Structural preferences shape the entropic force of disordered protein ensembles.

Intrinsically disordered protein regions (IDRs) make up over 30% of the human proteome and instead of a native, well-folded structure exist in a dynamic conformational ensemble. Tethering IDRs to a surface (for example, the surface of a well-folded region of the same protein) can reduce the number of accessible conformations in IDR ensembles. This reduces the ensemble's conformational entropy, generating an effective entropic force that pulls away from the point of tethering. Recent experimental work has shown that this entropic force causes measurable, physiologically relevant changes to protein function, but how the magnitude of this force depends on the IDR sequence remains unexplored. Here we use all-atom simulations to analyze how structural preferences encoded in dozens of IDR ensembles contribute to the entropic force they exert upon tethering. We show that sequence-encoded structural preferences play an important role in determining the magnitude of this force and that compact, spherical ensembles generate an entropic force that can be several times higher than more extended ensembles. We further show that changes in the surrounding solution's chemistry can modulate IDR entropic force strength. We propose that the entropic force is a sequence-dependent, environmentally tunable property of terminal IDR sequences.