Statistical Mechanics of DNA-Protein Interactions and Chromosome Organization

DNA-蛋白质相互作用和染色体组织的统计力学

• 批准号: 0715099
• 负责人: John Marko
• 金额: $ 48.4万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0715099&HistoricalAwards=false
• 关键词: Statistical; Mechanics; DNA; Protein; Interactions

TECHNICAL SUMMARY:This award is funded by the Division of Materials Research in the Mathematical and Physical Sciences Directorate and the Division of Molecular and Cellular Biosciences in the Biology Directorate. This award supports theoretical research and education on the application of statistical mechanics to elucidate the properties of DNA and other biomolecules and the interaction of DNA with proteins. Over the past decade, new techniques based on micromanipulation technology have enabled the study of the mechanical properties of single or small numbers of biomolecules. State-of-the-art methods can monitor biochemical reactions on micromanipulated DNA molecules, allowing direct statistical-mechanical study of the operation of biomolecular machinery. These types of experiments typically involve distance measurements in the nanometer range, and force measurements in the piconewton range.The PI will focus on developing theories in the areas of:1. single-molecule experiments on loop-forming proteins, with the dual objectives of studying DNA flexibility, and analyzing looping-complex geometry;2. single-molecule experiments on proteins which form nucleoprotein complexes along DNA, including DNA-bending proteins and nucleosomes, with particular attention being paid to binding and rearrangement dynamics of these proteins, and in the case of chromatin, development of models for enzymes which actively 'remodel' nucleosomes;3. single-molecule experiments on SMC (structural maintenance of chromosomes) protein complexes along DNA, which are thought to be responsible for organizing higher-order chromatin structure, and which recent experimental data suggest link DNA molecules; 4. other theoretical problems involving DNA-protein interactions and chromosome structure, including dynamics of target search by site-specific DNA binding proteins, and large-scale organization of chromosome structure.The methods to be used are equilibrium and nonequilibrium statistical mechanics, i.e. the basic tools of non-quantum-mechanical materials theory. More specifically, the methods of polymer statistical mechanics, which have already proven highly useful in interpretation of single-molecule experiments, will be further developed in application to situations where protein-DNA interactions will be studied. Also, stochastic dynamical theories similar to those used in the theory of the kinetics of phase transitions will be used to study the dynamics of reorganization of long DNA molecules by proteins which bind along its length. A combination of analytical and numerical calculations will be used.These studies will directly engage current experiments in the rapidly growing interdisciplinary field of single-molecule study of protein-DNA interactions, and will provide guidance in experiment design and interpretation. In addition to their connections to biochemistry, molecular biology and biological physics, the problems to be studied are unique in polymer materials science thanks to the degree of structural control possible during biopolymer self-assembly. So, the frontiers of basic polymer material science will also be advanced by the research. Broad impact will also follow from the training of graduate students and postdoctoral fellows in the ideas and methods relevant to application of ideas from condensed matter and materials theory to problems in molecular and cell biology, an area where trained young people are in great demand in both university and biotechnology industry settings.NON-TECHNICAL SUMMARY:This award is funded by the Division of Materials Research in the Mathematical and Physical Sciences Directorate and the Division of Molecular and Cellular Biosciences in the Biology Directorate. This award supports theoretical research and education at the interface of condensed matter physics and biology. The PI will apply the methods of statistical mechanics to develop a theoretical framework that can interpret experiments involving the manipulation of a single DNA molecule or a small number of molecules. Recently developed experimental techniques have enabled the study of the mechanical properties of single or small numbers of biomolecules. State-of-the-art experimental methods can monitor biochemical reactions on micromanipulated DNA molecules, allowing direct statistical-mechanical study of the operation of biomolecular machinery. These types of experiments typically involve distance measurements in the nanometer range, and force measurements in the piconewton range. The PI's interdisciplinary research provides theoretical developments that, combined with experiment, will elucidate physical and mechanical properties of DNA and other biomolecules, and how DNA interacts with proteins. In the long term, the PI aims to understand how chromosomes are structurally organized and to understand how communication processes occur along chromosomes. These studies will directly engage current experiments in the rapidly growing interdisciplinary field of single-molecule study of protein-DNA interactions, and will provide guidance in experiment design and interpretation. In addition to their connections to biochemistry, molecular biology and biological physics, the problems to be studied are unique in polymer materials science thanks to the degree of structural control possible during biopolymer self-assembly. So, the frontiers of basic polymer material science will also be advanced by the research. Broad impact will also follow from the training of graduate students and postdoctoral fellows in the ideas and methods relevant to application of ideas from condensed matter and materials theory to problems in molecular and cell biology, an area where trained young people are in great demand in both university and biotechnology industry settings.

