Finally, I am happy to say that I am trying to relocate to @bsky.app after a science social media hiatus. Looking forward to reconnect with you here. Please follow us if you find our work on protein folding interesting! 9/9

We have benefitted immensely from collaboration with Ed O'Brien, and this project was spearheaded by the remarkable team of Yang Jiang and
@friedlab.bsky.social's April Xia. Thanks to NSF and NIH for their support of this work. 8/9

To summarize, we think that entangled states represent a class of misfolding that can explain complex refolding kinetics & why some proteins do not refold efficiently. Since they are not easily caught by chaperones, they may pose dangers to our cells too. 7/9

We also used two types of structural mass spectrometry, LiP-MS and XL-MS, to characterize the topologically misfolded form of PGK and showed that these features match the entangled conformations from simulations quite well. 6/9

We showed this in a few ways. First, Yang ran extensive simulations on PGK, showing it gets entangled, and if you take the trajectories away with entanglements the stretched exponential signature also disappears. 5/9

But if this is true, what are these various non-native states that cannot just sort themselves out and get back on the normal folding path? We think they are "entangled states," or conformations with non-covalent lasso entanglements. 4/9

Physically, this could correspond to a scenario of a rough free energy landscape with many non-native minima that do not easily interconvert and which have a diverse spectrum of rate constants. 3/9

Where do we begin? In the late 90s, protein folders noticed that not all proteins fold with expected single-exponential kinetics. The enzyme from glycolysis, PGK, appears to follow a stretched exponential function instead. 2/9