Covalent Protein Painting to measure in vivo protein misfolding!

If there is an easier looking experimental method to measure protein misfolding in vivo, I've never seen it.

If you are interested in structural proteomics stuff at all, I highly recommend this preprint.

Formaldehyde is pretty efficient at binding to proteins! Turns out that:

1) you can get heavy stable isotopically labeled formaldehyde
2) in your cells the formaldehyde can only get access to the outside of your protein 3D structures, effectively "painting" the surface of them.
3) You can compare different biological conditions by using "heavy" and "light" formaldehyde.

Digest your proteins with chymotrypsin and 'voila -- you can quantitatively compare the outside of your proteins and protein-protein complexes!

The downside here is that you have to think hard about the peptide identifications as -- CDH2 : 13CH3 , 13CH3 : CDH2 , 13CHD2 : CD3 , CD3 : 13CHD2 -- could correspond to Disaster Level: "deuterated deamidation" study.

To fully eliminate this an issue, these authors acquired MS/MS at 120,000 resolution! Which...in my opinion is overkill, but on the instrument they used, theyv'e got 60,000 or 120,000 to choose from and 60,000 is going to get a little sketchy on the larger fragment ions. (Loosely related...I commonly run at 90,000 resolution on another instrument...)

Despite the decreased number of scans possible on an LC time scale, they come back with a tremendous amount of data.

In case any of the author see this -- Unless I'm completely misunderstanding what I'm seeing -- Extended Data Figure #4 is possibly my favorite visualization I've seen of anything so far this year. (Maybe I should put this commend on the bioRXIV thing like I'm supposed to....)

Oh yeah! I almost forgot! On top of how cool the technique is, the authors make some interesting findings regarding protein folding and alzheimers!