Protein-complex stability in cells and in vitro under crowded conditions

•Both steric repulsions and chemical interactions are important.•Systematic experiments involving temperature, crowder molecular weight and concentration are required to drive theory.•Data on protein complex formation in living cells are starting to become available. Biology is beginning to appreciate the effects of the crowded and complex intracellular environment on the equilibrium thermodynamics and kinetics of protein folding. The next logical step involves the interactions between proteins. We review quantitative, wet-experiment based efforts aimed at understanding how and why high concentrations of small molecules, synthetic polymers, biologically relevant cosolutes and the interior of living cells affect the energetics of protein-protein interactions. We then address popular theories used to explain the effects and suggest expeditious paths for a more methodical integration of experiment and simulation.