Theoretical Aspects of DNA Supercoiling

描述（申请人提供）：研究结合计算机模拟 （相邻基级能量优化和简正波分析） 对）与弹性杆理论的新发展，以检查 超螺旋DNA的结构和性质，拓扑约束 双螺旋的一种形式，受到高阶折叠和补偿 股绞。长丝状聚合物的序列依赖性特征 被纳入弹性杆的理论和处理的数值 模拟通过将分析研究与计算机模拟相结合， 获得补充信息，并具有一系列内置检查， 平衡来评估我们发现的重要性。计算 结果刺激新的理论发展，这反过来又可以用来 评估计算的有效性。的影响。 主链和局部化学环境被隐式地处理， 基于知识的潜力提取的高分辨率结构的双重 螺旋DNA，并在代表性的情况下，明确治疗 静电力我们的直接目标是描述链的结构， 在现实分子模型方面的性质。拟议的研究可 阐明主要化学特征的作用（碱基序列、糖-磷酸 骨架）和配体结合（蛋白质，药物）的整体折叠上， 双螺旋。我们的目标是开发一个准确和全面的模型， DNA环的构型特性 阻遏子-操纵子组装，有可能了解有关 DNA结构在转录调控中的作用。第二个目标是 揭示超螺旋诱导的DNA跃迁的结构细节，例如 生物过程中的螺旋解旋。在科学界 需要解决的问题是：（1）序列依赖的局部结构的作用 和特异性蛋白质构象对超螺旋链整体特征的影响; (2)序列和配体结合在大规模构型中作用 空间约束DNA的转换;（3）多个竞争效应 蛋白质对超螺旋双链体的形状和变形性的影响;（4） 超螺旋动力学中局部结构和全局结构的相互作用; 离子条件对回路构型的影响。

DESCRIPTION (provided by applicant): The research combines computer simulation (energy optimization and normal mode analysis at the level of neighboring base pairs) with new developments in the theory of elastic rods to examine the configurations and properties of supercoiled DNA, a topologically constrained form of the double helix subject to higher-order folding and compensatory strand twisting. Sequence-dependent features of the long, threadlike polymer are incorporated in the theory of elastic rods and treated by numerical simulations. By combining analytical studies with computer simulations, we obtain complementary information and have a series of built-in checks and balances for assessing the significance of our findings. The computational results stimulate new theoretical developments, which in turn can be used to assess the validity of the calculations. The effects of the polyelectrolyte backbone and local chemical environment are treated implicitly with knowledge-based potentials extracted from high resolution structures of double helical DNA and, in representative cases, with explicit treatment of electrostatic forces. Our immediate goal is to describe chain configuration and properties in terms of realistic molecular models. The proposed studies may clarify the role of primary chemical features (base sequence, sugar-phosphate backbone) and ligand binding (proteins, drugs) on the overall folding of the double helix. We aim to develop an accurate and comprehensive model of the configurational properties of the DNA loops tethered to the Lac repressor-operator assembly with the possibility of learning new details about the role of DNA structure in the regulation of transcription. A second goal is to uncover structural details of supercoil-induced transitions of DNA, such as the helical unwinding implicated in biological processes. Among the scientific issues to be addressed are: (1) the role of sequence-dependent local structure and specific protein conformation on the global features of supercoiled chains; (2) the role of sequence and ligand binding on large-scale configurational transitions of spatially constrained DNA; (3) the competing effects of multiple proteins on the shape and deformability of the supercoiled duplex; (4) the interplay of local and global structure in supercoiling dynamics; (5) the effect of ionic conditions on loop configuration.