The large volume of data available for protein-protein interaction networks has not been fully comprehended or validated. This project will combine protein structural modeling with these data to significantly enhance their value, and to develop a deeper understanding of these data. The aim is to test the data and discover missing interactions, to develop molecular models of most pairs of interactions, and in this way to learn about the compatibilities of the pairs of interactions. The molecular modeling will rely on available protein structures, comparative modeling for those not available in the PDB and docking of the individual protein pairs using software presently provided by others. Physical overlaps in binding sites will be used to determine whether interaction sites overlap and are thus incompatible or whether they can coexist in assemblages of multiple proteins. Clustering the proteins for related functions is important to limit the number of combinations of interactions to be considered and will compensate for some uncertainties in the modeling. The overall objective is to fully investigate all pairs of interactions and their interdependences. Validation of some newly predicted interactions will be carried out by mass spectrometry. Higher order assemblages will be constructed that are consistent with the structural models of the binding sites, leading to structural assemblages for specific functions, on the same pathway. These analyses are important for investigating the details of functional clusters of proteins. In this project, all of the individual clusters will be investigated for their functional relationships, for their molecular structures, and as an important way to annotate the protein-protein interaction networks.
Broader Impacts The protein-protein interaction annotation server will permit large numbers of users to access the whole body of information that will be generated during the project. Research-based graduate student training will be provided, and the student's educational experiences will be enhanced by this project. Native American, Hispanic and African-American students particularly will be sought for engagement in this project through collaborations at other Universities, having large populations of these students. All students for recruitment to this project will be targeted from these sources, enhancing the continuing search for more diverse future scientists from multiple programs and multiple institutions.
