arXiv:2602.13249q-bio.BMcs.AI2026-02被引 1

用蛋白-配体共折叠提升小分子表征,效果优于传统方法。

A Systematic Evaluation of Co-folding Model Representations for Small-Molecule Learning

  • 用Boltz2模型学习配体与蛋白的原子级相互作用。
  • 在ADMET测试中表现媲美甚至超过现有模型,生成更快、优化更高效。
  • 适合做药物发现的表征基础,尤其对结构引导设计有帮助。

小分子基础模型通常仅在独立分子数据上预训练,而视觉和语言模型常受益于跨模态或关系监督。蛋白-配体共折叠为分子学习提供了类似监督机制,通过暴露模型于原子级别的配体-蛋白相互作用,引发一个关键问题:共折叠模型能否生成强健的小分子表征?本文以现代共折叠模型Boltz2为例,将其原子级配体表示迁移到独立小分子任务中。通过系统探查与知识蒸馏,我们发现Boltz2表征在ADMET基准上达到或超越现有模型性能,加速分子生成建模,并提升结构引导配体优化的样本效率。进一步发现,Boltz2表征与传统独立分子监督学习得到的表征(包括3D构象、生物活性标签、量子化学性质)具有互补性。最后,我们将表征对齐扩展至强化学习,表明密集的表征级监督可有效补充标量奖励,在分子发现中发挥协同作用。这些结果确认蛋白-配体共折叠是小分子表征学习的有力预训练范式,确立Boltz2作为强大且即插即用的小分子基础模型。

原文摘要 · Abstract (English)

Small-molecule foundation models are typically pretrained on standalone molecular data, unlike vision and language models that often benefit from cross-modal or relational supervision. Protein-ligand co-folding provides a molecular analogue of such supervision by exposing models to atom-level ligand-protein interactions, raising the question of whether co-folding models can yield strong small-molecule representations. We study this question using Boltz2, a modern co-folding model, by transferring its atom-level ligand representations to standalone small-molecule tasks. Through systematic probing and distillation, we show that Boltz2 representations match or outperform existing models on the ADMET benchmark, accelerate molecular generative modeling, and improve sample efficiency in structure-guided ligand optimization. We further find that Boltz2 representations are complementary to those learned from conventional standalone molecular supervision, including 3D conformers, bioassay labels, and quantum-chemical properties. Finally, we extend representation alignment to reinforcement learning, showing that dense representation-level supervision can complement scalar rewards in molecular discovery. These results identify protein-ligand co-folding as a promising pretraining paradigm for small-molecule representation learning and position Boltz2 as a strong, off-the-shelf molecular foundation model.

小分子表征共折叠药物发现Boltz2

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