Biophysics of Protein Disorder and Complexity, Single Molecules to Mesoscales

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Intrinsically disordered proteins (IDPs) comprise a significant fraction of eukaryotic proteomes, and are critical for cellular function and several diseases. They are also involved in the formation and dynamics of membraneless organelles (MLOs) that are important for cellular biochemistry. Several important open questions remain to be answered regarding the detailed biophysics of IDPs and MLOs. Addressing these questions is the overall goal of the proposed work. Building on our past and ongoing efforts in this area, we will carry out work in several directions. Using peptide and protein systems that are linked to ALS and cancer, we will use both single-molecule and ensemble experiments to probe important aspects of these systems, including understanding the interplay of intra- and inter-molecular interactions, effects of reentrant transitions and asymmetries in the phase diagrams, and aging in droplet systems. We will also carry out experiments on understanding membrane-induced binding-folding and aggregation of the Parkinson’s disease related protein α-synuclein. Single-molecule tools will also be improved or further developed as needed during the project. These directions will also lead to more complex experiments both in vitro and in cells at later stages of the work or in future experiments. Overall, the proposed work is anticipated to lead to an improved understanding of the biophysical mechanisms underlying the cell biology and disease relevance of these important biological systems.