Protein abundances and interactions coevolve to promote functional complexes while suppressing non-specific binding

TL;DR

This study uses a biophysical model to explain how cells balance protein abundances and interactions, promoting functional complexes while minimizing non-specific binding, with implications for understanding yeast proteomes.

Contribution

It introduces a first-principle model linking protein interaction properties to cellular abundance regulation and demonstrates how this explains observed PPI network detection biases.

Findings

Functional interactions are more detectable at high protein abundances.

Strengthening functional interactions increases promiscuous binding risk.

Cells balance protein levels by modulating concentrations of hub and monomer proteins.

Abstract

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.