How different protein-protein interactions evolve

Protein-protein interactions (PPIs) have evolved to possess binding affinities that best satisfy their functional role. PPIs with different affinities could be structurally very similar, exhibiting similar number and type of intermolecular interactions. To understand how slight sequence variations translate into substantial differences in binding affinities, we study binding landscapes, i. e. changes in binding free energy due to all possible mutations. Recently, we developed state-of-the-art methodology for mapping of the binding landscapes that combines protein randomization, affinity sorting, deep sequencing and data normalization. We use this methodology to map binding landscapes of various PPIs including protease-inhibitor and signaling complexes. We demonstrate that PPI binding landscapes are highly dependent on the PPI function in the cell as well as on its evolutionary optimality.