Allosteric Dynamic Control of Binding

Abstract

Proteins have a highly dynamic nature and there is a complex interrelation between their structural dynamics and binding behavior. By assuming various conformational ensembles, they perform both local and global fluctuations to interact with other proteins in a dynamic infrastructure adapted to functional motion. Here, we show that there is a significant association between allosteric mutations, which lead to high-binding-affinity changes, and the hinge positions of global modes, as revealed by a large-scale statistical analysis of data in the Structural Kinetic and Energetic Database of Mutant Protein Interactions (SKEMPI). We further examined the mechanism of allosteric dynamics by conducting studies on human growth hormone (hGH) and pyrin domain (PYD), and the results show how mutations at the hinge regions could allosterically affect the binding-site dynamics or induce alternative binding modes by modifying the ensemble of accessible conformations. The long-range dissemination of perturbations in local chemistry or physical interactions through an impact on global dynamics can restore the allosteric dynamics. Our findings suggest a mechanism for the coupling of structural dynamics to the modulation of protein interactions, which remains a critical phenomenon in understanding the effect of mutations that lead to functional changes in proteins.

Long-range correlation in protein dynamics: Confirmation by structural data and normal mode analysis

“…Such a property plays an important role in the functionality of the proteins. For example, for allosteric proteins, long-range correlations warrant the binding at one site can be transmitted to other functional sites [13,14], and enable the high susceptibility for proteins in cellular environments. Based on the correlation analysis of structural ensembles determined by solution nuclear magnetic resonance (NMR), it was already demonstrated that the native proteins exhibit long-range correlations and high susceptibility in the native dynamics [15].…”

SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

“…The first release has been used as a basis for many further studies, including the development of energy functions [48], [46] which were subsequently implemented in the CCharPPI web server for characterising protein-protein interactions [49], as well as being used for ranking docked poses [45], [58], [6], [50]. SKEMPI has also been used to study human disease [56], [16], [55], assessing the role of dynamics on binding [69], exploring the conservation of binding regions [28], evaluating experimental affinity measurement methods [22], as well serving as a data source for models which predict dissociation rate changes upon mutation [1], pathological mutations [23], hotspot residues (e.g. [30], [44], [42], [66]) and changes in binding energy (e.g.…”

An optimal distance cutoff for contact-based Protein Structure Networks using side-chain centers of mass

“…Indeed, they can resemble bound states to a biological partner 6–10 , active states of enzymes 11–14 , or conformations that are stabilized by a post-translational modification (PTM) 6, 11 , as well as altered by a disease-related mutation 15 .…”