PRiSM -- A thought experiment on Protein rather than Peptide Spectral Matches!

(Image credit: Lucas Vieira for making this and putting it in the open domain!) 

Proteomics hasn't been around all that long (not real proteomics, anyway) but we have been around long enough to develop a nice cognitive box for us to work within. 

I like this new study because it goes out on a limb for shotgun proteomics and says "wait. why are we matching the peptide to the spectrum? could we just look at MS/MS directly against the protein sequences? If so, how would we do it? What would be the pros and cons?" 

The answers to to these questions are something like:

1) We do the peptide because it is WAY easier. 

2) You can do it. I mean....they did it.... I couldn't do it. 

3) You need some serious math and a lot of firepower. 

4) Pros? It totally works and they can find things that traditional engines can't.

5) Cons? It's hard. Like seriously hard. 3 hours per MS/MS spectrum per computational core hard, but this is a thought experiment, not a practical optimization study. 

We know there are places that our bottom-up search engines just don't work well. Maybe there is an alternative!