Protein–protein interaction prediction

Protein–protein interaction prediction is a field combining bioinformatics and structural biology in an attempt to identify and catalog physical interactions between pairs or groups of proteins. Understanding protein–protein interactions is important for the investigation of intracellular signaling pathways, modelling of protein complex structures and for gaining insights into various biochemical processes. Experimentally, physical interactions between pairs of proteins can be inferred from a variety of experimental techniques, including yeast two-hybrid systems, protein-fragment complementation assays (PCA), affinity purification/mass spectrometry, protein microarrays, fluorescence resonance energy transfer (FRET), and Microscale Thermophoresis (MST). Efforts to experimentally determine the interactome of numerous species are ongoing, and a number of computational methods for interaction prediction have been developed in recent years.

Proteins that interact are more likely to co-evolve, therefore, it is possible to make inferences about interactions between pairs of proteins based on their phylogenetic distances. It has also been observed in some cases that pairs of interacting proteins have fused orthologues in other organisms. In addition, a number of bound protein complexes have been structurally solved and can be used to identify the residues that mediate the interaction so that similar motifs can be located in other organisms.

Phylogenetic profiling finds pairs of protein families with similar patterns of presence or absence across large numbers of species. This method is based on the hypothesis that potentially interacting proteins should co-evolve and should have orthologs in closely related species. That is, proteins that form complexes or are part of a pathway should be present simultaneously in order for them to function. A phylogenetic profile is constructed for each protein under investigation. The profile is basically a record of whether the protein is present in certain genomes. If two proteins are found to be present and absent in the same genomes, those proteins are deemed likely to be functionally related. A similar method can be applied to protein domains, where profiles are constructed for domains to determine if there are domain interactions. Some drawbacks with the phylogenetic profile methods are that they are computationally expensive to perform, they rely on homology detection between distant organisms, and they only identify if the proteins being investigated are functionally related (part of complex or in same pathway) and not if they have direct interactions.

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