NSF/MCB-BSF: Direct force measurements and analysis of intrinsically disordered proteins

该项目旨在测量一类蛋白质的行为，这种蛋白质被称为“无序蛋白质”。与其他蛋白质不同，这些本质上杂乱无章的蛋白质是松散的和动态的。这个项目的一个主要目标是找到控制这种动态行为的关键分子尺度特征。无序蛋白质普遍存在于所有生物体中，它们的功能强烈依赖于它们形成的结构；因此，这项研究有可能广泛影响我们对生命分子过程的基本理解。这项研究将部分由研究生进行，他们将接受广泛的物理和化学方法的蛋白质研究培训，从而获得进入技术劳动力所需的技能。这项工作将与以色列一所大学的科学家一起完成，这将促进国际合作。该项目的另一个好处是传播了一种专门的实验技术，有望在生物分子的定量研究中得到广泛的应用。先前的工作表明，某些内在无序的蛋白质表现出异常的动力学和弹性，显然是由于所谓的“异质中观结构”：波动的聚合行为与分布的局部结构形成的相互作用。在这里，研究人员的目标是调查这些异常影响在生物发生的无序蛋白质中的总体发生率，并研究导致这种行为的分子决定因素。该项目是由关于与非均质细观结构相关的残基序列的度量的特定假设驱动的。这些基于序列的假说导致了几个无序蛋白质的鉴定，这些无序蛋白质预计会显示一系列结构行为。主要工作将包括使用新型单分子探针和系综分析对这些模型系统的结构和动力学进行实验研究。如果成功，该项目将提高对无序蛋白质的复杂结构行为及其与无序蛋白质序列的粗粒度描述的关系的理解。这一美国/以色列合作项目得到了美国国家科学基金会和以色列双国科学基金会的支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This project aims to measure the behavior of a certain class of proteins, termed ‘disordered proteins’. Unlike other proteins, these intrinsically disordered proteins are floppy and dynamic. A major goal of this project is to find the key molecular-scale features that control this dynamic behavior. Disordered proteins are commonly found in all living organisms, and their function strongly depends on the structures they form; thus, this research has the potential to broadly impact our basic understanding of the molecular processes of life. The research will be carried out, in part, by graduate students, who will be trained broadly in physical and chemical approaches to the study of proteins, and thus gain skills needed to enter the technical workforce. The work will be done along with scientists at an Israeli university, which will advance international collaboration. Another side benefit of the project will be the dissemination of a specialized experimental technique, which is expected to have wide utility in the quantitative study of biological molecules.Prior work has shown that a certain intrinsically disordered protein displays anomalous dynamics and elasticity, apparently due to what is termed ‘heterogeneous mesostructure’: the interplay of fluctuating, polymeric behavior with distributed local structure formation. Here, researchers aim to investigate the overall incidence of these anomalous effects across biologically-occurring disordered proteins, and to study the molecular determinants that cause the behavior. The project is driven by specific hypotheses regarding the metrics of residue sequence associated with heterogeneous mesostructure. These sequence-based hypotheses have led to the identification of several disordered proteins expected to display a range of structural behavior. The primary work will involve experimental investigation of the structure and dynamics of those model systems, using both novel single-molecule probes and ensemble assays. If successful, the project will improve understanding of complex structural behavior in disordered proteins and its relation to coarse-grained descriptions of disordered-protein sequence.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.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.