Traditional approaches to prediction of the structures of protein-protein complexes (protein-protein docking) sample the binding modes with no regard to similar experimentally determined structures (templates) of protein-protein complexes. 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. However, the results of a recent large scale, systematic study show that, surprisingly, in spite of the limited number of protein-protein complexes in the Protein Data Bank, docking templates can be found for complexes representing almost all known protein-protein interactions, provided the components themselves have a known structure or can be homology-built. This finding dramatically expands our ability to model protein interactions, and has far-reaching, paradigm-changing implications for the protein docking field in general. The major goal of this project is to investigate target-template structural and functional relationships and develop corresponding approaches to modeling of protein-protein interactions. The Objectives of the research are: (1) generate multiple diverse sets of structural templates according to different structural and functional criteria, (2) investigate target-template structural and functional relationships in protein-protein interactions (PPI) modeling, and (3) implement a publicly available database for template-based models. Existing sets of structural templates for PPI modeling are based on structure and/or sequence criteria. Libraries of templates based on a broad range of available information, including oligomeric state, molecular function, biological process, cellular localization, and physicochemical properties, will be generated. Representative diverse sets of protein-protein targets will be modeled by different structural alignment approaches, using different template pools. Target-template matching scores will be systematically analyzed and optimized. Target refinement procedures will be designed and implemented. The modeling approaches will be systematically validated on comprehensive benchmark sets of X-ray and modeled structures. The structures of protein-protein complexes from PPI sets will be generated, validated, and provided in a database, which will become a publicly available source of structural information on PPI. The advancement of the template-based modeling of PPI will transform the field of protein-protein docking by radically changing the docking paradigm, from currently universally accepted free docking, to comparative modeling. This will make possible much more accurate and reliable modeling of protein complexes, opening new frontiers in biological research.
The results of this project will be utilized by the larger research community interested in studying protein interactions in biological systems. They will be included in Bioinformatics course materials. Minority students and women will be involved in different parts of the proposed research. The PI's Laboratory is one of the centers of bioinformatics research and educational activities on campus, involving faculty, research staff, postdoctoral fellows, and students. The participants of the proposed project will be actively presenting their results at various multidisciplinary conferences, as they have done in the past. The PI's bi-annual Modeling of Protein Interactions meeting is an important event in the Computational Biology and Bioinformatics field, bringing together top experts on the broad subject of this proposal. The meeting provides a unique opportunity for the young scientists - students and postdocs - to prominently present their research and to interact with the leaders of the field. The results of the project will significantly contribute to the national and international community-wide efforts to structurally characterize protein interactome. The outcome of the proposed research will enhance research capabilities in fundamental biological research, biotechnology, and other areas of molecular biology, including interpretation of information encoded in genomes.
