In this work, we quantitatively investigate the thermodynamic analogy between the folding of monomeric proteins and the interactions of intrinsically disordered proteins (IDPs). Motivated by the hypothesis that similar hydrophobic forces guide both globular protein folding and also IDP interactions, we present a unified experimental and computational investigation of the coupling between the folding and binding of the intrinsically disordered tail of FCP1 when interacting with the cooperatively folding winged-helix domain of Rap74. Our calorimetric measurements quantitatively demonstrate the significance of hydrophobic interactions for this binding event. Our computational studies indicate that IDPs relieve frustration at the surface of ordered proteins to generate a minimally frustrated complex that is strikingly similar to a globular monomeric protein. In summary, these results not only quantify the thermodynamic forces driving disordered protein interactions but also highlight the role of ordered proteins for IDP function.
Keywords: FCP1; Rap74; funneled energy landscape; hydrophobic heat capacity; isothermal titration calorimetry; solvent-accessible surface area.