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Mentions: Figure 2 shows the distribution of the ρ values for the interfaces in homodimers and protein complexes. Almost three-quarters of the homodimeric interfaces have ρ values between 1.0 and 1.2. In case of the complexes, more than 50% of the interfaces belong to this range. The range of ρ values extends up to a much higher range in case of complexes compared to homodimers. Two examples of interfaces belonging to the protein complexes and having high ρ values are shown in Additional file 1, Figure S1B,C. Overall, this histogram shows that although individual interfaces show differences in their shapes and sizes and the absolute values of Ms,cons and Ms,int may vary within a certain range, for the majority of interfaces ρ > 1.0, implying that the group of conserved residues occurs clustered together rather than being scattered throughout the entire interface.
Conserved residue clusters at protein-protein interfaces and their use in binding site identification
Bottom Line: Residues comprising protein interfaces are often more conserved compared to those occurring elsewhere on the protein surface.An analysis of the residue types that are enriched within these conserved subsets compared to the overall interface showed that hydrophobic and aromatic residues are favored, but charged residues (both positive and negative) are less common.The clustered nature of evolutionarily conserved residues within interfaces as compared to those within other surface patches not involved in binding has important implications for the identification of protein-protein binding sites and would have applications in docking studies.
Affiliation: Bioinformatics Centre, Bose Institute, P-1/12 CIT Scheme VIIM, Kolkata, India.
Abstract: Biological evolution conserves protein residues that are important for structure and function. Both protein stability and function often require a certain degree of structural co-operativity between spatially neighboring residues and it has previously been shown that conserved residues occur clustered together in protein tertiary structures, enzyme active sites and protein-DNA interfaces. Residues comprising protein interfaces are often more conserved compared to those occurring elsewhere on the protein surface. We investigate the extent to which conserved residues within protein-protein interfaces are clustered together in three-dimensions.Out of 121 and 392 interfaces in homodimers and heterocomplexes, 96.7 and 86.7%, respectively, have the conserved positions clustered within the overall interface region. The significance of this clustering was established in comparison to what is seen for the subsets of the same size of randomly selected residues from the interface. Conserved residues occurring in larger interfaces could often be sub-divided into two or more distinct sub-clusters. These structural cluster(s) comprising conserved residues indicate functionally important regions within the protein-protein interface that can be targeted for further structural and energetic analysis by experimental scanning mutagenesis. Almost 60% of experimental hot spot residues (with DeltaDeltaG > 2 kcal/mol) were localized to these conserved residue clusters. An analysis of the residue types that are enriched within these conserved subsets compared to the overall interface showed that hydrophobic and aromatic residues are favored, but charged residues (both positive and negative) are less common. The potential use of this method for discriminating binding sites (interfaces) versus random surface patches was explored by comparing the clustering of conserved residues within each of these regions--in about 50% cases the true interface is ranked among the top 10% of all surface patches.Protein-protein interaction sites are much larger than small molecule biding sites, but still conserved residues are not randomly distributed over the whole interface and are distinctly clustered. The clustered nature of evolutionarily conserved residues within interfaces as compared to those within other surface patches not involved in binding has important implications for the identification of protein-protein binding sites and would have applications in docking studies.
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