Versatility and Invariance in the Evolution of Homologous Heteromeric Interfaces

Evolutionary pressures act on protein complex interfaces so that they preserve their complementarity. Nonetheless, the elementary interactions which compose the interface are highly versatile throughout evolution. Understanding and characterizing interface plasticity across evolution is a fundamental issue which could provide new insights into protein-protein interaction prediction. Using a database of 1,024 couples of close and remote heteromeric structural interologs, we studied protein-protein interactions from a structural and evolutionary point of view. We systematically and quantitatively analyzed the conservation of different types of interface contacts. Our study highlights astonishing plasticity regarding polar contacts at complex interfaces. It also reveals that up to a quarter of the residues switch out of the interface when comparing two homologous complexes. Despite such versatility, we identify two important interface descriptors which correlate with an increased conservation in the evolution of interfaces: apolar patches and contacts surrounding anchor residues. These observations hold true even when restricting the dataset to transiently formed complexes. We show that a combination of six features related either to sequence or to geometric properties of interfaces can be used to rank positions likely to share similar contacts between two interologs. Altogether, our analysis provides important tracks for extracting meaningful information from multiple sequence alignments of conserved binding partners and for discriminating near-native interfaces using evolutionary information. Unraveling how interfaces of protein complexes coevolved is of major importance to improve our ability to predict their structures and design novel binders. Proteins whose interaction was maintained throughout evolution generally have their homologs binding in a similar manner while their sequences can have significantly diverged. Constraints holding proteins together should be captured from the growing body of available multiple sequence alignments. However, it remains unclear which features of the interfaces provide most tolerance to mutations and it is unknown whether any invariant properties may help to extract meaningful signals from sequence alignments. To solve this issue, we tackled an unprecedented large scale analysis of more than 1000 non-redundant couples of structural interologs. Structural interologs are pairs of complexes of known structure whose chains are homologs. We quantitatively measured how the networks of contacts varied between two interfaces. Although highly versatile, we found that contact networks were more conserved for residues acting as anchors and for apolar contacts when they are clustered into surface patches. Altogether, our results provide major guidelines for exploiting the wealth of evolutionary information contained in the sequences of binding partners. On those bases we developed a method to predict which residues most likely conserve their contacts.