cs.LGJun 3, 2026

ProHiFlo: Hierarchical Flow Matching with Functional Guidance for De Novo Protein Generation

Authors: Chuanzhen WangMeade CletiPete Jano

Organizations: 3Tongji University · 1Arizona State University · University of Wisconsin-Madison

Abstract

De novo protein generation has transformative potential in therapeutic design, enzyme engineering, and synthetic biology. While diffusion-based and flow matching approaches have achieved progress, they typically operate at single resolution and lack mechanisms for incorporating functional constraints. We introduce ProHiFlo, a hierarchical flow matching framework with three innovations: (1) coarse-to-fine generation that models backbone geometry before refining to all-atom coordinates, reducing computational cost while maintaining accuracy; (2) functional guidance leveraging pretrained predictors to steer generation toward desired properties without retraining; (3) adaptive SE(3)-equivariant architecture for efficient multi-scale processing. Experiments on unconditional generation, motif scaffolding, and functional design demonstrate state-ofthe-art performance while requiring 4 fewer sampling steps. On enzyme active site scaffolding, ProHiFlo achieves 58.9% success rate compared to 41.2% for RFDiffusion.

Explore similar work

CardsList
  1. Emyx: Fast and efficient all-atom protein generation

    Jun 12, 2026Nicholas J. Williams, Ward Haddadin, Matteo P. Ferla +6Protein DesignProtein

  2. SPID: Distilled Protein Backbone Generation

    Oct 3, 2025Liyang Xie, Haoran Zhang, Zhendong Wang +2Protein Design