用少步生成高精度蛋白复合物结构,速度提升5倍
Few-step Cofolding with All-Atom Flow Maps

- 将扩散模型蒸馏为流形映射,仅需几步即可生成原子级结构
- 在Runs N' Poses上以5倍少的计算量实现更优的构象准确率
- 适合需要快速生成高精度生物分子结构的研究者使用
全原子生成建模已成为预测蛋白质及蛋白-配体复合物结构的主流方法。然而,高保真度的原子级生成通常依赖昂贵的迭代扩散推演,导致传统部署和推理时搜索成本高昂。本文提出基于去噪器的流形映射框架DeCAF,将最先进的全原子共折叠模型蒸馏为仅需少数推理步数即可生成高质量样本的全原子流形映射。该框架采用端点损失的去噪器形式,天然支持SE(3)刚性对齐,对训练精确模型至关重要。我们进一步推导了变量变换,使DeCAF可在EDM类架构的σ空间噪声调度中运行,从而直接从预训练的共折叠扩散模型蒸馏。结合DeCAF的流形前瞻能力,我们构建了专用于推理阶段的奖励引导搜索框架。实验证明,在挑战性的Runs N' Poses数据集上,DeCAF-Boltz在严格NFE预算下相比Boltz-1x在构象均方根偏差(RMSD)和物理合理性评分上均有提升;在PoseBusters上,所有计算预算下均展现更优的帕累托前沿。蒸馏自最先进珍珠模型(Pearl)的DeCAF-Pearl,在成功率上与教师模型相当,但仅需5倍少的NFE。代码已开源:https://github.com/genesistherapeutics/decaf。
原文摘要 · Abstract (English)
All-atom generative modeling of 3D biomolecular complexes has emerged as the dominant paradigm for predicting the structure of proteins and protein-ligand systems. Generating structures at the atomic level of fidelity, however, typically requires expensive iterative diffusion rollouts, making both conventional deployment and inference-time search techniques computationally costly. In this paper, we introduce the Denoiser Cofolding All-Atom Flowmap (DeCAF) framework for distilling state-of-the-art all-atom cofolding models into all-atom flow maps that produce high-quality samples in only a few inference steps. We build DeCAF on a denoiser-based formulation of flow maps with endpoint losses that naturally support SE(3) rigid alignment, which we show is critical for training accurate models. We further derive a simple change of variables that lets DeCAF operate in the σ-space noise schedule of EDM-style architectures, enabling direct distillation from pretrained cofolding diffusion models. Equipped with DeCAF's flowmap lookahead, we introduce a purpose-built inference-time framework that improves sampling through reward-guided search. Empirically, DeCAF-Boltz statistically improves over Boltz-1x in both accuracy (RMSD) and physical validity scores of protein-ligand poses at strict NFE budgets on the challenging Runs N' Poses, while also showing a more optimal Pareto frontier across all inference compute budgets on PoseBusters. Distilling the state-of-the-art Pearl cofolding model, DeCAF-Pearl outperforms diffusion-based cofolding models and matches its teacher on success rate while using 5x fewer NFEs. We release our code at https://github.com/genesistherapeutics/decaf.
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