Evolutionary changes in the host-virus interactome can alter the course of infection, but which and how often interactions evolve and how this is realized at the interface residue level, remain largely unexplored. Here, we focus on viral mimicry of motifs and domains of host proteins, that allow efficient binding to host proteins by mimicking interfaces of host proteins. Our results show that in contrast to the prevailing view of rapid interface evolution between host- and viral-interacting proteins, viruses evolved to target highly conserved host proteins. The similarity between viral mimics and their host mimicked proteins limits host capacity to escape interaction with mimics, enabling efficient viral interaction with host targets through mimicry. These results have important implications for our understanding of zoonotic events where novel host-virus protein interactions may evolve and for designing new antiviral drugs targeting interface regions between host and viral proteins.
