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

Intrinsically
disordered protein-regions (IDRs) make up roughly
30% of the human proteome and are central to a wide range of biological
processes. Given a lack of persistent tertiary structure, all residues
in IDRs 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. We
report a combined experimental, computational, and analytical framework
for high-throughput characterization of IDR sensitivity. Our framework
reveals that IDRs can expand or compact in response to changes in
their solution environment. Importantly, the direction and magnitude
of conformational change depend on both protein sequence and cosolute
identity. For example, some solutes such as short polyethylene glycol
chains exert an expanding effect on some IDRs and a compacting effect
on others. Despite this complex behavior, we can rationally interpret
IDR responsiveness to solution composition changes using relatively
simple polymer models. Our results imply that solution-responsive
IDRs are ubiquitous and can provide an additional layer of regulation
to biological systems.