Nonnative Interactions in Coupled Folding and Binding Processes of Intrinsically Disordered Proteins

Yongqi Huang,Zhirong Liu,Vladimir N Uversky

doi:10.1371/journal.pone.0015375

Yongqi Huang, Zhirong Liu + Show 1 more

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https://doi.org/10.1371/journal.pone.0015375

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Abstract

Proteins function by interacting with other molecules, where both native and nonnative interactions play important roles. Native interactions contribute to the stability and specificity of a complex, whereas nonnative interactions mainly perturb the binding kinetics. For intrinsically disordered proteins (IDPs), which do not adopt rigid structures when being free in solution, the role of nonnative interactions may be more prominent in binding processes due to their high flexibilities. In this work, we investigated the effect of nonnative hydrophobic interactions on the coupled folding and binding processes of IDPs and its interplay with chain flexibility by conducting molecular dynamics simulations. Our results showed that the free-energy profiles became rugged, and intermediate states occurred when nonnative hydrophobic interactions were introduced. The binding rate was initially accelerated and subsequently dramatically decreased as the strength of the nonnative hydrophobic interactions increased. Both thermodynamic and kinetic analysis showed that disordered systems were more readily affected by nonnative interactions than ordered systems. Furthermore, it was demonstrated that the kinetic advantage of IDPs (“fly-casting” mechanism) was enhanced by nonnative hydrophobic interactions. The relationship between chain flexibility and protein aggregation is also discussed.

Highlights

Deciphering how physical interactions affect protein behavior is fundamental to structural and functional biology
intrinsically disordered proteins (IDPs) are readily trapped into non-specific states To investigate the effects of nonnative hydrophobic interactions on the coupled folding and binding of IDPs, we modified a coarsegrained Go-like model of IDPs [62] to include a sequencedependent hydrophobic-polar (HP) component which accounts for the nonnative hydrophobic interactions [37]
A parameter a was introduced to scale the strength of the intra-molecular native interactions and tune the chain flexibility of phosphorylated kinase-inducible domain (pKID) [62], while another parameter KHP was used to describe the strength of the nonnative hydrophobic interactions

Summary

Introduction

Deciphering how physical interactions affect protein behavior is fundamental to structural and functional biology. Interactions presented in the native state (native interactions) dominate in processes such as protein folding and binding, resulting in a funnel-like energy landscape with minimal frustration [1,2,3]. Under such conditions, the Go-model [4,5] has been widely adopted to generate valuable insights into protein folding and binding [6,7,8,9,10]. Nonnative interactions have been recognized to be important in the initial formation of the non-specific encounter complexes, where long-range electrostatic interactions increase the diffusion process by the ‘‘steering effect’’, and short-range hydrophobic interactions facilitate the formation of the final specific complexes by a two-dimensional search on the surface [24,25,26,27]

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