Using systematic computational approaches to elucidate the molecular and network dynamics underlying a circadian clock

生物钟控制着生命王国中生物体的日常节奏，而生物钟的缺陷可能会影响个人和生态系统的健康。该项目使用与生化实验密切相关的计算模型，以更好地了解生物钟在分子水平上的工作原理。对这一研究目标的追求将有助于研究生和本科生的跨学科培养。反过来，这将使更年轻的学生接触STEM主题：继续一个非常成功的项目，将高三学生安排在芝加哥大学的实验室进行暑期研究，并更新伊利诺伊州公立学校教师的一门课程，该课程提供廉价、动手的方式，让学生参与进来，帮助他们理解生物学背后的物理规律。值得注意的是，蓝藻的核心生物钟可以在试管中重建。这使得控制良好的研究可以用来梳理复杂的行为，并将时钟功能与特定的分子事件联系起来。通过利用这个系统和计算方法的最新进展，关于时钟的主要悬而未决的问题将被解决：参与蛋白质折叠的缓慢切换是否决定了时钟的时间？信息是如何在时钟的时间编码部分和使其稳步前进的马达之间传递的？时钟如何在可能导致基本反应速率急剧变化的条件下保持近24小时的周期(即，是什么使时钟如此坚固)？该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Circadian clocks govern the daily rhythms of organisms across the kingdoms of life, and clock defects can impact the health of both individuals and ecosystems. This project uses computational models tied closely to biochemical experiments to better understand how circadian clocks work at the molecular level. Pursuit of this research objective will contribute to interdisciplinary training of graduate and undergraduate students. This, in turn, will enable efforts to expose younger students to STEM topics: continuation of a highly successful program that places high school juniors in laboratories at the University of Chicago for summer research and the update of a course for Illinois public school teachers that presents inexpensive, hands-on ways of engaging their students and helping them understand the physical laws underlying biology.Remarkably, the core circadian clock of cyanobacteria can be reconstituted in a test tube. This permits well-controlled studies that can be used to tease apart complex behaviors and connect clock function with specific molecular events. By leveraging this system and recent advances in computational methods, major outstanding questions about the clock will be addressed: Does the slow switch of a participating protein’s fold set the timing of the clock? How is information communicated between the part of the clock that encodes the time of day and the motor that keeps it advancing steadily forward? How does the clock maintain a near-24-hour period across conditions that can lead to dramatic changes in elementary reaction rates (i.e., what makes the clock so robust)?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.