# Non-Canonical Crosslinks Confound Evolutionary Protein Structure Models

arXiv: https://arxiv.org/abs/2503.17368 · HTML: https://mlsanity.com/paper/2503.17368/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 1 of its 35 references that are in the map.
- First posted on arXiv 9 Mar 2025.

## Builds on (most cited first, 1 of 1)

- [ProteinBench: A Holistic Evaluation of Protein Foundation Models](https://mlsanity.com/paper/2409.06744/) (2024)

## Abstract (arXiv)

Evolution-based protein structure prediction models have achieved breakthrough success in recent years. However, they struggle to generalize beyond evolutionary priors and on sequences lacking rich homologous data. Here we present a novel, out-of-domain benchmark based on sactipeptides, a rare class of ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by sulfur-to-α-carbon thioether bridges creating cross-links between cysteine residues and backbone. We evaluate recent models on predicting conformations compatible with these cross-links bridges for the 10 known sactipeptides with elucidated post-translational modifications. Crucially, the structures of 5 of them have not yet been experimentally resolved. This makes the task a challenging problem for evolution-based models, which we find exhibit limited performance (0.0% to 19.2% GDT-TS on sulfur-to-α-carbon distance). Our results point at the need for physics-informed models to sustain progress in biomolecular structure prediction.