Protein interaction networks structurally integrated

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As protein-protein interactions are central to all biological processes, a comprehensive determination of all interactions between proteins that take place in an organism provides a fundamental framework for understanding biology as an integrated system. Significant efforts by the research community in recent years have provided first maps of cellular protein-protein interaction (PPI) networks. These maps are major sources of information for discovering new drug targets and for identifying signaling circuits that can be rewired to generate new cellular behavior. However, in order to fully understand (a) cellular processes such as signal transduction (b) the emergence of phenotype from cellular complexity (c) to decipher the complex molecular mechanisms that underlie pathologies like cancer or neurodegeneration and (d) ultimately use this knowledge effectively in drug design and synthetic biology, we have to not only dissect the interactome, but also elucidate how the structure and dynamics of the constituent proteins affect their network function. The broad objectives of this research program are to develop new computational tools to determine the structures of protein complexes with a view to curate PPI maps and provide a solid framework that allows investigating communication in cellular systems and designing drugs that intervene in specific signaling pathways. Under this general theme, we will first pursue two avenues of research that aim at (i) predicting the structure of protein complexes in which one or several members undergo induced folding upon binding, i.e., are intrinsically disordered proteins (IDPs) and (ii) predicting structure and affinities of linear motif-domain complexes in order to evaluate the in vivo likelihood of PPIs that are mediated by this type of interactions and were seen in high-throughput screens.