# Generating Novel, Designable, and Diverse Protein Structures by Equivariantly Diffusing Oriented Residue Clouds

arXiv: https://arxiv.org/abs/2301.12485 · HTML: https://mlsanity.com/paper/2301.12485/

## Key facts

- Cited by 54 papers in the map (data through 14 Oct 2026).
- Builds on 17 of its 49 references that are in the map.
- First posted on arXiv 29 Jan 2023.

## Builds on (most cited first, 17 of 17)

- [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)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Hierarchical Text-Conditional Image Generation with CLIP Latents](https://mlsanity.com/paper/2204.06125/) (2022)
- [Neural Discrete Representation Learning](https://mlsanity.com/paper/1711.00937/) (2017)
- [Auto-Encoding Variational Bayes](https://mlsanity.com/paper/1312.6114/) (2013)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Analyzing and Improving the Image Quality of StyleGAN](https://mlsanity.com/paper/1912.04958/) (2019)
- [Large Scale GAN Training for High Fidelity Natural Image Synthesis](https://mlsanity.com/paper/1809.11096/) (2018)
- [Generating Diverse High-Fidelity Images with VQ-VAE-2](https://mlsanity.com/paper/1906.00446/) (2019)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Tackling the Generative Learning Trilemma with Denoising Diffusion GANs](https://mlsanity.com/paper/2112.07804/) (2021)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [Diffusion probabilistic modeling of protein backbones in 3D for the motif-scaffolding problem](https://mlsanity.com/paper/2206.04119/) (2022)
- [Protein structure generation via folding diffusion](https://mlsanity.com/paper/2209.15611/) (2022)
- [Protein Structure and Sequence Generation with Equivariant Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2205.15019/) (2022)
- [Improved Consistency Regularization for GANs](https://mlsanity.com/paper/2002.04724/) (2020)

## Built on by (most cited first, 30 of 54)

- [Generative Flows on Discrete State-Spaces: Enabling Multimodal Flows with Applications to Protein Co-Design](https://mlsanity.com/paper/2402.04997/) (2024)
- [SE(3)-Stochastic Flow Matching for Protein Backbone Generation](https://mlsanity.com/paper/2310.02391/) (2023)
- [Diffusion Language Models Are Versatile Protein Learners](https://mlsanity.com/paper/2402.18567/) (2024)
- [Proteina: Scaling Flow-based Protein Structure Generative Models](https://mlsanity.com/paper/2503.00710/) (2025)
- [DPLM-2: A Multimodal Diffusion Protein Language Model](https://mlsanity.com/paper/2410.13782/) (2024)
- [Generative Modeling of Molecular Dynamics Trajectories](https://mlsanity.com/paper/2409.17808/) (2024)
- [DEFT: Efficient Fine-Tuning of Diffusion Models by Learning the Generalised h-transform](https://mlsanity.com/paper/2406.01781/) (2024)
- [Efficient Diffusion Models: A Comprehensive Survey from Principles to Practices](https://mlsanity.com/paper/2410.11795/) (2024)
- [Sequence-Augmented SE(3)-Flow Matching For Conditional Protein Backbone Generation](https://mlsanity.com/paper/2405.20313/) (2024)
- [AbDiffuser: Full-Atom Generation of in vitro Functioning Antibodies](https://mlsanity.com/paper/2308.05027/) (2023)
- [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)
- [La-Proteina: Atomistic Protein Generation via Partially Latent Flow Matching](https://mlsanity.com/paper/2507.09466/) (2025)
- [Str2Str: A Score-based Framework for Zero-shot Protein Conformation Sampling](https://mlsanity.com/paper/2306.03117/) (2023)
- [A Survey of Generative AI for de novo Drug Design: New Frontiers in Molecule and Protein Generation](https://mlsanity.com/paper/2402.08703/) (2024)
- [A Latent Diffusion Model for Protein Structure Generation](https://mlsanity.com/paper/2305.04120/) (2023)
- [PPFlow: Target-aware Peptide Design with Torsional Flow Matching](https://mlsanity.com/paper/2405.06642/) (2024)
- [ProteinBench: A Holistic Evaluation of Protein Foundation Models](https://mlsanity.com/paper/2409.06744/) (2024)
- [DiffPack: A Torsional Diffusion Model for Autoregressive Protein Side-Chain Packing](https://mlsanity.com/paper/2306.01794/) (2023)
- [A framework for conditional diffusion modelling with applications in motif scaffolding for protein design](https://mlsanity.com/paper/2312.09236/) (2023)
- [SimpleFold: Folding Proteins is Simpler than You Think](https://mlsanity.com/paper/2509.18480/) (2025)
- [Inverse folding for antibody sequence design using deep learning](https://mlsanity.com/paper/2310.19513/) (2023)
- [Diffusion on language model encodings for protein sequence generation](https://mlsanity.com/paper/2403.03726/) (2024)
- [ReQFlow: Rectified Quaternion Flow for Efficient and High-Quality Protein Backbone Generation](https://mlsanity.com/paper/2502.14637/) (2025)
- [Towards Joint Sequence-Structure Generation of Nucleic Acid and Protein Complexes with SE(3)-Discrete Diffusion](https://mlsanity.com/paper/2401.06151/) (2023)
- [Riemannian MeanFlow](https://mlsanity.com/paper/2602.07744/) (2026)
- [Generating Highly Designable Proteins with Geometric Algebra Flow Matching](https://mlsanity.com/paper/2411.05238/) (2024)
- [Generative artificial intelligence for de novo protein design](https://mlsanity.com/paper/2310.09685/) (2023)
- [De novo antibody design with SE(3) diffusion](https://mlsanity.com/paper/2405.07622/) (2024)
- [RNA-FrameFlow: Flow Matching for de novo 3D RNA Backbone Design](https://mlsanity.com/paper/2406.13839/) (2024)
- [PDFBench: A Benchmark for De novo Protein Design from Function](https://mlsanity.com/paper/2505.20346/) (2025)

## Abstract (arXiv)

Proteins power a vast array of functional processes in living cells. The capability to create new proteins with designed structures and functions would thus enable the engineering of cellular behavior and development of protein-based therapeutics and materials. Structure-based protein design aims to find structures that are designable (can be realized by a protein sequence), novel (have dissimilar geometry from natural proteins), and diverse (span a wide range of geometries). While advances in protein structure prediction have made it possible to predict structures of novel protein sequences, the combinatorially large space of sequences and structures limits the practicality of search-based methods. Generative models provide a compelling alternative, by implicitly learning the low-dimensional structure of complex data distributions. Here, we leverage recent advances in denoising diffusion probabilistic models and equivariant neural networks to develop Genie, a generative model of protein structures that performs discrete-time diffusion using a cloud of oriented reference frames in 3D space. Through in silico evaluations, we demonstrate that Genie generates protein backbones that are more designable, novel, and diverse than existing models. This indicates that Genie is capturing key aspects of the distribution of protein structure space and facilitates protein design with high success rates. Code for generating new proteins and training new versions of Genie is available at https://github.com/aqlaboratory/genie.