Different Roles of Backbone-Originated and Native-Contact-Originated Flexibilities of an Intrinsically Disordered Protein in Fast Binding and Unbinding

Abstract

The intrinsically disordered protein (IDP) in the unbound state is so flexible that it does not adopt a unique structure. IDP may exploit this flexibility to function as a signaling molecule, switching on and off the signal by binding to and unbinding from the target molecule, considering that the binding/unbinding kinetics is largely affected by the flexibility. For example, it has been suggested that the flexibility enhances the binding rate by the fly-casting mechanism. However, some counter evidences have been reported, so the role of the flexibility on the fly-casting mechanism is still controversial. To address this problem, we examined the effect of two different types of flexibilities that were computationally imparted to IDP to which the one-bead (Cα) Gō-like model was applied; one is by softening the backbone rigidity and the other is by weakening the native contact. We used pKID (kinase inducible domain of CREB) as a model of IDP. pKID folds upon binding to the partner protein, KIX. We calculated the potential of mean force as a function of distance between pKID and KIX. We found that the backbone-originated flexibility and the native-contact-originated one exhibit different results. The native-contact-originated flexibility yielded larger capturing radius and faster binding, consistent with the fly-casting, but the backbone-originated one did not. The strength of the interaction between IDP and the target was also shown to play a critical role. As for unbinding, the backbone-originated flexibility destabilized the bound state more effectively, leading to faster unbinding. Therefore, IDP can exploit these two different types of flexibilities to optimize their signaling function.