Abstract

Intrinsically disordered proteins (IDPs) are functional proteins where a lack of stable tertiary structures is required for function. Many of the IDPs involved in cellular regulation and signaling have substantial residual structures in the unbound state and fold into stable structures upon binding to their biological partners. Specific roles of these residual structures in and the underlying mechanisms of coupled binding and folding are poorly understood. Here we use physics-based atomistic simulations to compute the multidimensional free energy surfaces of coupled folding and binding of the intrinsically disordered p53 extreme C-terminus to protein S100B(betabeta). The results show that, even though the unbound p53 peptide appears to sample several alternative folded states previously observed when in complex with various targets, it binds to S100B(betabeta) through formation of nonspecific complexes, i.e., a "fly-casting"-like process. The current work, together with previous NMR and coarse-grained modeling studies of another prototypical system, suggests that the main role of the residual structures in the unbound states of regulatory IDPs might be to provide thermodynamic control of binding through modulating the entropic cost of folding and not to enhance the binding rate by acting as initial contact sites.