However generated, the resulting RIN graphs are converted to an MSA-based indexing representation for conservation analysis. At this point, an appropriate reference structure is selected to project the results onto. Conservation scores are computed for each interaction possible within the target protein. This score can be computed in two alternative ways, either the ratio of the number of proteins where a contact is present divided by a total number of proteins or the ratio of the number of proteins where a contact is present divided by the number of proteins that contain the interacting residues at appropriate MSA positions. The second approach means that the conservation score is not penalized if it would be impossible for some structures to form certain interactions because either or both residues involved are not present. These two approaches are designed to account for structural diversity of a family. While many commonly studied families exhibit high structural homogeneity, intriguing mechanisms such as enzyme promiscuity and gene fusion are often observed in in families and superfamilies with a high level of diversity . In this study we perform all calculations with the first method, as the two results are nearly identical for a family of similar structures.