Research Infrastructure: 2021BBSRC-NSF/BIO UniPlex - Genome-Wide Protein Complex Prediction and Validation

Proteins are essential components that both build cellular structures and work as the tools that make the cell function. However, proteins do not operate in isolation and often form molecular machines in which several proteins bind together and with other biomolecules to act as a single entity called a molecular complex. This provides tremendous versatility and regulatory capacities, since by changing a single component of the complex, its function can be dramatically altered. Protein complexes often also form more stable structures than isolated proteins, and their formation creates new active sites as protein chains from different molecules assemble in close proximity. It is therefore of crucial importance to know the composition of complexes and study them as discrete functional entities in order to truly understand how cellular processes work. This project is an international collaboration between the University of Illinois at Chicago and the European Bioinformatics Institute (EMBL-EBI), Cambridge, UK. The Complex Portal (www.ebi.ac.uk/complexportal) is an encyclopaedic database that collates and summarizes information on stable, macromolecular complexes of known function from the scientific literature through manual curation. This project will extend the scope and relevance of the Complex Portal by using machine learning algorithms that can identify groups of proteins that are most likely to represent functional complexes which exist in the cell. These predictions of complexes will be validated against other experimental data and, where possible, also against literature evidence. We will also use large scale studies of protein expression in different cell types, tissues, and conditions to validate the predicted complexes and to differentiate between variants of complexes formed in different conditions. Complexes predicted to exist at high confidence will be made available through the Complex Portal website, properly identified as computationally inferred data, where they will both guide the work of Complex Portal curators and dramatically increase the amount of complexes available for researchers as reference entities. Additional information from other resources such as Reactome and PDB will be annotated to these entries and changes mapped to amino acids which are known to affect protein interaction strength and stability to complex binding interfaces from the IntAct database. This work will help accelerate understanding of complexes as the molecular machines essential to biological processes and support basic and applied research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.