Structural preferences modulate the entropic force exerted by disordered proteins.

Abstract

When tethered to surfaces such as lipid vesicles or well-folded proteins, polymers exert an entropic force that pulls against the point of tethering. This is because the motions produced by the protein's thermal fluctuations push against and away from the tethered surface. Intrinsically disordered protein regions (IDRs) commonly exist at the termini of proteins. When tethered to protein or membrane surfaces, IDRs were shown to exert an entropic force that is thought to largely depend on their length. However, IDPs are not homopolymers: their sequences can be complex and their conformational ensembles have structural preferences that will affect their average shape. We hypothesize that such IDR structural preferences also affect the entropic force exerted by the sequence. To test this hypothesis, we use all-atom simulations and an enhanced sampling strategy to quantify the entropic force exerted by over 100 IDR sequences. We find that IDRs with compact ensembles tend to induce a stronger entropic force than expanded IDRs. We also find that solution condition changes will alter IDR ensemble structure and thus alter the magnitude of the entropic force. Our work indicates that the structural preferences of IDRs, coupled with their interaction with the solution condition, can act together to dramatically increase the entropic force of some, but not all, IDRs.