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Center for Nonlinear Studies |
Which physical factors contribute to protein abundance in living cells and their response to protein overexpression (dosage sensitivity)? Here we address this problem by using a first-principle model cell for computer simulations whose phenotypic traits are directly determined from its genome through biophysical calculation of physical-chemical properties of protein structures and interactions. The model cell includes three independent pathways, whose functional topologies of PPI network are different, but whose functional concentrations equally contribute to cell fitness. The model cell evolves through genotypic mutations and phenotypic protein copy number variations. We found a strong relationship between physical-chemical properties of proteins such as their stability and participation in functional and non-functional (promiscuous) protein-protein interactions and their abundance in the cell cytoplasm. Such interplay between protein abundance and PPI is due to a peculiar ‘’frustration’’ effect: strengthening of functional interactions brings about hydrophobic surfaces which make proteins prone to non-functional promiscuous interactions. The balancing act is achieved by lowering concentration of hub proteins. Our funding is confirmed by the analysis of the relation between protein abundance and node degree in the confirmed PPI network in Saccharomyces cerevisiae as well as finding that PPI tend to be stoichiometric in cells. We found that proteins of greater degree in PPI exhibit stronger dosage sensitivity due to greater tendency to form non-functional complexes. We revisited the dosage specificity data for S. cerevisiae and determined that proteins, which are constitutively highly expressed, indeed show correlation between their node degree in PPI network and dosage sensitivity. Further, we present recent experimental data which shows how protein stability and function relate to cell phenotype.
Host: S. Gnanakaran, 5-1923, ghana@lanl.gov