Non-Canonical Crosslinks Confound Evolutionary Protein Structure Models

• URL: http://arxiv.org/abs/2503.17368v1
• Date: Sun, 09 Mar 2025 08:18:11 GMT
• Title: Non-Canonical Crosslinks Confound Evolutionary Protein Structure Models
• Abstract summary: We present an out-of-domain benchmark based on sacRitipeptides, a rare class of ribosomally synthesized and post-translationally modified peptides.<n>We evaluate recent models on predicting conformations compatible with cross-links bridges for the 10 known sactipeptides with elucidated post-translational modifications.<n>Our results point to the need for physics-informed models to sustain progress in biomolecular structure prediction.
• Score: 0.0
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: 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-$\alpha$-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-$\alpha$-carbon distance). Our results point at the need for physics-informed models to sustain progress in biomolecular structure prediction.

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