DNA SUPERCOILING--MACROSCOPIC MODELING

DNA超螺旋理论研究的三个目标是： (1)开发毫秒级通用动态方案 流体力学作用下的宏观聚合物模拟 通过曲线拟合技术。(2)发展新机场的扩建工程 用于DNA TO动态模拟的均质弹性棒能量模型 结合序列和蛋白质结合效应。(三)学习 系统地研究了DNA的全球结构和动力学特征 与站点并列相关的两个站点沿 由于超级卷曲，DNA在空间上变得非常接近； 这一一般性问题在遗传过程中有许多应用 并置是反应的先决条件，DNA在哪里 超螺旋起着机械性的作用，如转录调节， 重组和拓扑异构酶活性。不幸的是，这是非常 用仪器很难研究这些快速的过程。 我们的并置模拟将针对平均序列进行 DNA，特定成分的质粒，以及与蛋白质结合的DNA，具有 基因重组中位点-突触动力学的研究进展 解析器。这些研究将有助于澄清超级卷曲在 涉及超螺旋DNA和DNA/蛋白质相互作用的过程：如何 超螺旋是否增强了相对于线性DNA的并列？ 并列时间如何取决于位点分离、DNA长度、 盐浓度、DNA序列和结合蛋白？模拟将 还提出了超螺旋定向的具体生物学假说 关于实验测量的突触依赖性的机制 关于镍环的超螺旋密度和突触失效 DNA，超螺旋在特定部位的不可缺少 当三个位置突触而不是两个位置突触的重组，方向 依赖于超螺旋的复合反应中的选择性， 在分解酶中快速和特定于拓扑的并置，以及 分解酶中位点突触的动力学研究。新的建模和仿真 研究超螺旋生物有趣过程的协议 溶液中DNA的大规模和长时间也会产生。 这里探索的双螺旋的全球特征- 远距离DNA位点之间的相互作用，超螺旋动力学和 能量学--在新陈代谢的活动中扮演重要角色 与DNA相互作用的基本酶。我们在这方面的进一步进展 对超螺旋性的理解有许多实际好处： 理解并列率对外部和外部的依赖 内部因素也可能最终帮助设计条件增强 长DNA内的位点之间的识别，因此DNA和 蛋白质。DNA拓扑异构酶的基础重要性 超卷曲和打结导致了对拓扑异构酶的大量研究 作为抗癌或抗菌药物的抑制剂。因此，任何新的 超螺旋与DNA-蛋白质的结构和动力学信息 相互作用可能最终导致这些药物 申请。

The three objectives of this theoretical study of DNA supercoiling are: (1) Developing a general dynamic scheme capable of millisecond simulations for a macroscopic polymer subject to hydrodynamics modeled by curve-fitting techniques. (2) Developing an extension of the homogeneous, elastic rod energy model for dynamic simulations of DNA to incorporate sequence and protein-binding effects. (3) Studying systematically the global structural and dynamic features of DNA associated with site juxtaposition, the rate at which two sites along the DNA come into close spatial proximity as a result of supercoiling; this general problem has many applications to genetic processes where juxtaposition is a prerequisite for the reaction and where DNA supercoiling plays mechanistic roles, such as transcription regulation, recombination, and topoisomerase activity. Unfortunately, it is very difficult to study these fast processes by instrumentation. Our juxtaposition simulations will be performed for average-sequence DNA, plasmids of specific composition, and DNA bound to proteins, with a major focus on site-synapsis kinetics in the recombination of resolvase. The studies will help clarify the role of supercoiling in processes involving supercoiled DNA and DNA/protein interactions: How does supercoiling enhance juxtaposition with respect to linear DNA, and how do juxtaposition times depend on the site separation, DNA length, salt concentration, DNA sequence, and bound proteins? Simulations will also address specific biological hypotheses of supercoiled-directed mechanisms concerning the experimentally-measured dependence of synapsis on the superhelical density, the failure of synapsis for nicked circular DNA, the indispensability of supercoiling in site-specific recombinations where three sites synapse but not two, the orientation selectivity in recombination reactions that depend on supercoiling, the fast and topologically-specific juxtaposition in resolvase, and the kinetics of site synapsis in resolvase. New modeling and simulation protocols for studying biologically interesting processes of supercoiled DNA in solution that are large-scale and long-time will also result. The global characteristics of the double helix explored here - interactions among distant DNA sites, supercoiling dynamics and energetics - play important roles in the action of the metabolically essential enzymes that interact with DNA. Further progress in our understanding of superhelicity has many practical benefits: Understanding the dependence of juxtaposition rates on external and internal factors might also ultimately help design conditions to enhance recognition among sites within long DNA and hence also between DNA and proteins. The fundamental importance of DNA topoisomerases associated with supercoiling and knotting has led to much research on topoisomerase inhibitors that act as anticancer or antibacterial drugs. Thus, any new structural and dynamic information on supercoiling and DNA-protein interactions may ultimately contribute to these pharmaceutical applications.