arXiv:2510.10480cs.LGcs.AI2025-10NeurIPS

用已有蛋白结合界面引导生成新结合物,提升设计准确性和泛化能力。

Latent Retrieval Augmented Generation of Cross-Domain Protein Binders

  • 在统一对比潜空间中融合检索与生成,实现跨领域接口迁移。
  • 在结合亲和力、几何结构和相互作用恢复上显著优于基线模型。
  • 可从肽类、抗体等不同领域检索接口,增强对新靶点的适应能力。

设计针对特定位点的蛋白结合物,需生成真实且功能合理的相互作用模式,是药物发现中的核心挑战。现有基于结构的生成模型在生成具有足够合理性和可解释性的结合界面方面存在局限。本文提出 Retrieval-Augmented Diffusion for Aligned interface (RADiAnce) 框架,利用已知结合界面引导新型结合物的设计。通过在共享对比潜空间中统一检索与生成,模型能高效识别目标结合位点的相关接口,并通过条件潜空间扩散生成器无缝整合这些接口,实现跨域界面迁移。大量实验表明,RADiAnce 在多个指标上显著优于基线模型,包括结合亲和力、几何结构和相互作用的恢复度。额外实验验证了跨域泛化能力,证明从肽类、抗体和蛋白片段等多样化领域检索接口,可提升对其他领域结合物的生成性能。本工作建立了一种新范式,成功融合基于检索的知识与生成式AI,为药物发现开辟新路径。

原文摘要 · Abstract (English)

Designing protein binders targeting specific sites, which requires to generate realistic and functional interaction patterns, is a fundamental challenge in drug discovery. Current structure-based generative models are limited in generating nterfaces with sufficient rationality and interpretability. In this paper, we propose Retrieval-Augmented Diffusion for Aligned interface (RADiAnce), a new framework that leverages known interfaces to guide the design of novel binders. By unifying retrieval and generation in a shared contrastive latent space, our model efficiently identifies relevant interfaces for a given binding site and seamlessly integrates them through a conditional latent diffusion generator, enabling cross-domain interface transfer. Extensive exeriments show that RADiAnce significantly outperforms baseline models across multiple metrics, including binding affinity and recovery of geometries and interactions. Additional experimental results validate cross-domain generalization, demonstrating that retrieving interfaces from diverse domains, such as peptides, antibodies, and protein fragments, enhances the generation performance of binders for other domains. Our work establishes a new paradigm for protein binder design that successfully bridges retrieval-based knowledge and generative AI, opening new possibilities for drug discovery.

蛋白设计生成模型跨域迁移药物发现

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