Few-Step Cofolding with All-Atom Flow Maps

Abstract

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.