Coevolutionary patterns in cytochrome c oxidase subunit I depend on structural and functional context

The strength and pattern of coevolution between amino acid residues vary depending on their structural and functional environment. This context dependence, along with differences in analytical technique, is responsible for the different results among coevolutionary analyses of different proteins. It is thus important to perform detailed study of individual proteins to gain better insight into how context dependence can affect coevolutionary patterns even within individual proteins, and to unravel the details of context dependence with respect to structure and function. Here we extend our previous study by presenting further analysis of residue coevolution in cytochrome c oxidase subunit I sequences from 231 vertebrates using a statistically robust phylogeny-based maximum likelihood ratio method. As in previous studies, a strong overall coevolutionary signal was detected, and coevolution within structural regions was significantly related to the C-alpha distances between residues. While the strong selection for adjacent residues among predicted coevolving pairs in the surface region indicates that the statistical method is highly selective for biologically relevant interactions, the coevolutionary signal was strongest in the transmembrane region, although the distances between coevolving residues were greater. This indicates that coevolution may act to maintain more global structural and functional constraints in the transmembrane region. In the transmembrane region, sites that coevolved according to polarity and hydrophobicity rather than volume had a greater tendency to colocalize with just one of the predicted proton channels (channel H). Thus, the details of coevolution in cytochrome c oxidase subunit I depend greatly on domain structure and residue physicochemical characteristics, but proximity to function appears to play a critical role. We hypothesize that coevolution is indicative of a more important functional role for this channel.