This week I learned about Byonic, a 'next generation' search engine from Protein Metrics. And what I heard is really exciting, but I'll back up a few steps.
Dynamic modifications are functional groups or post-translational modifications that may or may not be present in your proteome. For example, when we are doing a phosphoproteomic study, we set +phospho as a dynamic modification that may, or may not, be on every serine, threonine and tyrosine in every protein in the proteome. Every modification dramatically increases the matrix that your spectra are searched against, leading to an increase in search time.
Back when I was doing phosphoproteomics with Bioworks (Sequest), I expected that a full human proteome search would nearly triple in search time when I added the possibility of just the three phosphorylation states mentioned above. While multi-core processors with multi-thread algorithms have cut this time, we are still practically limited in Sequest and Mascot to a small number of PTMs for the sake of time and bandwidth.
This is where Byonic steps in. Byonic can look at hundreds of potential modifications. How? I don't know exactly, but I have a suspicion. What if your reach engine ran through and identified every unmodified peptide. Even on a single core Sequest with plenty of RAM, you could complete that search in minutes. Then you took your identified peptides (you could use a very loose stringency) and you exported a FASTA file that only contained those proteins that might contain the peptides you probably ID'ed. In this step you would very quickly reduce your database at least 10 fold, but most likely, several hundred fold.
With this reduced database, you could add dynamic modifications willy-nilly without causing your searches to run for days or weeks.
Again, I have no idea if this is how Byonic works! This is simply a guess because it is the only way that I could think of to make a search of hundreds of dynamic mods fit into a reasonable amount of time.
Best part of this article? You can download Byonic and try it for free for 30 days. I'm going to dump a load of data into it this weekend. You can find out more about Byonic and Protein Metric here.