The overall goal of the Integrative Modeling Core is to facilitate the analysis and interpretation of multiple datatypes to identify and characterize the cellular proteins and networks that influence HIV virus replication. Interfacing with Projects 1-7, this core will employ existing bioinformatics and systems biology approaches, as well as develop approaches to facilitate unifying mechanistic and structural details with network biology. There will be a heavy emphasis on the analysis and integration of data derived from proteomic approaches, including protein-protein interaction (PPI) data derived from the AP-MS and APEX methods; global post-translational modification (PTM) data (phosphorylation, ubiquitination and acetylation) about host proteins from HIV-infected primary cells or cell lines, or after introduction of specific HIV proteins; and global protein abundance data after infection with WT or mutant versions of HIV (Core 1). These datasets will be analyzed separately (Aim 1) as well as jointly with other datatypes, followed by visualization to gain a deeper understanding of the functional pathways that are modulated during HIV infection (Aim 2). Finally, in Aim 3, we will determine structures of HIV-human protein complexes by an integrative approach based on various structural, biochemical, genetic and proteomic data generated by Cores 1, 3 and 6 for Projects 1, 3, 4, 5 and 6, using the open-source Integrative Modeling Platform (IMP) package developed in the Sali lab. We will initially focus on Vif-associated protein complexes using data from XL-MS (Core 1), cryo-EM (Core 3), small-angle x-ray scattering (SAXS), and X-ray crystallography (Core 6). Initial studies will focus on mapping interaction interfaces between Vif- CRL5 and APOBEC3 substrates (Project 1), but we will also apply the integrative structure determination pipeline to other HIV protein complexes, involving Vpu, Nef, Tat, and Rev proteins (Projects 3-6).
