Protein–Protein Interactions Essentials: Key Concepts to Building and Analyzing Interactome Networks

Decades of research into cell biology, molecular biology, biochemistry, structural biology, and biophysics have produced a remarkable compendium of knowledge on the function and molecular properties of individual proteins. This knowledge is well recorded and manually curated into major protein databases like UniProt [1,2]. However, proteins rarely act alone. Many times they team up into ‘‘molecular machines’’ and have intricate physicochemical dynamic connections to undertake biological functions at both cellular and systems levels. A critical step towards unraveling the complex molecular relationships in living systems is the mapping of protein-to-protein physical ‘‘interactions’’. The complete map of protein interactions that can occur in a living organism is called the interactome [3]. Interactome mapping has become one of the main scopes of current biological research, similar to the way ‘‘genome’’ projects were a driving force of molecular biology 20 years ago. Efficient large-scale technologies that measure proteome-wide physical connections between protein pairs are essential for accomplishing a comprehensive knowledge of the protein interactomes. In recent years, given an explosive development of highthroughput experimental technologies, the number of reported protein–protein interactions (PPIs) has increased substantially. Large collections of PPIs produce ‘‘omic’’ scale views of protein partners and protein memberships in complexes and assemblies [4]. Over the same period as the development of large-scale technologies, efficient collection of a lot of small-scale experimental data published in relevant scientific journals is also taking place. This data compilation work is just as essential to achieving comprehensive knowledge of the interactome. Important efforts have been made to build public repositories that integrate information from largeand small-scale PPI experiments reported in the scientific literature. A compendium of PPI databases can be found in http://www. pathguide.org/. To achieve appropriate understanding of PPIs and to design better ways for analyzing and interpreting them, this educational review presents several essential concepts and definitions intended to facilitate the use of PPI information both by computational and experimental biologists. The report is divided into five sections and a summary: (a) PPI definition; a definition of a protein-to-protein interaction compared to other biomolecular relationships or associations. (b) PPI determination by two alternative approaches: binary and co-complex; a description of the PPIs determined by the two main types of experimental technologies. (c) The main databases and repositories that include PPIs; a description and comparison of the main databases and repositories that include PPIs, indicating the type of data that they collect with a special distinction between experimental and predicted data. (d) Analysis of coverage and ways to improve PPI reliability; a comparative study of the current coverage on PPIs and presentation of some strategies to improve the reliability of PPI data. (e) Networks derived from PPIs compared to canonical pathways; a practical example that compares the characteristics and information provided by a canonical pathway and the PPI network built for the same proteins. Last, a short summary and guidance for learning more is provided.