DNA SUPERCOILING--MACROSCOPIC MODELING

DNA超螺旋理论研究的三个目标是： (1)开发一种通用的毫秒级动态方案 模拟宏观聚合物受流体力学建模 通过曲线拟合技术。(2)开发一个扩展的 均匀，弹性杆能量模型的动态模拟DNA， 结合序列和蛋白质结合作用。(3)研究 系统地研究了DNA的整体结构和动力学特征， 与站点并置相关，两个站点沿着 由于超螺旋作用，DNA在空间上接近; 这一普遍问题在遗传过程中有许多应用， 并置是反应的先决条件， 超螺旋发挥机械作用，如转录调控， 重组和拓扑异构酶活性。不幸的是， 很难用仪器来研究这些快速过程。 我们的并列模拟将进行平均序列 DNA、特定组成的质粒和与蛋白质结合的DNA， 一个主要的重点是在重组的位点突触动力学 分解酶 这些研究将有助于阐明超螺旋在 涉及超螺旋DNA和DNA/蛋白质相互作用的过程：如何 相对于线性DNA，超螺旋是否增强并置，以及 并置时间如何取决于位点间隔，DNA长度， 盐浓度、DNA序列和结合蛋白？模拟将 还解决了特定的生物学假说的超螺旋定向 关于实验测量的突触依赖性的机制 在超螺旋密度上，缺口环突触的失败， DNA，超螺旋在位点特异性 三个位点而不是两个位点突触的重组， 在依赖于超螺旋的重组反应中， 快速和拓扑特定的并置在resolvase，和 解离酶位点突触动力学。 新的建模和仿真 研究超螺旋的生物学有趣过程的协议 溶液中的DNA也会产生大规模和长时间的结果。 双螺旋结构的整体特征在这里被探索- 远距离DNA位点之间的相互作用，超螺旋动力学和 能量学-在新陈代谢的作用中发挥重要作用 与DNA相互作用的必需酶。 我们的进一步进展 理解超螺旋性有许多实际的好处： 理解并置率对外部和 内部因素也可能最终有助于设计条件， 在长DNA内的位点之间的识别，因此也在DNA和 proteins. DNA拓扑异构酶的重要性 超螺旋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 超螺旋和DNA-蛋白质结构和动力学信息 相互作用可能最终有助于这些药物 应用.

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.