Almost a year ago I tried to figure out "all of these diaPASEF methods and what they do" and one of the most innovative ones didn't make the list. Maybe I posted the preprint link, but I honestly couldn't figure out what the Albert Heck they were even typing about.
Today, thanks to the fact everyone in my house has been sick for an entire month I got to sit through a talk by Stefan Tenzer that is posted on YouTube, but you can only get the link for it by registering here.
My motivation was something called VistaScan that is now available on some/most(?) TIMSTOFs if you have TIMSControl 5 or higher. VistaScan is related to midiaPASEF, but on a limited scale.
My real motivation was trying to make VistaScan do something I want it to do that I can now say with absolute certainty that midiaPASEF can not do, nor will it ever be able to do it. Instead of being bitter about an hour of my life I will never ever get back (the video is shorter than that I had to stop and think about things and back up several times), I'm legitimately really happy to understand the concept.
Like the other diaPASEF methods, this one leverages the very handy properties of being able to discriminate peptides by retention time, ion mobility and accurate mass. What sets this one apart is that the quadrupole (the fastest part) is moving in overlapping windows. Obviously, not new stuff, and this method was inspired by MacCoss lab's multiplexed PRM stuff that is so smart that no one aside from the authors have ever been smart enough to use it themselves.
While on the surface you can look at the midiaPASEF posters and technical notes from the vendor and think - "okay, they're doing tiny window DIA while leveraging ion mobility" (okay, that's what I thought). It's not quite that. It is still using relatively large mass isolation windows, but because they're overlapping and the data acquisition is very very fast, they can deconvolute the data (again, similar to multiplexing PRMs).
The trick, then, is on the software side, where the data needs to be modeled over the sliding windows. If, for example, you see your precursor fall off as the quad slides past a certain point, then you know the upper mass range of that precursor. Where this gets really smart is that they also have to track the fragment ions the same way.
Your diaPASEF window is still loaded with fragments from everything within the 12 Th (or 16 Th, I forget) window, but by modeling the fragments that disappear as you tick the isolation window up or down, you can start to extract the fragments that correspond with that exact precursor.
You get the added benefit on top that you are altering the TIMS isolation as well. Where this becomes contrary to my motivations was that I was simply hoping to do the 2Da window overlapping DIA stuff that I was doing for SCoPE-MS on the ZenoTOF with an extra dimension - ion mobility.
But if I'm tracking reporter ions which are present in every MS2 scan, then these can't be modeled. It is definitely possible, however, to use the complementary ion pairs, but to process those data you've either got to have Thermo .RAW or have access to that super mysterious data processing server that has those capabilities. Neither of which match here.
Doesn't work for my application, but it's still super cool. Where I have a disconnect is the VistaScan thing which appears to be a limited version of midiaPASEF that only works for some applications. I'm hoping to test some things on it (just got a 5.0 upgrade) and I suspect that we can generate the data but not process much of it. We'll see though!
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