标题： 非规范交联干扰进化蛋白质结构模型 显示英文标题

标题： Non-Canonical Crosslinks Confound Evolutionary Protein Structure Models

摘要： 基于进化的方法在蛋白质结构预测模型方面近年来取得了突破性成功。 然而，它们难以超越进化先验并在缺乏丰富同源数据的序列上进行泛化。 在此，我们提出了一种基于sactipeptides的新颖的域外基准，sactipeptides是一种稀有的核糖体合成和翻译后修饰肽（RiPPs），其特征是硫原子与$\alpha$-碳原子之间的硫醚桥，形成半胱氨酸残基与主链之间的交联。 我们评估了最近的模型在预测与这些交联桥兼容的构象方面的能力，针对10种已阐明翻译后修饰的sactipeptides进行测试。 关键的是，其中5种的结构尚未被实验解析。 这使得该任务对基于进化的模型来说是一个具有挑战性的问题，我们发现这些模型的表现有限（硫原子与$\alpha$-碳原子距离的GDT-TS得分为0.0%至19.2%）。 我们的结果表明，需要引入物理信息的模型来维持生物分子结构预测的进展。 显示英文摘要

摘要： 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.