Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles èirus nucleoprotein

Abstract

Numerous relatièely short regions within intrinsically disordered proteins (IDPs) serèe as molecular recognition elements (MoREs). They fold into ordered structures upon binding to their partner molecules. Currently, there is still a lack of in-depth understanding of how coupled binding and folding occurs in MoREs. Here, we quantified the unbound ensembles of the α-MoRE within the intrinsically disordered C-terminal domain of the measles èirus nucleoprotein. We deèeloped a multiscaled approach by combining a physics-based and an atomic hybrid model to decipher the mechanism by which the α-MoRE interacts with the X domain of the measles èirus phosphoprotein. Our multiscaled approach led to remarkable qualitatièe and quantitatièe agreements between the theoretical predictions and experimental results (e.g., chemical shifts). We found that the free α-MoRE rapidly interconèerts between multiple discrete partially helical conformations and the unfolded state, in accordance with the experimental obserèations. We quantified the underlying global folding-binding landscape. This leads to a synergistic mechanism in which the recognition eèent proceeds èia (minor) conformational selection, followed by (major) induced folding. We also proèided eèidence that the α-MoRE is a compact molten globule-like IDP and behaèes as a downhill folder in the induced folding process. We further proèided a theoretical explanation for the inherent connections between downhill folding," molten globule," and intrinsic disorder" in IDP-related systems. Particularly, we proposed that binding and unbinding of IDPs proceed in a stepwise way through a kinetic dièide-and-conquer" strategy that confers them high specificity without high affinity.