Conformational Eequilibria of Intrinsically Disordered Proteins

本质无序蛋白质的构象平衡

• 批准号: 0718924
• 负责人: Rohit Pappu
• 金额: $ 60万
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0718924&HistoricalAwards=false
• 关键词: Conformational; Eequilibria; Intrinsically; Disordered; Proteins

The goal of this project is to develop a quantitative framework for conformational equilibria of intrinsically disordered proteins (IDPs), which are a class of functional proteins that are largely unfolded under physiological conditions. Conformational equilibria refer to ensemble average properties and spontaneous fluctuations of IDPs in their native milieus. Important biological functions are associated with intrinsic disorder. These include molecular recognition, self-assembly, post-translational modifications, and entropic machines. The question of how IDPS use disorder in function will remain unanswered pending the availability of accurate, quantitative physical models for conformational equilibria of IDPs. Most IDPs are deficient in hydrophobic residues and are rich in charged and polar residues and therefore they are akin to polyampholytes and polyelectrolytes. Research goals will be accomplished using a combination of techniques including molecular simulations, theoretical approaches based on polymer physics, and fluorescence correlation spectroscopy. The studies will cover a range of IDPs, which differ in their overall hydrophobicity, charge asymmetry, and sequence complexity. Results of these studies will lead to an improved mechanistic understanding of how IDPs use disorder for function. Recent data from the PI's group shows that backbones of generic polypeptides behave like chains in poor solvents in physiological milieus. This observation implies that theories for polyelectrolytes and polyampholytes in poor solvents provide the appropriate conceptual framework for developing quantitative models for conformational equilibria of IDPs. This project will test the hypothesis that IDPs assume conformations akin to so-called necklace globules, which is expected of polyampholytes and polyelectrolytes in poor solvents.Research on IDPs is a major growth area in protein biophysics. The PI's group is developing important tools for the simulation and analysis of conformational and phase equilibria of IDPs. As part of this project, the PI will disseminate these tools to the community, and continue the tradition of using these tools to collaborate with experimentalists. The PI has taken active interest in promoting the cause of IDPs as a major area of research in molecular biophysics. The PI played an important role in helping to draft the statement-of-significance to convince the Biophysical Society's council to create a special subgroup within the society for the discussion of issues central to research on IDPs. The PI is a member of the Biophysics steering committee at Washington University. In this role, the PI is developing stronger ties between biophysics and bioengineering, especially focusing on the areas of IDP function and self-assembly. The PI is also actively involved with the McDonnell International Scholars program at Washington University. One of the goals of this program is to be proactive about recruiting top-flight graduate students and postdoctoral fellows to join research programs at Washington University and contribute to a rich and diverse intellectual environment.

该项目的目标是建立一个定量框架，用于内在无序蛋白（IDP）的构象平衡，IDP是一类在生理条件下大部分未折叠的功能蛋白质。构象平衡是指IDP在其天然环境中的系综平均性质和自发波动。重要的生物学功能与内在障碍有关。这些包括分子识别、自组装、翻译后修饰和熵机器。如何IDPS使用功能障碍的问题将仍然没有答案，等待国内流离失所者的构象平衡的准确，定量的物理模型。大多数IDP缺乏疏水残基，富含带电和极性残基，因此它们类似于两性聚电解质和聚电解质。 研究目标将使用包括分子模拟，基于聚合物物理学的理论方法和荧光相关光谱技术的组合来实现。这些研究将涵盖一系列IDP，它们在整体疏水性，电荷不对称性和序列复杂性方面有所不同。这些研究的结果将导致对国内流离失所者如何利用功能障碍的机械理解。来自PI小组的最新数据表明，在生理环境中，通用多肽的主链在不良溶剂中表现得像链。 这一观察结果意味着，在不良溶剂中的聚电解质和两性聚电解质的理论提供了适当的概念框架，发展定量模型的构象平衡的IDPs。该项目将测试IDPs假设的构象类似于所谓的项链小球，这是预期的聚两性电解质和聚电解质在不良溶剂中。IDPs的研究是蛋白质生物物理学的一个主要增长领域。PI的小组正在开发用于模拟和分析IDPs构象和相平衡的重要工具。作为该项目的一部分，PI将向社区传播这些工具，并继续使用这些工具与实验者合作的传统。PI积极关注促进国内流离失所者事业，将其作为分子生物物理学研究的一个主要领域。PI在帮助起草重要性声明方面发挥了重要作用，以说服生物物理学会理事会在学会内设立一个特别分组，讨论对国内流离失所者研究至关重要的问题。PI是华盛顿大学生物物理学指导委员会的成员。在这个角色中，PI正在生物物理学和生物工程之间建立更强的联系，特别是专注于IDP功能和自组装领域。PI还积极参与华盛顿大学的麦克唐纳国际学者计划。该计划的目标之一是积极主动地招募一流的研究生和博士后研究员加入华盛顿大学的研究项目，并为丰富多样的知识环境做出贡献。