How do living cells achieve sufficient abundances of functional protein complexes while minimizing promiscuous non-functional interactions between their proteins ? Here we study this problem using a first-principle model of the cell whose phenotypic traits are directly determined from its genome through biophysical properties of protein structures and binding interactions in crowded cellular environment. The model cell includes three independent  pathways, whose topologies of PPI subnetworks are different, but whose functional concentrations equally contribute to cell's fitness . The model cells evolve through genotypic mutations and phenotypic protein copy number variations. We found a strong relationship between evolved physical-chemical properties of protein interactions and their abundances due to a "frustration" effect: strengthening of functional interactions brings about hydrophobic surfaces , which make proteins prone to promiscuous binding. The balancing act is achieved by lowering concentrations of hub proteins while raising solubilities and abundances of functional monomers. The non-monotonic relation between abundances and Protein-Protein Interaction network degrees of yeast proteins validates our predictions. Furthermore, in agreement with our model we found that highly abundant yeast proteins show a positive correlation between their degree and dosage sensitivity with respect to overexpression .
How do living cells achieve sufficient abundances of functional protein complexes while minimizing promiscuous non-functional interactions ? Here we study this problem using a first-principle model of the cell whose phenotypic traits are directly determined from its genome through biophysical properties of protein structures and binding interactions in crowded cellular environment. The model cell includes three independent prototypical pathways, whose topologies of Protein-Protein Interaction (PPI) sub-networks are different, but whose contributions to the cell fitness are equal. Model cells evolve through genotypic mutations and phenotypic protein copy number variations. We found a strong relationship between evolved physical-chemical properties of protein interactions and their abundances due to a "frustration" effect: strengthening of functional interactions brings about hydrophobic interfaces , which make proteins prone to promiscuous binding. The balancing act is achieved by lowering concentrations of hub proteins while raising solubilities and abundances of functional monomers. Based on these principles we generated and analyzed a possible realization of the proteome-wide PPI network in yeast. In this simulation we found that high-throughput affinity capture - mass spectroscopy experiments can detect functional interactions with high fidelity only for high abundance proteins while missing most interactions for low abundance proteins .
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between their proteins
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prototypical
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PPI subnetworks
Protein-Protein Interaction (PPI) sub-networks
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functional concentrations equally contribute to cell's fitness . The model
contributions to the cell fitness are equal. Model
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surfaces
interfaces
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The non-monotonic relation between abundances and Protein-Protein Interaction network degrees of yeast proteins validates our predictions. Furthermore, in agreement with our model
Based on these principles we generated and analyzed a possible realization of the proteome-wide PPI network in yeast. In this simulation
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highly abundant yeast proteins show a positive correlation between their degree and dosage sensitivity with respect to overexpression
high-throughput affinity capture - mass spectroscopy experiments can detect functional interactions with high fidelity only for high abundance proteins while missing most interactions for low abundance proteins