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

该项目旨在测量某类蛋白质的行为，称为“无序蛋白质”。 与其他蛋白质不同，这些内在无序的蛋白质是松软的和动态的。该项目的主要目标是找到控制这种动态行为的关键分子尺度特征。无序蛋白质通常存在于所有生物体中，它们的功能在很大程度上取决于它们形成的结构;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。研究将部分由研究生进行，他们将接受蛋白质研究的物理和化学方法的广泛培训，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沿着完成，这将促进国际合作。该项目的另一个附带好处将是传播一种专门的实验技术，预计该技术将在生物分子的定量研究中具有广泛的实用性。先前的工作表明，某种内在无序的蛋白质显示出异常的动力学和弹性，这显然是由于所谓的“异质介观结构”：波动的聚合物行为与分布式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效应在生物学上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。该项目是由特定的假设驱动的残基序列与异质性介观结构相关的度量。这些基于序列的假设已经导致了预期显示一系列结构行为的几种无序蛋白质的鉴定。主要的工作将涉及这些模型系统的结构和动力学的实验研究，使用新的单分子探针和合奏测定。如果成功，该项目将提高对无序蛋白质复杂结构行为的理解，以及它与无序蛋白质序列粗粒度描述的关系。以色列项目由美国国家科学基金会和以色列两国科学基金会支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的评估被认为值得支持。影响审查标准。

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.