Intrinsically disordered
protein regions (IDRs) make up over 30%
of the human proteome and exist in a dynamic conformational ensemble
instead of a native, well-folded structure. 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 these 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 IDR sequence remains
unexplored. Here, we use all-atom simulations to analyze how structural
preferences in 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:
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
the IDR entropic force strength. We propose that the entropic force
is a sequence-dependent, environmentally tunable property of terminal
IDR sequences.