Conformational Eequilibria of Intrinsically Disordered Proteins

这个项目的目标是开发一个定量框架来研究内在无序蛋白质(IDPs)的构象平衡，IDPs是一类在生理条件下基本上展开的功能蛋白质。构象平衡是指国内流离失所者在其原生环境中的集合平均性质和自发波动。重要的生物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。国内流离失所者如何利用功能障碍的问题仍未得到回答，直到有了准确的、定量的国内流离失所者构象平衡物理模型。大多数国内流离失所者缺乏疏水残基，而富含带电残基和极性残基，因此它们类似于聚两性离子和聚电解质。研究目标将使用包括分子模拟、基于聚合物物理的理论方法和荧光相关光谱在内的技术组合来实现。这些研究将涵盖一系列IDPs，它们在总体疏水性、电荷不对称性和序列复杂性方面存在差异。这些研究的结果将导致对国内流离失所者如何利用紊乱来实现功能的更好的机械性理解。PI小组的最新数据表明，在生理环境中，通用多肽的骨架在不良溶剂中的行为就像链一样。这一观察结果表明，在劣质溶剂中的聚电解质和聚两性电解质的理论为开发国内流离失所者构象平衡的定量模型提供了适当的概念框架。这个项目将检验这样的假设，即国内流离失所者假设的构象类似于所谓的项链球体，这是在较差的溶剂中预期的聚两性离子和聚电解质的构象。对国内流离失所者的研究是蛋白质生物物理学中的一个主要增长领域。PI的小组正在开发重要的工具，用于模拟和分析国内流离失所者的构象和相平衡。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。作为分子生物物理学的一个主要研究领域，国际社会积极致力于促进国内流离失所者的事业。非政府组织在帮助起草重要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小组，讨论国内流离失所者研究的核心问题。国际和平研究所是华盛顿大学生物物理学指导委员会的成员。在这一角色中，PI正在生物物理学和生物工程之间建立更紧密的联系，特别是专注于IDP功能和自我组装领域。该协会还积极参与了华盛顿大学的麦克唐奈国际学者项目。该项目的目标之一是积极主动地招募顶尖研究生和博士后研究员加入华盛顿大学的研究项目，并为丰富和多样化的知识环境做出贡献。

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.