Thanks. I'm always game for a good debate. As I mentioned, my thesis-in-progress (T-minus 3 months...fingers crossed!) is in a related field (evolutionary dynam

Thanks. I'm always game for a good debate. As I mentioned, my thesis-in-progress (T-minus 3 months...fingers crossed!) is in a related field (evolutionary dynamics/computational biochemistry), but I used to be more involved in protein structure/bioinformatics back in the day (worked, for a time, in the lab that maintains ecogene.org). The last debate I had regarding convergent evolution of protein folds got rather heated. This is one of those classic problems that can't be approached without some amount of hand-waving, and depending on which way you wave, you can arrive at different results. In some respects it boils down to Levinthal's paradox, except with evolutionary moves in place of topological ones. The one big unknown that you would need to find before you could make any sort of educated approach at the issue is what fraction of all possible protein chains of a certain size have stable, fast-folding structural minima. If that number is high, then short hops from one to the other could very likely result in convergence. As for the SCOP/PFAM part of the story, the 25-30% "twilight zone" for sequences yielding related structures has a counterpart with structures that are topologically related but with low (or I've even seen cases of essentially no) sequence identity. That is, if you look at a group in PFAM, then take all of the members with structures in that group, gather all of the corresponding SCOP groups, add the members from the SCOP groups, then for each of those look for related PFAMs or other sequences...essentially, what you're doing is a structure informed PSI-BLAST (sort of what ESPRESSO is to T-COFFEE). Now, if you attempt to fill the gaps from lack of structures by running each of your sequences through something like Skolnics TASSER threading algorithm, and using the best predicted folds to grow your group, this is how you can use distant sequence and structure homologies to construct "master" fold groups. This is, roughly speaking, how the 800-1300 number is arrived at. Admittedly, the more structures we solve and genomes we sequence, the better this sort of technique will get. In many ways, this is biology's analog to cosmology and the big bang: we can look further and further out into space, but at some point, we can know what happened any earlier than some small time after the big bang without recreating those conditions. Likewise, we can sequence and solve more structures, but I don't doubt that at some point we will hit a wall and need to start attempting to recreate abiogenesis. Interesting times!