Structural characterization of protein interactions is essential for interpretation of genetic variation. A vast amount of information on single amino acid variants will be available from sequencing. The project focuses on application of computational approaches to the development of a public resource incorporating structural modeling with genetic amino acid variants and assessment of their functional impact. The resource will facilitate better understanding of principles of protein interaction and structure/function relationships. The long-term goal of this research is to gain insights into fundamental principles of molecular processes in living systems, leading to structure-based description of the cell. The collaborative project combines highly complementary areas of expertise of the US team, on high-throughput modeling of protein-protein interactions, and the UK team, on protein structure prediction and effects of genetic variation. The teams will coordinate research and training activities, based on the project, with graduate and undergraduate programs locally, nationally and internationally. Minority students and women will be involved in different parts of the research, including those within established minority-oriented programs. The project will enhance infrastructure for research and education. The US and UK teams have an extensive and well proven record of developing and disseminating public resources, used by many researchers worldwide. The project participants will be actively presenting their results at various multidisciplinary conferences and workshops.
The project will continue development of an integrated approach to high-throughput modeling of proteins and their complexes. The objectives of the project are: (1) to develop advanced high-throughput approaches to modeling of protein interactome; (2) to provide assessment of phenotypic effects of genetic variation; and (3) to develop and implement genome-wide resource for structural characterization of interactome and phenotypic effects of genetic variation. The structure modeling approaches will be based on new search, scoring and refinement strategies, and will integrate the tertiary and quaternary structure prediction. The prediction of the mutation effect will evaluate the change in protein interactions. The genome-wide GWYRE resource will incorporate structurally refined protein complexes for model organisms annotated by the phenotypic effects of the single amino acid variants. The project outcome will have a significant impact on the research field by integrating template-based tertiary and quaternary structure prediction, and development of a comprehensive public resource for structural characterization of interactomes and assessment of phenotypic effects of genetic variation. The results of the project will be available at www.gwyre.org and also at http://vakser.compbio.ku.edu and www.sbg.bio.ic.ac.uk.
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.
