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Temperature-dependent solvation modulates the dimensions of disordered proteins

Significance A large number of naturally occurring proteins are now known to be unstructured under physiological conditions. Many of these intrinsically disordered proteins (IDPs) bind other biological macromolecules or ligands and are involved in important regulatory processes in the cell. For understanding the structural basis of these functional properties, it is essential to quantify the balance of interactions that modulate the heterogeneous conformational distributions of IDPs and unfolded proteins in general. In contrast to the behavior expected for simple polymers with temperature-independent intramolecular interactions, unfolded proteins become more compact when the temperature is raised. Here, we show that the temperature dependence of the interactions of the constituent amino acid residues with the aqueous solvent have a dominant effect on this behavior. For disordered proteins, the dimensions of the chain are an important property that is sensitive to environmental conditions. We have used single-molecule Förster resonance energy transfer to probe the temperature-induced chain collapse of five unfolded or intrinsically disordered proteins. Because this behavior is sensitive to the details of intrachain and chain–solvent interactions, the collapse allows us to probe the physical interactions governing the dimensions of disordered proteins. We find that each of the proteins undergoes a collapse with increasing temperature, with the most hydrophobic one, λ-repressor, undergoing a reexpansion at the highest temperatures. Although such a collapse might be expected due to the temperature dependence of the classical “hydrophobic effect,” remarkably we find that the largest collapse occurs for the most hydrophilic, charged sequences. Using a combination of theory and simulation, we show that this result can be rationalized in terms of the temperature-dependent solvation free energies of the constituent amino acids, with the solvation properties of the most hydrophilic residues playing a large part in determining the collapse.