Ummm...okay...so, I've kinda been uncharitable toward spectral libraries in proteomics in the past. Yes, they are rocket fast. Yes, they have great intrinsic matches and low false discovery rates, but I'm generally not looking for stuff that has already been identified. I'm looking for new stuff, and you can't do that with spectral libraries --- til now!!
What's it do? It takes aim at exactly what I just talked about. Imagine you upload a huge set of spectral libraries from NIST and it has all the unmodified peptides anyone has found so far for your organism.
You search this with MSPepSearch versus your newly acquired spectra. In the past, if you've got an acetylated peptide you fragmented, it won't match anything and the engine goes right on by.
Hybrid Search will go to that spectra and look at everything it has in the spectral library. If your experimental spectra matches something in the library -- if you shift a couple fragment ions and the precursor mass by exactly an acetylation -- BOOM! Match.
If you write it out like that it sounds really simple. I'm sure it wasn't or someone would have done it a while back -- but it's done now and integrated into the free for everybody MSPepSearch.
EDIT: 4/16/17 -- I got a little ahead of myself. I downloaded MSPepSearch this morning from NIST, and the HybridSearch function doesn't appear to have gone live for external users yet. I didn't realize the paper was JPR ASAP (published online ahead of print date). I'd expect to see the new version rolled out soon (but probably not before the paper is actually published!)