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

职业：开发计算工作流程来量化原子级变构机制

• 批准号: 2238706
• 负责人: Martin McCullagh
• 金额: $ 56.98万
• 依托单位: Oklahoma State University
• 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: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2238706&HistoricalAwards=false
• 关键词: CAREER; Developing; Computational; Workflow; Quantify

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.

在化学理论，模型和计算方法的支持下，化学划分的计划以及刺激竞争研究的既定计划（EPSCOR），Martin McCullagh及其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。 蛋白质的变构可以通过分子在蛋白质上的二级位点的结合来打开和关闭主要功能。 这种行为是治疗剂以及新型蛋白质设计的重要手段。 McCullagh组开发的计算工作流将用于量化变构反应，并确定新的变构位点，以进一步调节蛋白质。 McCullagh小组还将开发基于Jupyter笔记本的化学课程，以新颖的方式介绍化学概念，并将编码的各个方面引入本科化学专业的学生。McCullaghGroup将开发和验证计算工作流程，以量化变形响应并介绍这种行为的原子级别细节。变构是由于远端位点的酶扰动而在一个部位的酶功能的改变。尽管在这个主题上进行了一个多世纪的工作，但两个关键问题仍未得到解决：（1）在完整的四州热力学周期中导致变构的原子级变化是什么？ （2）我们可以利用原子水平的变构机制来确定新目标以影响观察到的变构。 该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对照阀。 该项目还将开发和自由分发基于jupyter笔记本的化学课程。该奖项反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响评估标准，被视为值得通过评估来获得支持。