Probing the Hidden Sensitivity of Intrinsically Disordered Proteins to their Chemical Environment

Intrinsically disordered proteins and protein-regions (IDRs) make up roughly 30% of the human proteome and play vital roles in a wide variety of biological processes. Given a lack of persistent tertiary structure, all of the residues in an IDR are, to some extent, solvent exposed. This extensive surface area, coupled with the absence of strong intramolecular contacts, makes IDRs inherently sensitive to their chemical environment. Despite this sensitivity, our understanding of how IDR structural ensembles are influenced by changes in their chemical environment is limited. This is particularly relevant given a growing body of evidence showing that IDR function is linked to the underlying structural ensemble. We develop and use a combined experimental, computational, and analytical framework for high-throughput characterization of IDR sensitivity we call solution space scanning. Our framework reveals that IDRs show sequence-dependent sensitivity to solution chemistry, with complex behavior that can be interpreted through relatively simple polymer models. Our results imply that solution-responsive IDRs are ubiquitous and can provide an additional layer of biological regulation.