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.

职务名称：蛋白质是我们身体和所有其他生物体，植物，细菌，鱼类，动物中的分子，它们完成了维持和繁殖生命的大部分工作。它们是由小分子化学物质组成的链，称为氨基酸，连接在一起。氨基酸的数量和顺序决定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，但是为了完成它们的工作，比如消化食物或产生使鸟类和昆虫飞行的力量，它们必须改变它们的形状。这项研究旨在了解氨基酸序列如何定义蛋白质的折叠以及它们如何改变其形状以发挥功能。了解蛋白质序列如何控制它们的形状和功能将在设计新的蛋白质在生物技术中的应用有很大的用处。例如，可以为绿色化学生物反应器设计更好、更有活性和更稳定的蛋白质，使日常生活中使用的化学品不会对环境造成危害。蛋白质是纳米机器和纳米材料，将在电子、计算、生物传感和纳米制造中找到许多应用。所有这些技术进步都将基于对蛋白质序列、稳定性和功能之间关系的理解。这项研究所基于的强大的国际合作将为学生提供科学奋进的世界观，并帮助他们建立国际网络，帮助他们追求职业生涯。研究生和本科生谁将参与研究将沉浸在一个全面的跨学科环境，结合多种实验和计算方法。该研究产生的大型NMR数据集与NSF赞助的RPI计算机科学本科专业的本科教育计划，即数据分析本科数学计划（DATUM）共享。将为生物技术中心运行的本科生研究计划提供支持。这项研究还将涉及RPI高中实习计划由生物技术中心运行的特洛伊地区高中（与大量的少数民族人口）。该项目的目标是通过实验绘制选定的模型蛋白质的折叠自由能景观，并确定其折叠协同性，起始和途径的序列和结构决定因素。 这将通过利用压力扰动与特定位点NMR、荧光、SAXS和其他生物物理方法相结合的优点来实现。本建议的基本前提是，压力，由于其独特的作用机制，可以提供独家见解蛋白质折叠。在主要目标的框架内，将解决三个具体问题：序列如何编码蛋白质折叠协同性。 蛋白质的协同作用是如何与它们的体积热膨胀相联系的。 压力未折叠状态下的残余天然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核心突出问题，首先通过显着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同性。最后，它将揭示序列如何专门控制折叠景观上的激发态。 该项目由生物科学理事会分子和细胞生物科学部的分子生物物理学小组和数学和物理科学理事会物理部的生命系统物理学项目共同资助。