CAREER: Developing a Computational Workflow to Quantify Atomic-level Allosteric Mechanisms

在化学系化学理论、模型和计算方法计划以及已建立的刺激竞争研究计划(EPSCoR)的支持下，Martin McCullagh和他在俄克拉荷马州立大学的研究小组将开发计算方法和工作流程，以量化蛋白质中的变构反应。蛋白质中的变构可以通过与蛋白质上第二位点的分子结合来开启和关闭主要功能。这一行为对于治疗的发展以及新蛋白质的设计具有重要的作用。McCullagh小组开发的计算工作流程将用于量化变构反应以及识别新的变构位点，以进一步调节蛋白质。McCullagh小组还将开发基于Jupyter笔记本的化学课，以新颖的方式介绍化学概念，并向本科生介绍编码方面的内容。McCullagh小组将开发和验证量化变构反应的计算工作流程，并描述这一行为背后的原子水平细节。变构是由于远端位置的酶的扰动而导致一个位置的酶功能的改变。尽管在这个问题上做了一个多世纪的工作，但有两个关键问题仍然没有得到回答：(1)在一个完整的四态热力学循环中，哪些原子水平的变化对变构有贡献？(2)我们能否利用原子水平的变构机制来确定影响观察到的变构的新靶点？这个项目将使用两个丙酮酸激酶同工酶作为模型系统来解决这些问题。这些酶的K型变构反应是糖酵解最后一步的关键控制阀。该项目还将开发和免费分发基于Jupyter笔记本的在线化学课程。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。

With support from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry, and the Established Program to Stimulate Competitive Research (EPSCoR), Martin McCullagh and his research group at Oklahoma State University will develop computational methods and workflows to quantify allosteric response in proteins. Allostery in proteins can switch on and off the primary function through the binding of a molecule at a secondary site on the protein. This behavior serves as important handle for the development of therapeutics as well as the design of novel proteins. The computational workflows developed in the McCullagh group will be used to quantify allosteric response as well as identify new allosteric sites for further regulation of the protein. The McCullagh group will also develop jupyter notebook-based chemistry lessons to both introduce chemistry concepts in a novel way and introduce aspects of coding to undergraduate chemistry students.The McCullagh group will develop and verify a computational workflow to quantify allosteric response and describe the atomic-level details that underlie this behavior. Allostery is the altering of enzyme function at one site due to a perturbation of the enzyme at a distal site. Despite over a century of work on this topic, two key questions remain unanswered: (1) What are the atomic-level changes that contribute to allostery in a complete four-state thermodynamic cycle? (2) Can we harness the atomic-level allosteric mechanisms to identify new targets to impact the observed allostery? This project will address these questions using two pyruvate kinase isozymes as model systems. The K-type allosteric response of these enzymes is a pivotal control valve for the last step in glycolysis. This project will also develop and freely distribute online jupyter notebook-based chemistry lessons.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.