Statistical Mechanics of DNA-Protein Interactions and Chromosome Organization

技术摘要：该奖项由数学和物理科学局的材料研究司和生物学局的分子和细胞生物科学司资助。该奖项支持应用统计力学来阐明DNA和其他生物分子的性质以及DNA与蛋白质的相互作用的理论研究和教育。在过去的十年里，基于微操作技术的新技术使得研究单个或少量生物分子的力学性质成为可能。最先进的方法可以监测微操作DNA分子上的生化反应，允许直接对生物分子机械的操作进行统计-机械研究。这些类型的实验通常涉及纳米范围的距离测量和皮牛顿范围的力测量。PI将专注于发展以下领域的理论：1.关于环形成蛋白质的单分子实验，其双重目标是研究DNA柔性，并分析环状复合体的几何结构；2.关于沿DNA形成核蛋白复合体的蛋白质的单分子实验，包括DNA弯曲蛋白质和核小体，特别关注这些蛋白质的结合和重排动力学，以及在染色质的情况下，发展主动‘重构’核小体的酶的模型；3.对DNA上负责组织高阶染色质结构的SMC(SMC)蛋白质复合体进行单分子实验，最近的实验数据表明它与DNA分子有关；4.其他涉及DNA-蛋白质相互作用和染色体结构的理论问题，包括特定位点DNA结合蛋白的靶标搜索动力学和染色体结构的大规模组织。更具体地说，已被证明在解释单分子实验中非常有用的聚合物统计力学方法将在研究蛋白质-DNA相互作用的情况下得到进一步发展。此外，类似于相变动力学理论中使用的随机动力学理论将被用来研究沿其长度结合的蛋白质重组长DNA分子的动力学。将采用解析和数值计算相结合的方法。这些研究将直接使当前的实验参与到蛋白质-DNA相互作用的单分子研究这一迅速发展的跨学科领域，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外，由于生物聚合物自组装过程中可能存在的结构控制程度，所要研究的问题在聚合物材料科学中是独一无二的。因此，这项研究也将推动基础聚合物材料科学的前沿。对研究生和博士后研究员的培训也将产生广泛的影响，他们的想法和方法与将凝聚态和材料理论的想法应用于分子和细胞生物学问题有关，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。非技术概述：该奖项由数学和物理科学局的材料研究部和生物局的分子和细胞生物科学部资助。该奖项支持凝聚态物理和生物学交界处的理论研究和教育。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分子或少量分子的操作的实验。最近发展起来的实验技术使研究单个或少量生物分子的力学性质成为可能。最先进的实验方法可以监测微操作DNA分子上的生化反应，允许直接对生物分子机械的操作进行统计-机械研究。这些类型的实验通常涉及纳米范围的距离测量和皮牛顿范围的力测量。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性质，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结构组织的，并了解沿染色体发生的沟通过程。这些研究将直接在蛋白质-DNA相互作用的单分子研究这一快速发展的跨学科领域中参与当前的实验，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外，由于生物聚合物自组装过程中可能存在的结构控制程度，所要研究的问题在聚合物材料科学中是独一无二的。因此，这项研究也将推动基础聚合物材料科学的前沿。还将对研究生和博士后研究员进行有关将凝聚态和材料理论的想法和方法应用于分子和细胞生物学问题的培训，这是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。

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.