That’s a bit of relief at least! 🐚🦪

Pierre Clostermann during WWII

Thanks to Hannah @wastyk.bsky.social & Will at InterfaceBio for advice on sactipeptides, and to the authors of AlphaFold 2 & 3, ESMFold, Boltz-1 (@gcorso.bsky.social), and more!

📝 Link to paper: biorxiv.org/content/10.1...

💻 Link to code: github.com/rlacombe/Sac...

Excited to be presenting this work at the
@stanfordbiosci.bsky.social workshop on Experimental Design in AI for Science next week!

More info on the event here: edai4science.github.io

These results highlight the limits of the (extremely successful) evolutionary approach to protein structure prediction.

We will likely need physics-informed models to reach accurate 3D structure predictions on rare PTMs and out-of-domain proteins beyond evolutionary priors.

No model achieved crosslink distances near the experimentally observed 1.8Å sulfur-to-α-carbon bond length, with average performance at 10-12Å.

Most models incorrectly predicted disulfide bonds instead of thioether crosslinks, highlighting their reliance on evolutionary priors.

We evaluate 6 leading protein structure predictors—AlphaFold 2 and 3, Boltz-1, ESMFold, OmegaFold, and RoseTTAFold 2—on the 10 known sactipeptides.

All models exhibit limited performance, with an average GDT-TS of only 11.5% for known sactipeptides and 12.6% for unknown ones.

This helps us probe how deep learning models generalize beyond evolutionary priors.

We introduce a new, zero-shot benchmark for structure models: measuring how the 3D conformations predicted for sactipeptides match the geometry imposed by their known thioether crosslinks.

These non-canonical crosslinks are challenging and underrepresented in structural datasets. Crucially, *only 5* of the 10 known sactipeptides have a resolved 3d conformation with a PDB entry. *But* their 2d crosslink structure is known, which constrains possible 3d geometries!

Evolution-based protein structure prediction models have revolutionized structural biology but struggle with rare post-translational modifications (PTMs). We evaluate them on sactipeptides, a rare class of 10 known peptides with unique sulfur-to-α-carbon thioether crosslinks.

Pre-ordered! 🛍️🤞

Oooh that looks beautiful! When can we pre-order?

Anecdotally, @dcrainmaker.com has a treasure trove of GPS accuracy tests in land and marine conditions for most watches and trackers on the market.

This guy is *such* a jerk. Ugh! Only good thing is it’s out in the open for anyone to see.