Competing interactions give rise to two-state behavior and switch-like transitions in charge-rich intrinsically disordered proteins

Abstract

Significance Intrinsically disordered regions (IDRs) of proteins, when tethered to folded domains, function either as flexible tails or as linkers between domains. Most IDRs are polyampholytes that comprise a mixture of oppositely charged residues. Recent measurements of tethered polyampholytes showed the tendency of arginine- and lysine-rich sequences to behave very differently from one another. Using computer simulations, we show that these differences are determined by differences in free energies of hydration, steric volumes, and other considerations. Further, the interplay between electrostatic attractions and favorable free energies of hydration creates distinct stable states for polyampholytic IDRs. These findings have implications for switch-like transitions and the regulation of effective concentrations of interaction motifs by IDRs.