High-Resolution Modeling of Protein-Protein Interaction Networks Within and Between Species

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A major focus of the emerging field of host-microbe systems biology is the elucidation of general principles governing host-microbe protein-protein interaction networks. However, current analyses generate limited insights into host-microbe interactions as they operate on a highly abstract level, treating proteins as nodes and protein-protein interactions as edges. A key bottleneck is the lack of a three-dimensional (3D), atomistic view of the host-microbe biomolecular interaction network at the genomic scale. Recently, we constructed the first 3D structural map of the network of interactions among human proteins and viral proteins. The resulting host-virus structural interaction network provided significant insights into host-virus interactions. However, our preliminary map of human-microbe structural interaction network is severely limited in coverage and accuracy. The long-term objective of the proposed research program is to develop and apply novel methods to build 3D atomistic structural models for known human-human and human-microbe protein-protein interactions with the highest possible accuracy and coverage. Such a high-resolution view of cellular circuitry will enable algorithm development for better prediction of gene function and better understanding of normal and disease biology, enable the discovery of new principles governing intra- and inter-species interactions that are otherwise hidden in the binary network, and enable the construction of in silico whole-cell models for predictive simulation of cell behavior. To achieve this long-term objective, five short-term objectives are proposed. First, we will construct 3D structural models for within-human and human-microbe protein-protein interactions using homology modeling. Second, we will improve the coverage of within-human and human-microbe structural interaction networks by building structural models not only for interactions between globular domains, but also for the equally abundant interactions between linear motif binding domains and the substrate domains that contain the linear peptide motifs. Third, we will improve the coverage of within-human and human-microbe structural interaction networks by developing new threading- and docking-based algorithms for structural interaction modeling. Fourth, we will build accurate structural models of within-human and human-microbe protein-protein interactions by explicitly using 3D structural information to improve sequence alignment. Fifth, we will validate our predictions by a combination of computational analyses and experimental collaborations. The proposed research program will significantly advance the state-of-the-art in host-microbe systems biology by constructing a 3D structural view of human-human and human-microbe interactions that are otherwise hidden in the binary network. The proposed work is the first to apply a structural systems biology approach to host-microbe interaction and infectious disease research. Successful completion of the research program will lead to structural models of human-human and human-microbe protein-protein interactions with significantly improved accuracy and coverage, new tools for structural modeling of within-host and host-microbe protein-protein interaction networks, and improved systems-level understanding of host-microbe interactions and infectious diseases. Finally, the execution of this proposal will provide a set of algorithms, tools, and datasets that serve to maximize the impact of structural systems biology approaches on host-microbe interaction research.