title: Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein.
abstract: Numerous relatively short regions within intrinsically disordered proteins (IDPs) serve 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 virus nucleoprotein. We developed 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 virus phosphoprotein. Our multiscaled approach led to remarkable qualitative and quantitative agreements between the theoretical predictions and experimental results (e.g., chemical shifts). We found that the free α-MoRE rapidly interconverts between multiple discrete partially helical conformations and the unfolded state, in accordance with the experimental observations. We quantified the underlying global folding-binding landscape. This leads to a synergistic mechanism in which the recognition event proceeds via (minor) conformational selection, followed by (major) induced folding. We also provided evidence that the α-MoRE is a compact molten globule-like IDP and behaves as a downhill folder in the induced folding process. We further provided 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 divide-and-conquer" strategy that confers them high specificity without high affinity.
authors.affiliation: State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiakun
authors.initials: X
authors.lastname: Chu
authors.forename: Sonia
authors.initials: S
authors.lastname: Longhi
authors.forename: Philippe
authors.initials: P
authors.lastname: Roche
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Erkang
authors.initials: E
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
mesh_terms: D001703:Biophysics; D007700:Kinetics; D008459:Measles virus / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D014764:Viral Proteins / Q000737:chemistry*
chemical_list: D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D014764:Viral Proteins; C058314:nucleoprotein, Measles virus
keywords: flexible binding; flexible recognition; free-energy surface; hybrid structure-based model; multiscale simulation
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