Protein-protein interfaces from cytochrome c oxidase I evolve faster than nonbinding surfaces, yet negative selection is the driving force.

Respiratory complexes are encoded by two genomes (mitochondrial DNA [mtDNA] and nuclear DNA [nDNA]). Although the importance of intergenomic coadaptation is acknowledged, the forces and constraints shaping such coevolution are largely unknown. Previous works using cytochrome c oxidase (COX) as a model enzyme have led to the so-called "optimizing interaction" hypothesis.