Drugging Disordered Proteins by Conformational Selection to Inform Therapeutic Intervention

Drugging intrinsically disordered proteins (IDPs) has
historically
been a major challenge due to their lack of stable binding sites,
conformational heterogeneity, and rapid ability to self-associate
or bind nonspecific neighbors. Furthermore, it is unclear whether
binders of disordered proteins (i) induce entirely new conformations
or (ii) target transient prestructured conformations via stabilizing
existing states. To distinguish between these two mechanisms, we utilize
molecular dynamics simulations to induce structured conformations
in islet amyloid polypeptide (IAPP), a disordered endocrine peptide
implicated in Type II Diabetes. Using umbrella sampling, we measure conformation-specific affinities of molecules previously
shown to bind IAPP to determine if they can discriminate between two
distinct IAPP conformations (fixed in either α-helix or β-sheet).
We show that our two-state model of IAPP faithfully predicts the experimentally
observed selectivity of two classes of IAPP binders while revealing
differences in their molecular binding mechanisms. Specifically, the
binding preferences of foldamers designed for human IAPP were not
fully accounted for by conformational selection, unlike those of β-breaking
peptides designed to mimic IAPP self-assembly sequences. Furthermore,
the binding of these foldamers, but not β-breaking peptides,
was disrupted by changes in the rat IAPP sequence. Taken together,
our data quantify the sequence and conformational specificity for
IAPP binders and reveal that conformational selection sometimes overrides
sequence-level specificity. This work highlights the important role
of conformational selection in stabilizing IDPs, and it reveals how
fixed conformations can provide a tractable target for developing
disordered protein binders.