Electrostatic interactions compensate energetic frustration in the coupled folding and binding of intrinsically disordered proteins

Intrinsically disordered protein regions (IDRs) establish highly specific protein-protein interactions that play key roles in cell signaling. Many IDRs adopt an ordered structure upon binding to folded protein domains, but the energy landscape for coupled folding and binding (CFB) is poorly understood. Here, we elucidate the energy landscape for CFB using the LxCxE motif from the human papillomavirus E7 protein (LxCxEWT) as a minimal model system. Kinetic and structural analysis uncovers strong compensatory energetics whereby stabilizing electrostatic interactions counterbalance energetic frustration in the rate-limiting step for CFB. This mechanism, which we refer to as electrostatic compensation, enables a dynamic search for native contacts while preventing complex dissociation. A global analysis reveals energetic frustration in earliest steps of CFB for many IDRs. Electrostatic compensation may be a widespread mechanism evolved to allow fine-tuning of the affinity and specificity of IDR interactions, which dictates functional selection for charge content within IDRs.