The Relationship Between Sequence and Interaction Divergence in Proteins

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Traditional approaches to protein-protein docking sample the binding modes with no regard to similar experimentally determined structures (templates) of protein-protein complexes. Emerging template-based docking approaches utilize such similar complexes to determine the docking predictions. The docking problem assumes the knowledge of the participating proteins' structures. Thus, it provides the possibility of aligning the structures of the proteins and the template complexes. The progress in the development of template-based docking and the vast experience in template-based modeling of individual proteins show that, generally, such approaches are more reliable than the free modeling. The key aspect of this modeling paradigm is the availability of the templates. The current common perception is that due to the difficulties in experimental structure determination of protein-protein complexes, the pool of docking templates is insignificant, and thus a broad application of template-based docking is possible only at some future time. The results of our large scale, systematic study show that, surprisingly, in spite of the limited number of proteinprotein complexes in the Protein Data Bank, docking templates can be found for complexes representing almost all the known proteinprotein interactions, provided the components themselves have a known structure or can be homology-built. About one-third of the templates are of good quality when they are compared to experimental structures in test sets extracted from the Protein Data Bank and would be useful starting points in modeling the complexes. This finding dramatically expands our ability to model protein interactions, and has far-reaching implications for the protein docking field in general.protein modeling | protein recognition | structural bioinformatics | structure alignment P rotein-protein interactions (PPI) are a key component of life processes at the molecular level, and the number detected in genome-wide studies is fast growing. We want to understand their properties and be able to manipulate them for structure-based drug design. For this purpose, we must characterize PPI structurally, but their study by X-ray and NMR methods is demanding and slow, and computational methods appear to be a necessary complement.The structural predictions of PPI generally rely on docking procedures that can be roughly divided into: (i) template-free docking, where many or all the possible binding modes of two proteins are explored with no a priori knowledge of the structure of the complex, and (ii) template-based docking, where the similarity with previously known complexes determines the prediction. Template-free docking methods rely on the geometric and chemicalphysical complementarity of the protein surfaces (1), now often supplemented by statistical potentials (2, 3), and subject to a variety of constraints (4). The template-free modeling can also be applied to prediction of domain-domain structures (5, 6). The Critical Assessment of Predicted Interactions (CAPRI) blind predi...

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Templates are available to model nearly all complexes of structurally characterized proteins

Kundrotas

Zhu²,

Janin³

et al. 2012

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“…Aloy et al have estimated that there are ∼10;000 types of proteinprotein interactions, based on the data from high-throughput experiments and the assumption that proteins with more than 30% sequence identity share similar interaction modes (14,15). Although their estimate is reasonable for categorizing homologous protein interfaces, it does not necessarily mean that there exist 10,000 protein interface structures with unique geometries.…”

Section: Discussionmentioning

confidence: 99%

“…To compare two quaternary structures, one needs to align the two structures. One early study, which measures the relationships of dramatically simplified dimeric protein structures, concludes that homologous proteins (with >30% pairwise sequence identity) form structurally similar complexes (14). Based on this and data from high-throughput experiments, it was estimated that there exist about 10,000 types of protein quaternary structures, only a small fraction of which have been solved (15).…”

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confidence: 99%

Structural space of protein–protein interfaces is degenerate, close to complete, and highly connected

Gao

Skolnick

2010

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At the heart of protein-protein interactions are protein-protein interfaces where the direct physical interactions occur. By developing and applying an efficient structural alignment method, we study the structural similarity of representative protein-protein interfaces involving interactions between dimers. Even without structural similarity between individual monomers that form dimeric complexes, ∼90% of native interfaces have a close structural neighbor with similar backbone C α geometry and interfacial contact pattern. About 80% of the interfaces form a dense network, where any two interfaces are structurally related using a transitive set of at most seven intermediate interfaces. The degeneracy of interface space is largely due to the packing of compact, hydrogen-bonded secondary structure elements. This packing generates relatively flat interacting surfaces whose geometries are highly degenerate. Comparative study of artificial and native interfaces argues that the library of protein interfaces is close to complete and comprised of roughly 1,000 distinct interface types. In contrast, the number of possible quaternary structures of dimers is estimated to be about 10 4 times larger; thus, an experimentally determined database of all representative quaternary structures is not likely in the near future. Nevertheless, one could in principle exploit the completeness of protein interfaces to predict most dimeric quaternary structures. Finally, our results provide a structural explanation for the prevalence of promiscuous protein interactions. By side-chain packing adjustments, we illustrate how multiprotein specificity can be attained at a promiscuous interface.

“…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.…”

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confidence: 99%

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

Madaoui

Guérois

2008

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...