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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Projection of surface electrostatic potential onto a sphere, calculation of multipole moments by multipole expansion and prediction of the surface potential for (A) Ubiquitin and (B) Ubiquitin-like SMT3 precursor. Negative potential is indicated in red, positive potential in blue and hydropathy in yellow. Electrostatic potential on the protein surface was obtained from eF-site12. The electrostatic potential on the surface of the sphere were visualized using Molscript33 and Raster3D34. Dipole, Quadrupole and Octupole values indicated are those calculated for 60 random points on the surface of the sphere.
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f1-3_27: Projection of surface electrostatic potential onto a sphere, calculation of multipole moments by multipole expansion and prediction of the surface potential for (A) Ubiquitin and (B) Ubiquitin-like SMT3 precursor. Negative potential is indicated in red, positive potential in blue and hydropathy in yellow. Electrostatic potential on the protein surface was obtained from eF-site12. The electrostatic potential on the surface of the sphere were visualized using Molscript33 and Raster3D34. Dipole, Quadrupole and Octupole values indicated are those calculated for 60 random points on the surface of the sphere.

Mentions: In order to determine the distribution of charges on the surfaces of hubs as compared to non-hubs, we performed multipole expansion of the surface electrostatic potential on 50 hubs and 131 non-hubs. As indicated in the Methods section, we calculated the monopole, dipole, quadrupole and octupole moments of the surface electrostatic potential of the sphere using multipole expansion. To validate our calculations, we predicted the electrostatic potential on the surface of the sphere using the values of the multipole moments obtained and checked this prediction against the actual values on the protein surface. Figure 1 shows the surface electrostatic potential of the protein, the potential mapped onto a sphere, the calculated multipole moments and the predicted surface potential from the multipole moments, for two proteins — Ubiquitin and Ubiquitin-like SMT3 precursor. It can be seen that predicted surface electrostatic potential roughly follows the trends of the actual potential, though sharp changes in the potential are lost. The values for individual multipole moments, for some of the hubs and non-hubs, are shown in Supplementary Tables S1 and S2.


The role of charged surface residues in the binding ability of small hubs in protein-protein interaction networks
Projection of surface electrostatic potential onto a sphere, calculation of multipole moments by multipole expansion and prediction of the surface potential for (A) Ubiquitin and (B) Ubiquitin-like SMT3 precursor. Negative potential is indicated in red, positive potential in blue and hydropathy in yellow. Electrostatic potential on the protein surface was obtained from eF-site12. The electrostatic potential on the surface of the sphere were visualized using Molscript33 and Raster3D34. Dipole, Quadrupole and Octupole values indicated are those calculated for 60 random points on the surface of the sphere.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036656&req=5

f1-3_27: Projection of surface electrostatic potential onto a sphere, calculation of multipole moments by multipole expansion and prediction of the surface potential for (A) Ubiquitin and (B) Ubiquitin-like SMT3 precursor. Negative potential is indicated in red, positive potential in blue and hydropathy in yellow. Electrostatic potential on the protein surface was obtained from eF-site12. The electrostatic potential on the surface of the sphere were visualized using Molscript33 and Raster3D34. Dipole, Quadrupole and Octupole values indicated are those calculated for 60 random points on the surface of the sphere.
Mentions: In order to determine the distribution of charges on the surfaces of hubs as compared to non-hubs, we performed multipole expansion of the surface electrostatic potential on 50 hubs and 131 non-hubs. As indicated in the Methods section, we calculated the monopole, dipole, quadrupole and octupole moments of the surface electrostatic potential of the sphere using multipole expansion. To validate our calculations, we predicted the electrostatic potential on the surface of the sphere using the values of the multipole moments obtained and checked this prediction against the actual values on the protein surface. Figure 1 shows the surface electrostatic potential of the protein, the potential mapped onto a sphere, the calculated multipole moments and the predicted surface potential from the multipole moments, for two proteins — Ubiquitin and Ubiquitin-like SMT3 precursor. It can be seen that predicted surface electrostatic potential roughly follows the trends of the actual potential, though sharp changes in the potential are lost. The values for individual multipole moments, for some of the hubs and non-hubs, are shown in Supplementary Tables S1 and S2.

View Article: PubMed Central - PubMed

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.

No MeSH data available.