Very excited to share that our work on Protein Nonrefoldability is out today in @J_A_C_S! #AlphaFold might be great at finding proteins' native structures... but turns out many proteins themselves are not! Short 🧵1/7
pubs.acs.org/doi/full/10.10…
pubs.acs.org/doi/full/10.10…
We developed a mass spec approach to probe the refoldability of the proteome. First we unfold & refold E. coli extracts, then use a protease to interrogate the structures of 'refolded' proteins. The resulting peptide fragments are sequenced by LC-MS & compared to native. 2/7 
We found that most simple 'model' proteins are well-behaved and can refold on their own. But lots of multi-subunit assemblies, multi-domain proteins, and certain fold-types cannot fully refold intrinsically. 3/7
One finding that surprised us a lot is that the E. coli large subunit of the ribosome apparently CAN REFOLD out of a complex mixture, but the small subunit CANNOT. This might have interesting implications for the #OriginsOfLife. 4/7
Rather than look at nonrefoldability as 'pathological,' we think it should be seen as a 'starting point' for understanding what cellular factors and processes (like chaperones or translation) are necessary to support the biogenesis of complex proteins. 5/7
These findings highlight that protein folding is a journey, not just a destination, and there's much more to learn! Structure prediction is powerful, but still only one part of the #ProteinFolding story. 6/7
Finally, I want to thank the amazing @fried_lab team @PtoChem, Briana Whitehead, and HaleyTarbox @CbiJhu; and mentors @MarquseeLab & Doug Barrick. And especially Dan Tawfik @WeizmannScience, who openly reviewed the paper and made it MUCH better. We miss you so much already.
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