SGER: Dynamic Evolution of DNA Supercoils and Loops

SGER：DNA 超螺旋和环的动态演化

• 批准号: 0439574
• 负责人: Noel Perkins
• 金额: $ 4.45万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0439574&HistoricalAwards=false
• 关键词: SGER; Dynamic; Evolution; DNA; Supercoils

DYNAMIC EVOLUTION OF DNA SUPERCOILS AND LOOPSNoel Perkins and Edgar MeyhoferMechanical EngineeringUniversity of MichiganAnn Arbor, MI 48109-2125Our proposed research employs methods of nonlinear dynamical systems to explore the fundamental biological functions of DNA. Critical biological functions such as replication and transcription are influenced by the shape or "structure" of DNA. This very long molecule (length is thousand times longer than diameter) is extraordinarily flexible, and it can undergo nonlinear motions that can regulate (i.e. control) gene expression. For example, proteins can force segments of DNA into loops that prevent transcription. In addition, thermal energy excites vibrations of DNA and resulting changes in supercoiled states can promote transcription. The motions described above occur over very long length scales (hundreds to tens of thousands of nanometers) and on very long time scales (microsecond to millisecond) relative to atomic dimensions (angstrom) and molecular dynamic rates (picosecond and smaller). It is the long-term objective of our research program to understand these dynamical processes through novel theories and experiments on DNA structural dynamics. A promising dynamical theory for long length/time scales follows from treating the long chain molecule as a dynamic continuum rod. The first step in our research plan is to develop a nonlinear computational rod model for DNA supercoils and loops. Major challenges to be considered include 1) the nonlinear deformation, 2) spatial non-uniformity and anisotropy (e.g., "sequence-dependent" stiffness and "intrinsic" curvature and twist), 3) self-contact/electrostatics and interwinding, 4) dissipation, and 5) efficient numerical algorithms. We will then employ our computational model in two strategic case studies. The first case study focuses on the dynamic evolution of supercoils for strands subjected to controlled end rotation as observed in recent single molecule experiments. The second case study explores the looping of DNA when subjected to a bound protein known as the lac repressor. Our interdisciplinary research team, which possesses the requisite background in dynamical systems and molecular biology, is well-positioned to make these fundamental investigations of DNA dynamics by advancing methods from the engineering sciences.

MICHIGANANN ARBOR，MI 48109-2125OR的动态演变和Loopsnoel Perkins和Edgar Meyhofermechanical工程学的动态演化采用了非线性动力学系统的方法来探索DNA的基本生物学功能的非线性动力学系统。诸如复制和转录之类的关键生物学功能受DNA的形状或“结构”影响。这个很长的分子（长度比直径长千倍）是非常灵活的，并且可以进行非线性运动，以调节（即对照）基因表达。 例如，蛋白质可以将DNA的片段迫使阻止转录的环。另外，热能激发了DNA的振动和超螺旋状态的变化可以促进转录。上述动作发生在很长的尺度上（数百到数十万纳米），并且相对于原子维度（埃符（Angstrom）和分子动态速率（picsecond及更小），相对于原子尺寸（Angstrom）和分子动态速率（且较小），并且在很长的时间尺度（微秒至毫秒）上发生。我们的研究计划的长期目标是通过新颖的理论和DNA结构动力学的实验来了解这些动力学过程。 长长/时间尺度的有前途的动力学理论是将长链分子视为动态连续杆的。我们的研究计划的第一步是开发用于DNA超炮和循环的非线性计算杆模型。要考虑的主要挑战包括1）非线性变形，2）空间不均匀性和各向异性（例如，“序列依赖性”刚度和“固有”曲率和曲折），3）自我接触/静电和交互，4）耗散，以及5）耗散量，以及5）有效的数值藻类。然后，我们将在两个战略案例研究中采用计算模型。第一个案例研究的重点是在最近的单分子实验中观察到的受控终端旋转的链的超级旋转的动态演变。第二个案例研究探讨了DNA的循环，当时经受了称为LAC阻遏物的结合蛋白。我们的跨学科研究团队具有动力学系统和分子生物学中必要的背景，可以很好地进行这些基本研究，从而对DNA动力学进行了基本研究，从而通过推进工程科学的方法。