  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.
