Coevolution at protein complex interfaces can be detected by the complementarity trace with important impact for predictive docking

Abstract

Protein surfaces are under significant selection pressure to maintain interactions with their partners throughout evolution. Capturing how selection pressure acts at the interfaces of proteinprotein complexes is a fundamental issue with high interest for the structural prediction of macromolecular assemblies. We tackled this issue under the assumption that, throughout evolution, mutations should minimally disrupt the physicochemical compatibility between specific clusters of interacting residues. This constraint drove the development of the so-called Surface COmplementarity Trace in Complex History score (SCOTCH), which was found to discriminate with high efficiency the structure of biological complexes. SCOTCH performances were assessed not only with respect to other evolution-based approaches, such as conservation and coevolution analyses, but also with respect to statistically based scoring methods. Validated on a set of 129 complexes of known structure exhibiting both permanent and transient intermolecular interactions, SCOTCH appears as a robust strategy to guide the prediction of protein-protein complex structures. Of particular interest, it also provides a basic framework to efficiently track how protein surfaces could evolve while keeping their partners in contact.evolution ͉ prediction ͉ protein-protein interaction T he modular assembly of proteins is a key determinant in the regulation of biological systems. Combinations of inter-and intramolecular interactions hold the cell machineries and govern the flow of information transmitted through cell signaling pathways. To unravel the complexity of cell organization, atlases of the physical interactome have been obtained for several model organisms (1, 2). To further elucidate the competitions and synergies ruling the molecular logic of these protein-protein interaction networks, a critical step relies on the structural characterization of the protein complexes. However, there is still a huge gap between the proteome-wide data accumulating and the available structural details of macromolecular complexes.A number of studies have tackled the large-scale analysis of protein-protein complexes from a structural perspective (3-7). They have emphasized that size, shape, and the physicochemical complementarities at the interfaces are key descriptors that could be used to develop computational methods able to predict protein-binding sites from sequences or structures (8)(9)(10)(11)(12)(13)(14). In the context of evolution, seminal studies compared the binding modes of domain-domain interactions between homologous proteins and concluded that they tend to interact similarly, even if sequence identity has been maintained as low as 30% (15, 16). Such a low conservation threshold suggests that interaction surfaces can evolve significantly while maintaining sufficient specificity between the binding partners. The paradox between sequence divergence and structural conservation of macromolecular assemblies has been recently related to the notion of superfamily, and the exis...

Protein interactions and ligand binding: From protein subfamilies to functional specificity

“…This possibility has indeed been previously illustrated for the class III aminotransferase family, where we see how SDPs linking the ligand-binding site with the homodimerization interface determine the specificity of the protein. At this moment, it is interesting to point out that the definition of SDPs is to some degree related with the concept of "correlated mutations" (27), and that the physical proximity of SDPs to protein-binding regions resembles the distributions of correlated positions (28)(29)(30)(31).…”

Coevolution Predicts Direct Interactions between mtDNA-Encoded and nDNA-Encoded Subunits of Oxidative Phosphorylation Complex I

“…17,18 Analysis of correlated mutations assisted in the successful identification of interdomain or interprotein docking configurations. 19,20 Moreover, coevolving amino acids were found to be prevalent among interacting residue pairs within and between proteins ('in silico two-hybrid system'). 21 Taken together, these findings indicate that although the coevolution signal may not be sufficient to discern actual contacting residue pairs, it may be informative for identifying physically interacting protein pairs.…”

Evolutionary rate covariation reveals shared functionality and coexpression of genes

“…Early studies assumed that ERC resulted solely from intermolecular coevolution that occurs at the physical interface between interacting proteins (Goh et al 2000;Pazos and Valencia 2001;). There is evidence that some residues across interaction interfaces change in a statistically correlated manner to maintain binding complementarity (Moyle et al 1994;Travers and Fares 2007;Madaoui and Guerois 2008;Kann et al 2009). However, it is unclear if intermolecular coevolution at the limited number of interface residues is sufficient to create the observed signatures of ERC that typically involve the entire protein sequence (Lovell and Robertson 2010).…”