Theoretical Investigations of Dynamic Aspects of Protein-DNA Interactions

William Marsh Rice大学的Anatoly Kolomeisky获得了化学系化学理论，模型和计算方法项目的奖项，从理论上研究了两大类生物分子之间的相互作用：DNA和蛋白质。该项目由分子和细胞生物科学部的分子生物物理学项目共同资助。 DNA编码所有生物体的遗传计划。蛋白质读取这些信息并在细胞中执行。由于活细胞的动态性质，适当的时机是蛋白质-DNA相互作用的一个关键方面。如果在正确的时间没有发生适当的相互作用，整个生物系统可能会灾难性地失败。了解蛋白质-DNA相互作用可以为药物发现带来新的见解，并有助于技术突破，如生物启发或仿生材料。Kolomeisky教授正在结合理论建模，模拟和生物信息学，以了解蛋白质-DNA相互作用的时间依赖性和效率的分子基础。具体问题包括：蛋白质如何在执行其功能时识别正确的DNA结合位点; DNA环形成对可以在不同DNA位点结合的多位点蛋白质的影响;使用新发现的CRISPR相关蛋白质技术进行DNA编辑的机制;以及了解在确定蛋白质如何与DNA结合时强结合和快速识别之间的权衡。与实验和理论小组的密切合作将使新模型的测试成为可能，并促进对这些复杂自然过程的更深入理解。 Kolomeisky教授正在为来自代表性不足群体的高中和本科生提供参与这项研究的机会，并为他们未来的职业生涯获得宝贵的培训和经验。开展的活动包括高中科学项目竞赛、大学生化学研究研讨会的联合组织、在Rice Science Café等场所举办的公开讲座，以及与Rice机器人系统实验室继续合作，根据本研究成果制作网络游戏。本项目的重点是开发分析蛋白质-DNA相互作用的时间依赖性的理论程序。这些基本的相互作用进行了分析，使用各种理论工具，包括离散状态随机模型，首次通过分析，生物信息学方法和广泛的蒙特卡洛计算机模拟。这种多尺度方法的优点是，它以一致的方式考虑到在复杂的细胞环境中相互作用的DNA和蛋白质的主要物理和化学性质。与实验研究小组合作，使用各种技术测试理论预测，包括单分子光谱学，化学动力学和生物信息学分析。Kolomeisky教授制定的一项推广计划为当地高中生和来自代表性不足的少数群体的本科生提供了在学术环境中参与科学研究的机会。该项目还突出了科学对社会的好处，在咖啡馆讨论的非正式环境中直接向当地社区介绍科学发现，并与当地报纸的科学作家进行交流，并参与科学互联网博客讨论。该项目的更广泛影响包括为不同层次的年轻研究人员提供多学科培训计划，使他们为未来的技术和工业挑战做好准备。

Anatoly Kolomeisky of William Marsh Rice University is supported by an award from the Chemical Theory, Models and Computational Methods Program in the Chemistry Division to theoretically investigate interactions between two major classes of biological molecules: DNA and proteins. This project is co-funded by the Molecular Biophysics Program in the Molecular and Cellular Biosciences Division. DNA encodes the genetic plans for all living organisms. Proteins read this information and implement it in the cell. Proper timing is a key aspect of protein-DNA interactions due to the dynamic nature of living cells. If the proper interactions do not occur at the right time, the entire biological system can fail catastrophically. Understanding protein-DNA interactions can lead to new insights for drug discovery and contribute to technological breakthroughs such as bio-inspired or biomimetic materials. Professor Kolomeisky is combining theoretical modeling, simulation, and bioinformatics to understand the molecular foundations of the temporal dependence and efficiency of protein-DNA interactions. Specific questions include: how proteins identify the correct DNA binding sites in performing their functions; the effects of DNA loop formation on multi-site proteins that can bind at different DNA sites; mechanisms of DNA editing using the newly-discovered CRISPR associated protein technology; and understanding the tradeoff between strong binding and fast recognition in determining how proteins bind to DNA. Close collaborations with experimental and theoretical groups will enable testing of the new models, and promote a deeper understanding of these complex natural processes. Professor Kolomeisky is providing opportunities for high school and undergraduate students from underrepresented groups to participate in this research and gain valuable training and experience for their future careers. Outreach activities include a high-school scientific projects competition, co-organization of an undergraduate chemistry research symposium, public lectures delivered at venues such as the Rice Science Café, and continued collaboration with the Rice robotics systems lab to create online games based on the results of this research.This project focuses on developing a theoretical program to analyze the temporal dependence of protein-DNA interactions. These fundamental interactions are analyzed using a variety of theoretical tools including discrete-state stochastic models, first-passage analysis, bioinformatics methods and extensive Monte Carlo computer simulations. The advantage of this multiscale approach is that it takes into account in a consistent manner the major physical and chemical properties of DNA and proteins interacting in the complex cellular environment. In collaboration with experimental research groups, theoretical predictions are tested using various techniques, including single-molecule spectroscopy, chemical kinetics, and bioinformatic analysis. An outreach program developed by Professor Kolomeisky provides the opportunity for local high-school students and undergraduate students from underrepresented minority groups to participate in scientific research in an academic setting. The project also highlights the benefits of science for society by directly presenting scientific findings to the local community in the informal setting of café discussions, as well as communicating with science writers in local newspapers and participating in scientific Internet blog discussions. The broader impacts of this project include a multidisciplinary training program for young researchers of different levels that will prepare them better for future technological and industrial challenges.