Statistical Mechanics of DNA-Protein Interactions and Chromosome Organization

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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.