THEORETICAL ASPECTS OF DNA SUPERCOILING

本研究的主要目的是了解和可视化 超螺旋DNA的结构和性质。长期的轨道 用曲线拟合生成空间受限分子 计算机辅助设计和工程中常用的技术。这些 方法自动满足循环的环闭合约束 DNA和/或对空间固定的开放DNA的端对端限制，以及 涉及相对有限数量的独立变量。因为 数学表示的使用，变量的数量， 被放置在曲线上是无限的，并且可以治疗很长时间 链状分子此外，由于独立变量的数量 是有限的，它是可能的，以模拟大的构象变化， 在超螺旋DNA中发现的这项研究的直接目标是 描述链的结构和属性， 分子模型DNA的能量将用以下术语来描述： 简单的弹性项，模拟序列相关的弯曲， 在地方一级观察到的链条扭曲。拟议的研究 可以阐明局部结构的作用（初级碱基序列和 糖-磷酸骨架）和配体结合（蛋白质和 药物）对链的整体折叠。第二个目标是揭示 超螺旋诱导的DNA跃迁的结构细节，例如 包括左右手的双链体这项研究结合了各种 计算方法（蒙特卡罗和分子动力学 模拟，势能最小化，有限元分析， 系统分子建模）以及弹性理论的新发展。 其中要解决的科学问题是：（1）竞争效应 两个或多个结合蛋白的空间构型和范围上的 （2）双螺旋的灵活性;（3）高度弯曲的可能作用 片段对动质体DNA微环整体结构的影响; 局部序列在多大程度上固定了长的、自然的分支 出现超螺旋;（4）扭曲密度和碎片长度的影响 对大尺度超螺旋转变的影响;（5）非均匀性程度 蛋白质结合DNA的局部扭曲;（6）链波动的作用 超螺旋DNA的X射线散射;（7）相对时间尺度 （8）盐浓度的影响 和/或外部电场对分子形状和柔性的影响。

The major objective of this research is to understand and visualize the structure and properties of supercoiled DNA. The trajectories of the long spatially constrained molecules are generated with curve fitting techniques commonly used in computer aided design and engineering. These approaches automatically satisfy the ring closure constraints of cyclic DNA and/or the end-to-end limitations on spatially fixed open DNA, and involve a relatively limited number of independent variables. Because of the use of mathematical representations, the number of variables that can be placed on the curves is unlimited and it is possible to treat very long chain molecules. Furthermore, because the number of independent variables is limited, it is possible to simulate the large conformational changes found in supercoiled DNAs. The immediate goal of the research is to describe chain configuration and properties in terms of realistic molecular models. The energy of the DNA will be described in terms of simple elastic terms that mimic the sequence-dependent bending and twisting of the chain observed at the local level. The proposed studies may clarify the role of local structure (primary base sequence and polyelectrolyte sugar-phosphate backbone) and ligand binding (proteins and drugs) on the overall folding of the chain. A second goal is to uncover structural details of supercoil-induced transitions of DNA, such as those involving right- and left-handed duplexes. The research combines a variety of computational approaches (Monte Carlo and molecular dynamics simulations, potential energy minimizations, finite element analysis, systematic molecular modeling) with new developments in elasticity theory. Among the scientific issues to be addressed are: (1) the competing effects of two or more bound proteins on the spatial configurations and range of flexibility of the double helix; (2) the possible role of highly bent fragments on the overall structure of kinetoplast DNA minicircles; (3) the extent to which local sequence fixes the branching in long, naturally occurring supercoils; (4) the effects of twist density and fragment length on large-scale supercoiling transitions; (5) the degree of non-uniformity of local twist in protein-bound DNAs; (6) the role of chain fluctuations on the X-ray scattering of supercoiled DNA; (7) the relative time scales of different supercoiling motions; (8) the effect of salt concentration and/or external electric field on molecular shape and flexibility.