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Coherent conformational degrees of freedom as a structural basis for allosteric communication.

Mitternacht S, Berezovsky IN - PLoS Comput. Biol. (2011)

Bottom Line: Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom.We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones.Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Unit/Uni Research, University of Bergen, Bergen, Norway.

ABSTRACT
Conformational changes in allosteric regulation can to a large extent be described as motion along one or a few coherent degrees of freedom. The states involved are inherent to the protein, in the sense that they are visited by the protein also in the absence of effector ligands. Previously, we developed the measure binding leverage to find sites where ligand binding can shift the conformational equilibrium of a protein. Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom. In this paper, to analyze allosteric communication between binding sites, we introduce the concept of leverage coupling, based on the assumption that only pairs of sites that couple to the same conformational degrees of freedom can be allosterically connected. We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones. Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites.

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Related in: MedlinePlus

Phosphofructokinase (PFK).All 3D structures in this paper were drawn with PyMol. (A) Structure of PFK (PDB entry 3pfk). The effector ADP is drawn with orange spheres, and the substrate F6P with yellow spheres, ligand coordinates were taken from PBD entry 4pfk. (B) Leverage coupling DPi between ADP site of one chain (lower right ADP) and the rest of the protein. The surface is colored in a gradient from cyan to magenta where cyan represents the lowest measured value of DPi and magenta the highest value. (C) Same as (B) but for one of the F6P sites (lower right one).
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pcbi-1002301-g004: Phosphofructokinase (PFK).All 3D structures in this paper were drawn with PyMol. (A) Structure of PFK (PDB entry 3pfk). The effector ADP is drawn with orange spheres, and the substrate F6P with yellow spheres, ligand coordinates were taken from PBD entry 4pfk. (B) Leverage coupling DPi between ADP site of one chain (lower right ADP) and the rest of the protein. The surface is colored in a gradient from cyan to magenta where cyan represents the lowest measured value of DPi and magenta the highest value. (C) Same as (B) but for one of the F6P sites (lower right one).

Mentions: To illustrate the communication between sites we color the surface of the protein by the leverage coupling between one site and each residue of the protein, DPi (see Methods) in Figure 4, the raw data can be found in Figure S2. The coloring in this figure, and in similar ones below, uses cyan for DPi = 0, and magenta for the maximal value of DPi over all residues i for a given site P, i.e. the coloring gives the pattern of communication for a given site, but no indication of coupling strength compared to other sites P. The studied effector site in PFK communicates most strongly with the other effector sites (Figure 4B), whereas the active site is connected with the other active sites, as well as the allosteric site (Figure 4C). This apparent asymmetry comes from the fact that the interaction between effector sites is stronger than between anything else, but the connection between the active site and the effector site has approximately the same strength as the connections between active sites. Noteworthy is also the fact that neither site has any strong connections to sites other than the functional ones.


Coherent conformational degrees of freedom as a structural basis for allosteric communication.

Mitternacht S, Berezovsky IN - PLoS Comput. Biol. (2011)

Phosphofructokinase (PFK).All 3D structures in this paper were drawn with PyMol. (A) Structure of PFK (PDB entry 3pfk). The effector ADP is drawn with orange spheres, and the substrate F6P with yellow spheres, ligand coordinates were taken from PBD entry 4pfk. (B) Leverage coupling DPi between ADP site of one chain (lower right ADP) and the rest of the protein. The surface is colored in a gradient from cyan to magenta where cyan represents the lowest measured value of DPi and magenta the highest value. (C) Same as (B) but for one of the F6P sites (lower right one).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3234217&req=5

pcbi-1002301-g004: Phosphofructokinase (PFK).All 3D structures in this paper were drawn with PyMol. (A) Structure of PFK (PDB entry 3pfk). The effector ADP is drawn with orange spheres, and the substrate F6P with yellow spheres, ligand coordinates were taken from PBD entry 4pfk. (B) Leverage coupling DPi between ADP site of one chain (lower right ADP) and the rest of the protein. The surface is colored in a gradient from cyan to magenta where cyan represents the lowest measured value of DPi and magenta the highest value. (C) Same as (B) but for one of the F6P sites (lower right one).
Mentions: To illustrate the communication between sites we color the surface of the protein by the leverage coupling between one site and each residue of the protein, DPi (see Methods) in Figure 4, the raw data can be found in Figure S2. The coloring in this figure, and in similar ones below, uses cyan for DPi = 0, and magenta for the maximal value of DPi over all residues i for a given site P, i.e. the coloring gives the pattern of communication for a given site, but no indication of coupling strength compared to other sites P. The studied effector site in PFK communicates most strongly with the other effector sites (Figure 4B), whereas the active site is connected with the other active sites, as well as the allosteric site (Figure 4C). This apparent asymmetry comes from the fact that the interaction between effector sites is stronger than between anything else, but the connection between the active site and the effector site has approximately the same strength as the connections between active sites. Noteworthy is also the fact that neither site has any strong connections to sites other than the functional ones.

Bottom Line: Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom.We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones.Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Unit/Uni Research, University of Bergen, Bergen, Norway.

ABSTRACT
Conformational changes in allosteric regulation can to a large extent be described as motion along one or a few coherent degrees of freedom. The states involved are inherent to the protein, in the sense that they are visited by the protein also in the absence of effector ligands. Previously, we developed the measure binding leverage to find sites where ligand binding can shift the conformational equilibrium of a protein. Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom. In this paper, to analyze allosteric communication between binding sites, we introduce the concept of leverage coupling, based on the assumption that only pairs of sites that couple to the same conformational degrees of freedom can be allosterically connected. We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones. Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites.

Show MeSH
Related in: MedlinePlus