Dataset Information

Folding Free Energy Landscape of Ordered and Intrinsically Disordered Proteins.

ABSTRACT: Folding funnel is the essential concept of the free energy landscape for ordered proteins. How does this concept apply to intrinsically disordered proteins (IDPs)? Here, we address this fundamental question through the explicit characterization of the free energy landscapes of the representative ?-helical (HP-35) and ?-sheet (WW domain) proteins and of an IDP (pKID) that folds upon binding to its partner (KIX). We demonstrate that HP-35 and WW domain indeed exhibit the steep folding funnel: the landscape slope for these proteins is ca. -50?kcal/mol, meaning that the free energy decreases by ~5?kcal/mol upon the formation of 10% native contacts. On the other hand, the landscape of pKID is funneled but considerably shallower (slope of -24?kcal/mol), which explains why pKID is disordered in free environments. Upon binding to KIX, the landscape of pKID now becomes significantly steep (slope of -54?kcal/mol), which enables otherwise disordered pKID to fold. We also show that it is the pKID-KIX intermolecular interactions originating from hydrophobic residues that mainly confer the steep folding funnel. The present work not only provides the quantitative characterization of the protein folding free energy landscape, but also establishes the usefulness of the folding funnel concept to IDPs.

SUBMITTER: Chong SH

PROVIDER: S-EPMC6797787 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Folding Free Energy Landscape of Ordered and Intrinsically Disordered Proteins.

Chong Song-Ho SH Ham Sihyun S

Scientific reports 20191017 1

Folding funnel is the essential concept of the free energy landscape for ordered proteins. How does this concept apply to intrinsically disordered proteins (IDPs)? Here, we address this fundamental question through the explicit characterization of the free energy landscapes of the representative α-helical (HP-35) and β-sheet (WW domain) proteins and of an IDP (pKID) that folds upon binding to its partner (KIX). We demonstrate that HP-35 and WW domain indeed exhibit the steep folding funnel: the ...[more]

PMID: 31624293

Similar Datasets

Project description:Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes and preform critical roles in many cellular processes, most often through the association with globular proteins. Despite lacking a stable three-dimensional structure by themselves, they may acquire a defined conformation upon binding globular targets. The most common type of secondary structure acquired by these binding motifs entails formation of an α-helix. It has been hypothesized that such disorder-to-order transitions are associated with a significant free energy penalty due to IDP folding, which reduces the overall IDP-target affinity. However, the exact magnitude of IDP folding penalty in α-helical binding motifs has not been systematically estimated. Here, we report the folding penalty contributions for 30 IDPs undergoing folding-upon-binding and find that the average IDP folding penalty is +2.0 kcal/mol and ranges from 0.7 to 3.5 kcal/mol. We observe that the folding penalty scales approximately linearly with the change in IDP helicity upon binding, which provides a simple empirical way to estimate folding penalty. We analyze to what extent do pre-structuring and target-bound IDP dynamics (fuzziness) reduce the folding penalty and find that these effects combined, on average, reduce the folding cost by around half. Taken together, the presented analysis provides a quantitative basis for understanding the role of folding penalty in IDP-target interactions and introduces a method estimate this quantity. Estimation and reduction of IDP folding penalty may prove useful in the rational design of helix-stabilized inhibitors of IDP-target interactions. STATEMENT: The α-helical binding motifs are ubiquitous among the intrinsically disordered proteins (IDPs). Upon binding their targets, they undergo a disorder-to-order transition, which is accompanied by a significant folding penalty whose magnitude is generally not known. Here, we use recently developed statistical-thermodynamic model to estimate the folding penalties for 30 IDPs and clarify the roles of IDP pre-folding and bound-state dynamics in reducing the folding penalty.

Project description:Achieving facile specific recognition is essential for intrinsically disordered proteins (IDPs) that are involved in cellular signaling and regulation. Consideration of the physical time scales of protein folding and diffusion-limited protein-protein encounter has suggested that the frequent requirement of protein folding for specific IDP recognition could lead to kinetic bottlenecks. How IDPs overcome such potential kinetic bottlenecks to viably function in signaling and regulation in general is poorly understood. Our recent computational and experimental study of cell-cycle regulator p27 (Ganguly et al., J. Mol. Biol. (2012)) demonstrated that long-range electrostatic forces exerted on enriched charges of IDPs could accelerate protein-protein encounter via "electrostatic steering" and at the same time promote "folding-competent" encounter topologies to enhance the efficiency of IDP folding upon encounter. Here, we further investigated the coupled binding and folding mechanisms and the roles of electrostatic forces in the formation of three IDP complexes with more complex folded topologies. The surface electrostatic potentials of these complexes lack prominent features like those observed for the p27/Cdk2/cyclin A complex to directly suggest the ability of electrostatic forces to facilitate folding upon encounter. Nonetheless, similar electrostatically accelerated encounter and folding mechanisms were consistently predicted for all three complexes using topology-based coarse-grained simulations. Together with our previous analysis of charge distributions in known IDP complexes, our results support a prevalent role of electrostatic interactions in promoting efficient coupled binding and folding for facile specific recognition. These results also suggest that there is likely a co-evolution of IDP folded topology, charge characteristics, and coupled binding and folding mechanisms, driven at least partially by the need to achieve fast association kinetics for cellular signaling and regulation.

Dataset Information

Folding Free Energy Landscape of Ordered and Intrinsically Disordered Proteins.

Publications

Folding Free Energy Landscape of Ordered and Intrinsically Disordered Proteins.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets