I have two proteins that have unrelated sequences but folds that neatly overlay one another. How do I go about determining whether they share a common ancestor, or arrived at the same fold convergently?
I have two proteins that have unrelated sequences
What does this mean exactly? It is well known that proteins can have the same fold with less than 20-30% identity. Furthermore, distant protein homology can be proven even when percent identity is in single digits.
https://pubmed.ncbi.nlm.nih.gov/12012339/
Although it is politically correct to always leave a possibility open that two distantly related proteins with the same fold could have arrived at similar structures by convergent evolution, I can't remember a single example from the nature where convergent evolution has been conclusively proven. There are synthetic proteins designed to have a certain fold that have very low sequence identity to natural proteins, and obviously have not reached that fold by evolutionary divergence. But in nature it seems much more likely that similar structures have started from similar sequence. It is just that sometimes the evolutionary distance is large and many mutations and rearrangements have happened, so it is difficult to make a connection at the sequence level.
I recently co-authored a paper where we showed that RNaseA and EndoU can be connected at a sequence level, even though it is very difficult to do so. Without that connection it may seem that their folds, and in particular their active sites, have been formed convergently.
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