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

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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.