The Evolutionary Origin of Non-Equilibrium Order

非平衡秩序的进化起源

• 批准号: 2310781
• 负责人: Arvind Murugan
• 金额: $ 79.99万
• 依托单位: University of Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2310781&HistoricalAwards=false
• 关键词: Evolutionary; Origin; Non; Equilibrium; Order

This project aims to understand the evolutionary origin of kinetic proofreading, a mechanism that increases biochemical accuracy while consuming energy. Proofreading mechanisms are thought to be exploited by numerous biological processes, ranging from the replication of DNA to pass information with fidelity down over generations to the immune system to distinguish foreign viral proteins from our own. While the biophysics of kinetic proofreading are understood, the forces that led to its evolution are still unknown. Intuition and current theory predicts that molecular machines that are more accurate will be slower because they spend more time checking errors. However, these theories have not been tested and this project will test whether higher accuracy implies higher speed or lower speed. Some data has suggested that counterintuitively, more accurate molecular machines might in fact be faster. In this award, the research team will develop a novel experimental platform to study the evolution of this mechanism in DNA polymerases, the molecular machines that copy information in our DNA so it can be transmitted over generations. This novel platform will allow the researchers to study the speed and accuracy of 1000s of mutants of this machine in a single experiment. The research team will exploit this platform to evolve DNA polymerases for higher speed alone, without any selection for higher or lower accuracy and measure the resulting mutation rates. In this way, the team will the hypothesis that proofreading in polymerases can evolve due to selection for higher speed, even without selection for accuracy. The team will then develop a theoretical framework for the origin of non-equilibrium order, extending current models to include memory effects and entropy of mutations.This research will have important consequences for our understanding of how mutation rates in viruses and pathogens can help them avoid the immune system. Viruses must mutate to evade the human immune system and propagate but the rate at which viruses mutate is a double-edged sword. This rate of mutations for a virus is partly determined by the viral replication machinery and its proofreading abilities. The work here will inform the development of new treatments that target proofreading during viral replication and increase mutation rates to a point where viral fitness is harmed. The results will also be useful in bioengineering, where balancing speed and accuracy is crucial for enzymes like Rubisco, which is important for carbon fixation. It is often believed that if a molecular machine like an enzyme works quickly, it is less accurate. However, this research will determine when faster enzymes can be more accurate too. Knowing when this happens is important for creating useful enzymes for commercial and medical applications.The project will also advance our understanding of a frontier region of physics, namely non-equilibrium dynamics. While physicists have a deep understanding and predictive frameworks for passive equilibrium systems, physicists lack general theoretical frameworks for understanding how systems can consume energy and create more ordered states than otherwise possible. This project will reveal relationships between energy cost, time cost and accuracy in non-equilibrium systems.The interdisciplinary research will educate a new generation of students skilled in both non-equilibrium statistical mechanics and molecular biology techniques. The project will train a physics graduate student and involving undergraduates from biological and biomedical sciences at the University of Chicago, exposing them to the benefits of quantitative and physics-oriented thinking in biology. To reach a wider audience, a series of demos and games called "Thriving through mistakes" will be developed. These activities, similar to the Wordle game, will teach about the role of mutations in virus evolution and how quantitative research can help create treatments that target these processes. These educational resources will be shared with local K-12 students on the South Side of Chicago through outreach events on campus.This award is co-funded by the Genetic Mechanisms and Molecular Biophysics programs in the Division of Molecular and Cellular Biosciences/Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目旨在了解动力学校对的进化起源，这种机制在消耗能量的同时提高了生化准确性。校对机制被认为是通过许多生物学过程来利用的，从复制DNA到以世代相传的忠诚传递信息，再到免疫系统，以将外源病毒蛋白与我们自己区分开。 尽管了解了动力学校对的生物物理学，但导致其进化的力量仍然未知。直觉和当前理论预测，更准确的分子机将较慢，因为它们花费更多的时间检查错误。但是，这些理论尚未进行测试，该项目将测试较高的准确性是否意味着更高的速度或更低的速度。一些数据表明，违反直觉，更准确的分子机实际上可能更快。在该奖项中，研究团队将开发一个新型的实验平台，以研究该机制在DNA聚合酶中的演变，DNA聚合酶是在我们的DNA中复制信息的分子机器，因此可以在几代人中传播。这个新颖的平台将使研究人员能够在单个实验中研究该机器突变体的速度和准确性。 研究团队将利用该平台来发展DNA聚合酶，仅用于更高速度，而无需选择更高或更低的精度并测量所得的突变率。通过这种方式，团队将假设聚合酶中的校对可以由于选择更高速度而发展，即使没有选择准确性。然后，该团队将为非平衡顺序的起源开发一个理论框架，扩展当前模型以包括记忆效应和突变的熵。这项研究将对我们对病毒和病原体突变如何帮助他们避免免疫系统的突变率有重要影响。病毒必须突变以逃避人类免疫系统并传播，但病毒突变的速度是双刃剑。病毒的突变速率部分取决于病毒复制机制及其校对能力。 这里的工作将为靶向病毒复制期间校对的新疗法的发展提供信息，并将突变率提高到损害病毒适应性的程度。结果也将在生物工程中有用，在生物工程中，平衡速度和准确性对于像Rubisco这样的酶至关重要，Rubisco对碳固定很重要。 人们通常认为，如果像酶这样的分子机迅速工作，则不太准确。但是，这项研究将确定何时更快的酶也可以更准确。知道这种情况何时发生对于为商业和医疗应用创建有用的酶很重要。该项目还将提高我们对物理领域（即非平衡动力学）的理解。尽管物理学家对被动平衡系统具有深刻的理解和预测框架，但物理学家缺乏一般的理论框架来理解系统如何消耗能量并创造比其他可能的秩序状态。该项目将揭示非平衡系统中能源成本，时间成本和准确性之间的关系。跨学科的研究将教育一群熟练的非平衡统计力学和分子生物学技术的学生。该项目将培训一名物理研究生，并涉及芝加哥大学生物学和生物医学科学的大学生，使他们对生物学的定量和物理学思维的好处。 为了吸引更广泛的观众，将开发一系列称为“蓬勃发展”的演示和游戏。这些类似于Wordle游戏的活动将教授突变在病毒进化中的作用，以及定量研究如何帮助创建针对这些过程的治疗方法。这些教育资源将通过校园中的外展活动与芝加哥南侧的本地K-12学生共享。该奖项由分子和蜂窝生物科学局/生物科学局的遗传机制和分子生物物理学计划共同资助，这些奖项反映了NSF的众多范围，并通过评估了NSF的范围，这是众多的范围。 标准。