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The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks.

ABSTRACT: Hubs are highly connected proteins in a protein-protein interaction network. Previous work has implicated disordered domains and high surface charge as the properties significant in the ability of hubs to bind multiple proteins. While conformational flexibility of disordered domains plays an important role in the binding ability of large hubs, high surface charge is the dominant property in small hubs. In this study, we further investigate the role of the high surface charge in the binding ability of small hubs in the absence of disordered domains. Using multipole expansion, we find that the charges are highly distributed over the hub surfaces. Residue enrichment studies show that the charged residues in hubs are more prevalent on the exposed surface, with the exception of Arg, which is predominantly found at the interface, as compared to non-hubs. This suggests that the charged residues act primarily from the exposed surface rather than the interface to affect the binding ability of small hubs. They do this through (i) enhanced intra-molecular electrostatic interactions to lower the desolvation penalty, (ii) indirect long - range intermolecular interactions with charged residues on the partner proteins for better complementarity and electrostatic steering, and (iii) increased solubility for enhanced diffusion-controlled rate of binding. Along with Arg, we also find a high prevalence of polar residues Tyr, Gln and His and the hydrophobic residue Met at the interfaces of hubs, all of which have the ability to form multiple types of interactions, indicating that the interfaces of hubs are optimized to participate in multiple interactions.

SUBMITTER: Patil A

PROVIDER: S-EPMC5036656 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks.

Patil Ashwini A Nakamura Haruki H

Biophysics (Nagoya-shi, Japan) 20070721

Hubs are highly connected proteins in a protein-protein interaction network. Previous work has implicated disordered domains and high surface charge as the properties significant in the ability of hubs to bind multiple proteins. While conformational flexibility of disordered domains plays an important role in the binding ability of large hubs, high surface charge is the dominant property in small hubs. In this study, we further investigate the role of the high surface charge in the binding abili ...[more]

PMID: 27857564

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Project description:BackgroundIn the post-genomic era, a central and overarching question in the analysis of protein-protein interaction networks continues to be whether biological characteristics and functions of proteins such as lethality, physiological malfunctions and malignancy are intimately linked to the topological role proteins play in the network as a mathematical structure. One of the key features that have implicitly been presumed is the existence of hubs, highly connected proteins considered to play a crucial role in biological networks. We explore the structure of protein interaction networks of a number of organisms as metric spaces and show that hubs are non randomly positioned and, from a distance point of view, centrally located.ResultsBy analysing how the human functional protein interaction network, the human signalling network, Saccharomyces cerevisiae, Arabidopsis thaliana and Escherichia coli protein-protein interaction networks from various databases are distributed as metric spaces, we found that proteins interact radially through a central node, high degree proteins coagulate in the centre of the network, and those far away from the centre have low degree. We further found that the distribution of proteins from the centre is in some hierarchy of importance and has biological significance.ConclusionsWe conclude that structurally, protein interaction networks are mathematical entities that share properties between organisms but not necessarily with other networks that follow power-law. We therefore conclude that (i) if there are hubs defined by degree, they are not distributed randomly; (ii) zones closest to the centre of the network are enriched for critically important proteins and are also functionally very specialised for specific 'house keeping' functions; (iii) proteins closest to the network centre are functionally less dispensable and may present good targets for therapy development; and (iv) network biology requires its own network theory modelled on actual biological evidence and that simply adopting theories from the social sciences may be misleading.

Project description:What are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are two major questions of molecular biology, whose answers bring important implications both from a theoretical and applicative point of view. Here, we analyze chemical and physical features on a large dataset of protein-protein complexes with reliable experimental binding affinity data and compare them with a set of monomeric proteins for which melting temperature data was available. In particular, we probed the spatial organization of protein (1) intramolecular and intermolecular interaction energies among residues, (2) amino acidic composition, and (3) their hydropathy features. Analyzing the interaction energies, we found that strong Coulombic interactions are preferentially associated with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with stronger protein-protein binding affinity. Statistical analysis of amino acids abundances, exposed to the molecular surface and/or in interaction with the molecular partner, confirmed that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. Leveraging on the important role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces in the binding regions and evaluated their shape complementarity, decomposing the molecular patches in the 2D Zernike basis. For the first time, we quantified the correlation between local shape complementarity and binding affinity via the Zernike formalism. In addition, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary as much as the correlation between van der Waals energy and binding affinity. In turn, these relationships pave the way to the fast and accurate prediction and design of optimal binding regions as the 2D Zernike formalism allows a rapid and superposition-free comparison between possible binding surfaces.

Dataset Information

The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks.

Publications

The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks.

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