Here, we applied co-fractionation mass spectrometry and computational modeling to quantify and profile the interactions of ~2,000 proteins in the bacterium Escherichia coli cultured under ten distinct culture conditions. The resulting quantitative co-elution patterns revealed large-scale condition-dependent interaction remodeling among protein complexes involved in diverse biochemical pathways in response to the unique environmental challenges. Network-level analysis highlighted interactome-wide biophysical properties and structural patterns governing interaction remodeling. Our results provide evidence of the local and global plasticity of the E. coli interactome.