Pressure-Based Mapping of Protein Free Energy Landscapes

基于压力的蛋白质自由能景观图

• 批准号: 1514575
• 负责人: Catherine Royer
• 金额: $ 114.98万
• 依托单位: Rensselaer Polytechnic Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1514575&HistoricalAwards=false
• 关键词: Pressure; Based; Mapping; Protein; Free

Title: Pressure Based Mapping of Protein Free Energy LandscapesProteins are the molecules in our bodies and in all other living organisms, plants, bacteria, fish, animals, that do most of the work to maintain and reproduce life. They are chains of small chemicals, called amino acids that are linked together. The number and order of the amino acids defines the shape or structure of the protein and also its function. Proteins fold up into compact shapes, but to do their jobs like digesting food or generating the force that makes birds and insects fly, they have to change their shape. This research is aimed at understanding how the sequence of amino acids defines the folding of proteins and how they change their shapes to function. Understanding how protein sequences control their shape and function will be of great use in designing new proteins for applications in biotechnology. For example, better, more active and more stable proteins can be designed for green chemistry bioreactors to make the chemicals used in daily life without harming the environment. Proteins are nano-machines and nanomaterials that will find numerous applications in electronics, computing, biosensing and nano-fabrication. All of these technological advances will be based on the understanding of the relationship between protein sequence, stability and function. The strong international collaboration on which this research is based will provide the students with a world-view of the scientific endeavor, and help them establish international networks that will aid them as they pursue their careers. The graduate and undergraduate students who will participate in the research will be immersed in a comprehensive interdisciplinary environment, incorporating multiple experimental and computational approaches. The large NMR data sets generated by the research are shared with the NSF sponsored undergraduate educational program in the undergraduate computer science major at RPI, the Data Analytics Through-out Undergraduate Mathematics program (DATUM). Support will be provided for the undergraduate research program run by the Center for Biotechnology. The research will also involve the RPI high school internship program run by the Center for Biotechnology for Troy area high schools (with a large minority population). The objective of this project is to map experimentally the folding free energy landscapes for selected model proteins, and to identify the sequence and structural determinants of their folding cooperativity, initiation and pathways. This will be accomplished by exploiting the advantages of pressure perturbation coupled with site specific NMR, fluorescence, SAXS and other biophysical approaches. The underlying premise of the present proposal is that pressure, due to its unique mechanism of action, can provide exclusive insights into protein folding. Within the framework of the main objective, three specific questions will be addressed: How does sequence code for protein folding cooperativity. How are protein cooperative interactions linked to their volumetric thermal expansion. How do residual native interactions in pressure unfolded states affect folding mechanisms. This project will address central outstanding issues in protein folding and conformational dynamics, first by significantly and systematically increasing the experimental database of detailed protein folding energy landscapes. Secondly, it will provide experimental scenarios describing how sequence defines folding routes and cooperativity. Finally, it will reveal how sequence specifically controls access to excited states on folding landscapes. This project is jointly funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Physics of Living Systems Program in the Division of Physics in the Directorate of Mathematical and Physical Sciences.

标题：蛋白质自由能景观蛋白的基于压力的映射是我们体内以及所有其他生物，植物，细菌，鱼类，动物的分子，这些分子在维持和繁殖寿命。它们是小型化学物质的链，称为氨基酸，它们连接在一起。氨基酸的数量和顺序定义了蛋白质的形状或结构及其功能。蛋白质折叠成紧凑的形状，但要做自己的工作，例如消化食物或产生使鸟类和昆虫飞翔的力，它们必须改变形状。这项研究旨在了解氨基酸的序列如何定义蛋白质的折叠以及它们如何将其形状更改为功能。了解蛋白质序列如何控制其形状和功能将在设计新的蛋白质中用于生物技术的应用。例如，可以为绿色化学生物反应器设计更好，更活跃，更稳定的蛋白质，以使日常生活中使用的化学物质而不会损害环境。蛋白质是纳米机器和纳米材料，可以在电子，计算，生物传感和纳米制作中找到许多应用。所有这些技术进步将基于对蛋白质序列，稳定性和功能之间关系的理解。这项研究基于的强大国际合作将为学生提供科学努力的世界观，并帮助他们建立国际网络，以帮助他们从事职业。将参加研究的研究生和本科生将沉浸在一个全面的跨学科环境中，并结合多种实验和计算方法。该研究生成的大型NMR数据集与NSF赞助的本科本科教育计划RPI的本科生教育计划共享，数据分析贯穿了本科生数学计划（Datum）。将为生物技术中心开展的本科研究计划提供支持。该研究还将涉及由Troy地区高中生物技术中心（少数人口）开展的RPI高中实习计划。该项目的目的是通过实验绘制选定模型蛋白的折叠自由能景观，并确定其折叠协同，启动和途径的序列和结构决定因素。 这将通过利用压力扰动的优势以及位点特异性NMR，荧光，SAXS和其他生物物理方法来实现。本提案的基本前提是，由于其独特的作用机理，压力可以为蛋白质折叠提供独家见解。在主要目标的框架内，将解决三个具体问题：如何用于蛋白质折叠合作的序列代码。 蛋白质合作相互作用如何与它们的体积热膨胀有关。 压力展开状态中残留的本地相互作用如何影响折叠机制。该项目将解决蛋白质折叠和构象动力学中的中心杰出问题，首先要大量和系统地增加详细的蛋白质折叠能量景观的实验数据库。其次，它将提供实验场景，描述序列如何定义折叠路线和协作性。最后，它将揭示序列如何专门控制折叠景观上激发态的访问。 该项目是由分子生物物理学群集共同资助的，该项目在生物科学局和生物科学局的分子和细胞生物科学划分中，在数学和物理科学局的物理学部门的生命系统计划中共同资助。