旋、延伸的麻花状超螺旋和分支的超超螺旋之间的竞争所支配。这些结果捕捉到了在超螺旋DNA的实验沉降研究中观察到的大小与超螺旋程度之间的非单调关系，并且我们的结果为这种行为背后的构象转变提供了物理解释。这里研究的长度尺度和超螺旋状态与超螺旋拓扑结构域转录偶联重塑相关的那些尺度和状态一致，并且我们根据细菌染色体组织中转录与拓扑之间的相互作用讨论了这些发现的可能含义。
