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

arXiv: https://arxiv.org/abs/2606.11243 · HTML: https://mlsanity.com/paper/2606.11243/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 21 of its 46 references that are in the map.
- First posted on arXiv 3 Jun 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 21 of 21)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Neural Ordinary Differential Equations](https://mlsanity.com/paper/1806.07366/) (2018)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [SE(3)-Transformers: 3D Roto-Translation Equivariant Attention Networks](https://mlsanity.com/paper/2006.10503/) (2020)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [Equiformer: Equivariant Graph Attention Transformer for 3D Atomistic Graphs](https://mlsanity.com/paper/2206.11990/) (2022)
- [SE(3) diffusion model with application to protein backbone generation](https://mlsanity.com/paper/2302.02277/) (2023)
- [Protein Design with Guided Discrete Diffusion](https://mlsanity.com/paper/2305.20009/) (2023)
- [SE(3)-Stochastic Flow Matching for Protein Backbone Generation](https://mlsanity.com/paper/2310.02391/) (2023)
- [Generating Novel, Designable, and Diverse Protein Structures by Equivariantly Diffusing Oriented Residue Clouds](https://mlsanity.com/paper/2301.12485/) (2023)
- [Equivariant Graph Neural Networks for 3D Macromolecular Structure](https://mlsanity.com/paper/2106.03843/) (2021)
- [Out of Many, One: Designing and Scaffolding Proteins at the Scale of the Structural Universe with Genie 2](https://mlsanity.com/paper/2405.15489/) (2024)
- [R2I-Bench: Benchmarking Reasoning-Driven Text-to-Image Generation](https://mlsanity.com/paper/2505.23493/) (2025)
- [GUI Agents for Continual Game Generation](https://mlsanity.com/paper/2605.28258/) (2026)
- [MemMark: State-Evolution Attribution Watermarking for Agent Long-Term Memory Systems](https://mlsanity.com/paper/2605.25002/) (2026)
- [MVI-Bench: A Comprehensive Benchmark for Evaluating Robustness to Misleading Visual Inputs in LVLMs](https://mlsanity.com/paper/2511.14159/) (2025)
- [SuperFlow: Training Flow Matching Models with RL on the Fly](https://mlsanity.com/paper/2512.17951/) (2025)
- [From Noise to Nuance: Advances in Deep Generative Image Models](https://mlsanity.com/paper/2412.09656/) (2024)
- [Advanced Deep Learning Methods for Protein Structure Prediction and Design](https://mlsanity.com/paper/2503.13522/) (2025)

## Abstract (arXiv)

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.