该奖项由数学和物理科学理事会材料研究部和生物学理事会分子和细胞生物科学部资助。该奖项支持应用统计力学的理论研究和教育，以阐明DNA和其他生物分子的性质以及DNA与蛋白质的相互作用。在过去的十年中，基于微操作技术的新技术已经能够研究单个或少量生物分子的机械特性。国家的最先进的方法可以监测微操作的DNA分子上的生化反应，允许直接的生物分子机器的操作的物理机械研究。这些类型的实验通常涉及纳米范围内的距离测量，以及皮牛顿范围内的力测量。PI将专注于以下领域的理论发展：1. 环形成蛋白的单分子实验，具有研究DNA灵活性和分析环复合物几何形状的双重目标;2.单分子实验的蛋白质形成核蛋白复合物沿着DNA，包括DNA弯曲蛋白质和核小体，特别注意这些蛋白质的结合和重排动力学，并在染色质的情况下，积极“重塑”核小体的酶模型的发展;3.沿着DNA的SMC（染色体的结构维持）蛋白质复合物的单分子实验，其被认为负责组织高阶染色质结构，并且最近的实验数据表明连接DNA分子; 4.涉及DNA-蛋白质相互作用和染色体结构的其他理论问题，包括位点特异性DNA结合蛋白的靶搜索动力学和染色体结构的大尺度组织。所使用的方法是平衡和非平衡统计力学，即非量子力学材料理论的基本工具。更具体地说，聚合物统计力学的方法，这已经被证明是非常有用的单分子实验的解释，将进一步发展在应用的情况下，蛋白质-DNA相互作用将被研究。此外，类似于相变动力学理论中所用的随机动力学理论将被用于研究长DNA分子被沿其长度结合沿着的蛋白质重组的动力学。这些研究将结合分析计算和数值计算，直接参与当前快速发展的蛋白质-DNA相互作用单分子研究跨学科领域的实验，并为实验设计和解释提供指导。除了它们与生物化学，分子生物学和生物物理学的联系之外，由于生物聚合物自组装过程中可能的结构控制程度，要研究的问题在聚合物材料科学中是独一无二的。因此，高分子材料基础科学的前沿也将被推进。对研究生和博士后研究员进行有关思想和方法的培训也将产生广泛的影响，这些思想和方法与从凝聚态物质和材料理论到分子和细胞生物学问题的思想应用有关，这是大学和生物技术行业都非常需要受过培训的年轻人的领域。该奖项由数学和物理科学理事会材料研究部和分子和物理科学部资助。细胞生物科学在生物学理事会。该奖项支持凝聚态物理学和生物学接口的理论研究和教育。PI将应用统计力学的方法来开发一个理论框架，可以解释涉及单个DNA分子或少量分子操作的实验。最近发展起来的实验技术已经能够研究单个或少量生物分子的机械性能。最先进的实验方法可以监测微操作DNA分子上的生化反应，从而可以直接对生物分子机器的操作进行物理机械研究。这些类型的实验通常涉及纳米范围内的距离测量和皮牛顿范围内的力测量。PI的跨学科研究提供了理论发展，结合实验，将阐明DNA和其他生物分子的物理和机械特性，以及DNA如何与蛋白质相互作用。从长远来看，PI的目标是了解染色体是如何在结构上组织起来的，并了解沿着染色体的通讯过程是如何发生的。这些研究将直接参与当前快速发展的蛋白质-DNA相互作用单分子研究跨学科领域的实验，并将为实验设计和解释提供指导。除了它们与生物化学，分子生物学和生物物理学的联系之外，由于生物聚合物自组装过程中可能的结构控制程度，要研究的问题在聚合物材料科学中是独一无二的。因此，高分子材料基础科学的前沿也将被推进。对研究生和博士后研究员进行有关思想和方法的培训也将产生广泛的影响，这些思想和方法与从凝聚态物质和材料理论到分子和细胞生物学问题的思想应用有关，这是一个大学和生物技术行业都非常需要训练有素的年轻人的领域。