Dataset Information

Coupled folding-binding in a hydrophobic/polar protein model: impact of synergistic folding and disordered flanks.

ABSTRACT: Coupled folding-binding is central to the function of many intrinsically disordered proteins, yet not fully understood. With a continuous three-letter protein model, we explore the free-energy landscape of pairs of interacting sequences and how it is impacted by 1), variations in the binding mechanism; and 2), the addition of disordered flanks to the binding region. In particular, we focus on two sequences, one with 16 and one with 35 amino acids, which make a stable dimeric three-helix bundle at low temperatures. Three distinct binding mechanisms are realized by altering the stabilities of the individual monomers: docking, coupled folding-binding of a single ?-helix, and synergistic folding and binding. Compared to docking, the free-energy barrier for binding is reduced when the single ?-helix is allowed to fold upon binding, but only marginally. A greater reduction is found for synergistic folding, which in addition results in a binding transition state characterized by very few interchain contacts. Disordered flanking chain segments attached to the ?-helix sequence can, despite a negligible impact on the dimer stability, lead to a downhill free-energy surface in which the barrier for binding is eliminated.

SUBMITTER: Bhattacherjee A

PROVIDER: S-EPMC3274785 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Coupled folding-binding in a hydrophobic/polar protein model: impact of synergistic folding and disordered flanks.

Bhattacherjee Arnab A Wallin Stefan S

Biophysical journal 20120207 3

Coupled folding-binding is central to the function of many intrinsically disordered proteins, yet not fully understood. With a continuous three-letter protein model, we explore the free-energy landscape of pairs of interacting sequences and how it is impacted by 1), variations in the binding mechanism; and 2), the addition of disordered flanks to the binding region. In particular, we focus on two sequences, one with 16 and one with 35 amino acids, which make a stable dimeric three-helix bundle a ...[more]

PMID: 22325280

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Project description: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 the 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. The 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, which is internally conformation- and externally salt-controlled with respect to diffusion.

Dataset Information

Coupled folding-binding in a hydrophobic/polar protein model: impact of synergistic folding and disordered flanks.

Publications

Coupled folding-binding in a hydrophobic/polar protein model: impact of synergistic folding and disordered flanks.

Similar Datasets

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