Protein-protein association rates captured in a single geometric parameter

Understanding factors that drive protein-protein association is of fundamental importance. We show that a single geometric parameter in crystal structures of protein-protein complexes, the angle between the electric dipole of one subunit and the partner-generated electric field at the same subunit, linearly correlates with experimentally determined protein-protein association rates. Imprint of a dynamic kinetic process in a single static geometric parameter, associated with mutual electrostatic orientation of subunits in protein-protein complexes, is elegant and demonstrates the universality of electrostatic steering in attenuating protein-protein association rates. That the essence of a complex phenomenon could be captured by properties of the final crystal structure of the complex implies that the electrostatic orientations of protein subunits in crystal structures and the associated transition states are nearly identical. Further, the cosine of the angle, alone, is shown to be sufficient in predicting association rate constants, with accuracies comparable to currently available predictors that use more intricate methodologies. Our results offer mechanistic insights and could be useful in development of coarse-grained models.