# Frame-based Equivariant Diffusion Models for 3D Molecular Generation

arXiv: https://arxiv.org/abs/2509.19506 · HTML: https://mlsanity.com/paper/2509.19506/

## Key facts

- Cited by 2 papers in the map (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 20 of its 25 references that are in the map.
- First posted on arXiv 23 Sep 2025.

## 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, 20 of 20)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Scalable Diffusion Models with Transformers](https://mlsanity.com/paper/2212.09748/) (2022)
- [Generative Modeling by Estimating Gradients of the Data Distribution](https://mlsanity.com/paper/1907.05600/) (2019)
- [Stable Video Diffusion: Scaling Latent Video Diffusion Models to Large Datasets](https://mlsanity.com/paper/2311.15127/) (2023)
- [Video Diffusion Models](https://mlsanity.com/paper/2204.03458/) (2022)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [On the Bottleneck of Graph Neural Networks and its Practical Implications](https://mlsanity.com/paper/2006.05205/) (2020)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [ChemRL-GEM: Geometry Enhanced Molecular Representation Learning for Property Prediction](https://mlsanity.com/paper/2106.06130/) (2021)
- [Geometric Latent Diffusion Models for 3D Molecule Generation](https://mlsanity.com/paper/2305.01140/) (2023)
- [Equivariance with Learned Canonicalization Functions](https://mlsanity.com/paper/2211.06489/) (2022)
- [Breaking the Limits of Message Passing Graph Neural Networks](https://mlsanity.com/paper/2106.04319/) (2021)
- [Equivariant Point Cloud Analysis via Learning Orientations for Message Passing](https://mlsanity.com/paper/2203.14486/) (2022)
- [A Canonicalization Perspective on Invariant and Equivariant Learning](https://mlsanity.com/paper/2405.18378/) (2024)
- [Beyond Canonicalization: How Tensorial Messages Improve Equivariant Message Passing](https://mlsanity.com/paper/2405.15389/) (2024)
- [Using Multiple Vector Channels Improves E(n)-Equivariant Graph Neural Networks](https://mlsanity.com/paper/2309.03139/) (2023)
- [Symmetry-Aware Generative Modeling through Learned Canonicalization](https://mlsanity.com/paper/2501.07773/) (2025)
- [Scalable Non-Equivariant 3D Molecule Generation via Rotational Alignment](https://mlsanity.com/paper/2506.10186/) (2025)

## Built on by (most cited first, 2 of 2)

- [Fixed-Dimensional Latent Flow for Generating Variable-Size 3D Molecules](https://mlsanity.com/paper/2609.08333/) (2026)
- [Diffusion Models at the Drug Discovery Frontier: A Review on Generating Small Molecules versus Therapeutic Peptides](https://mlsanity.com/paper/2511.00209/) (2025)

## Abstract (arXiv)

Recent methods for molecular generation face a trade-off: they either enforce strict equivariance with costly architectures or relax it to gain scalability and flexibility. We propose a frame-based diffusion paradigm that achieves deterministic E(3)-equivariance while decoupling symmetry handling from the backbone. Building on this paradigm, we investigate three variants: Global Frame Diffusion (GFD), which assigns a shared molecular frame; Local Frame Diffusion (LFD), which constructs node-specific frames and benefits from additional alignment constraints; and Invariant Frame Diffusion (IFD), which relies on pre-canonicalized invariant representations. To enhance expressivity, we further utilize EdgeDiT, a Diffusion Transformer with edge-aware attention. On the QM9 dataset, GFD with EdgeDiT achieves state-of-the-art performance, with a test NLL of -137.97 at standard scale and -141.85 at double scale, alongside atom stability of 98.98%, and molecular stability of 90.51%. These results surpass all equivariant baselines while maintaining high validity and uniqueness and nearly 2x faster sampling compared to EDM. Altogether, our study establishes frame-based diffusion as a scalable, flexible, and physically grounded paradigm for molecular generation, highlighting the critical role of global structure preservation.