Theoretical Investigations of Dynamic Aspects of Protein-DNA Interactions

蛋白质-DNA 相互作用动态方面的理论研究

基本信息

批准号：
1664218
负责人：
Anatoly Kolomeisky
金额：
$ 43.5万
依托单位：
William Marsh Rice University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1664218&HistoricalAwards=false
关键词：
Theoretical Investigations Dynamic Aspects Protein

项目摘要

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.

威廉·马什·赖斯大学（William Marsh Rice University）的Anatoly Kolomeisky得到了化学理论，模型和计算方法计划的奖项，用于化学分部的理论研究部门，两种主要类别的生物分子：DNA和蛋白质之间的相互作用。该项目由分子生物物理学计划在分子和细胞生物科学划分中共同资助。 DNA编码所有生物体的遗传计划。蛋白质阅读此信息并将其实现在单元格中。适当的时机是由于活细胞的动态性质，蛋白质-DNA相互作用的关键方面。如果在适当的时间没有适当的相互作用，则整个生物系统可能会灾难性地失败。了解蛋白质-DNA相互作用会导致对药物发现的新见解，并有助于诸如生物启发或仿生材料之类的技术突破。 Kolomeisky教授将理论建模，模拟和生物信息学结合在一起，以了解蛋白质-DNA相互作用的暂时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回路形成对可以在不同DNA位点结合的多位蛋白的影响；使用新发现的CRISPR相关蛋白质技术进行DNA编辑的机制；在确定蛋白质如何与DNA结合时，了解强结合和快速识别之间的权衡。与实验和理论组的密切合作将实现对新模型的测试，并更深入地了解这些复杂的自然过程。 Kolomeisky教授为来自代表性不足小组的高中和本科生提供了机会，以参加这项研究，并为他们的未来职业获得宝贵的培训和经验。外展活动包括一场高中科学项目竞赛，本科化学研究研讨会的共组织，在赖斯科学咖啡馆等场地进行的公开演讲，以及继续与Rice Robotics Systems Lab合作创建在线游戏，以这项研究的结果创建在线游戏。这些研究的重点是开发一项研究理论来开发protemartion earmyerage proteanthe proteante opartions proteanthe proteante reportare依赖性依赖性依赖性依赖性依赖性依赖性依赖性。这些基本相互作用是使用多种理论工具进行分析的，包括离散状态随机模型，第一播种分析，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了DNA和蛋白质在复杂细胞环境中相互作用的主要物理和化学特性。与实验研究组合作，使用各种技术（包括单分子光谱，化学动力学和生物信息学分析）测试了理论预测。 Kolomeisky教授开发的宣传计划为来自代表性不足的少数群体的当地高中生和本科生提供了机会，以在学术环境中参与科学研究。该项目还通过直接在咖啡馆讨论的非正式环境中向当地社区展示科学发现，并与当地报纸上的科学作家交流并参与科学互联网博客讨论，从而突出了科学对社会的好处。该项目的更广泛的影响包括针对不同级别的年轻研究人员的多学科培训计划，这将为未来的技术和工业挑战做好准备。