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Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding.

ABSTRACT: The sequence-structure-function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well-defined three-dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

SUBMITTER: Yang J

PROVIDER: S-EPMC6798136 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding.

Yang Jing J Gao Meng M Xiong Junwen J Su Zhengding Z Huang Yongqi Y

Protein science : a publication of the Protein Society 20190904 11

The sequence-structure-function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well-defined three-dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While grea ...[more]

PMID: 31441158

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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.

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

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding.

Publications

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding.

Similar Datasets

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