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Position-, Disorder-, and Salt-Dependent Diffusion in Binding-Coupled-Folding of Intrinsically Disordered Protein


Successful extensions of protein-folding energy landscape theory to intrinsically disordered proteins’ (IDPs’) binding-coupled-folding transition can enormously simplify this biomolecular process into diffusion along a limited number of reaction coordinates, and the dynamics subsequently is described by Kramers’ rate theory. As the critical pre-factor, the diffusion coefficient D has direct implications on binding kinetics. Here, we employ a structure-based model (SBM) to calculate D in the binding–folding of an IDP prototype. We identify a strong position-dependent D during binding by applying a reaction coordinate that directly measures the fluctuations in a Cartesian configuration space. Using the malleability of the SBM, we modulate the degree of conformational disorder in an isolated IDP and determine complex effects of intrinsic disorder on D varying for different binding stages. Here, D tends to increase with disorder during initial binding but shows a non-monotonic relationship with disorder in terms of a decrease-followed-by-increase in D during the late binding stage. Salt concentration, which correlates with electrostatic interactions via Debye–Hückel theory in our SBM, also modulates D in a stepwise way. The speeding up of diffusion by electrostatic interactions is observed during the formation of the encounter complex at the beginning of binding, while the last diffusive binding dynamics is hindered by non-native salt bridges. Because D describes the diffusive speed locally, which implicitly reflects the roughness of the energy landscape, we are eventually able to portray the binding energy landscape, including that from IDPs’ binding, then to binding with partial folding, and finally to rigid docking, as well as that under different environmental salt concentrations. Our theoretical results provide key mechanistic insights into IDPs’ binding–folding that is internally conformation- and externally salt-controlled with respect to diffusion.

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Publication details

The article was received on 01 Nov 2018, accepted on 12 Feb 2019 and first published on 12 Feb 2019

Article type: Paper
DOI: 10.1039/C8CP06803H
Citation: Phys. Chem. Chem. Phys., 2019, Accepted Manuscript

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    Position-, Disorder-, and Salt-Dependent Diffusion in Binding-Coupled-Folding of Intrinsically Disordered Protein

    X. Chu and J. Wang, Phys. Chem. Chem. Phys., 2019, Accepted Manuscript , DOI: 10.1039/C8CP06803H

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