The cellular interior is characterised by high concentrations of macromolecules. Compared with dilute conditions, the crowd modifies proteins' ability to fold, diffuse and, ultimately, carry out their biological functions. Cellular fitness depends on ensuring an adequate balance between interactivity and diffusivity.

In this thesis, I discuss how a colloidal description of the cell highlights the central role of electrostatics in protein surface optimisation. By recognising that the modulation of protein-protein interactions concerns the whole proteome, I map the physicochemical preferences of cellular organisms across taxonomic and ecological divisions. Moreover, I propose that all surface residues participate in tuning protein interactions to the correct affinity, within a continuum that spans several orders of magnitude. Finally, I turn to horizontally spreading inteins to gauge the strength of the selective pressures acting on protein surfaces.