Does structural and chemical divergence play a role in precluding undesirable protein interactions?

To understand the evolutionary forces establishing, maintaining, breaking, or precluding protein-protein interactions, a comprehensive data set of protein complexes has been analyzed to examine the overlap between protein interfaces and the most conserved or divergent protein surface areas. The most divergent areas tend to be found predominantly away from protein interfaces, although when found at interfaces, they are associated with specific lack of cross-reactivity between close homologues, like in antibody-antigen complexes. Moreover, the amino acid composition of highly variable regions is significantly different from any other protein surfaces. The variable regions present higher structural plasticity as a result of insertions and deletions, and favor charged over hydrophobic residues, a known strategy to minimize aggregation. This suggests that (1) a rapid rate of mutations at these regions might be continuously altering their properties, making difficult the coadaptation, in shape and chemical complementarity, to potential interacting partners; and (2) the existence of some form of selective pressure for variable areas away from interfaces to accumulate charged residues, perhaps as an evolutionary mechanism to increase solubility and minimize undesirable interactions within the crowded cellular environment. Finally, these results are placed into the context of the aberrant oligomerization of sickle-cell anemia hemoglobin and prion proteins.