Ultra-weak protein-protein interactions can modulate proteome-wide searching and binding

Research on protein-protein interaction (PPIs) tends to focus on high affinity interactions. Weaker interactions ( K d >1 μM ) recently understood as contributing to intracellular phase separation suggest that even-weaker PPIs might also matter in as-yet unknown ways. However, ultra-weak PPIs ( K d >1 mM ) are not readily accessible by in vivo techniques. Here we use protein electrostatics to estimate PPI strengths and spatially-resolved dynamic simulations to investigate the potential impacts of ultra-weak PPIs within dense protein suspensions. We find that ultra-weak PPIs can drive formation of transient clusters that last long enough to enable enzyme-catalyzed reactions and accelerate the sampling of protein associations. We apply our method to Mycoplasma genitalium , finding that ultra-weak PPIs should be ubiquitous among cytoplasmic proteins. We also predict that the proteome-wide interactome can be shifted to favor ‘binding-dominant’ ultra-weak PPIs via the introduction of a few charged protein complexes. We speculate that ultra-weak PPIs could contribute to cellular fitness by facilitating sampling and colloidal-scale transport of proteins involved in biological processes, including protein synthesis. ### Competing Interest Statement The authors have declared no competing interest.