Macromolecular Crowding and Intrinsically Disordered Proteins: A Polymer Physics Perspective

Abstract The cell is a crowded environment where a relevant fraction of the available space is occupied by proteins, nucleic acids, and metabolites. Here we discuss recent advancements in the understanding of crowding effects on intrinsically disordered proteins. Differently from their structured counterparts, these proteins do not adopt a stable three‐dimensional structure and remain flexible and dynamic in solution. The physics of polymers and colloids provides a framework to interpret how crowding modulates conformations, dynamics, and interactions of disordered proteins. Flory‐Huggins models enable rationalizing the different degree of compaction induced by crowding agents in terms of depletion interactions. The same interactions modulate the diffusion of the disordered proteins in a crowded milieu and the association and dissociation rates when interacting with a ligand. Altogether, this theoretical framework provides new insights into the interpretation of the effects of the cellular environment on disordered proteins.