# Latent Space Diffusion Models of Cryo-EM Structures

arXiv: https://arxiv.org/abs/2211.14169 · HTML: https://mlsanity.com/paper/2211.14169/

## Key facts

- Cited by 6 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 42 of its 67 references that are in the map.
- First posted on arXiv 25 Nov 2022.

## 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, 30 of 42)

- [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)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Hierarchical Text-Conditional Image Generation with CLIP Latents](https://mlsanity.com/paper/2204.06125/) (2022)
- [Photorealistic Text-to-Image Diffusion Models with Deep Language Understanding](https://mlsanity.com/paper/2205.11487/) (2022)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Auto-Encoding Variational Bayes](https://mlsanity.com/paper/1312.6114/) (2013)
- [Neural Ordinary Differential Equations](https://mlsanity.com/paper/1806.07366/) (2018)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Elucidating the Design Space of Diffusion-Based Generative Models](https://mlsanity.com/paper/2206.00364/) (2022)
- [UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction](https://mlsanity.com/paper/1802.03426/) (2018)
- [Image Super-Resolution via Iterative Refinement](https://mlsanity.com/paper/2104.07636/) (2021)
- [Palette: Image-to-Image Diffusion Models](https://mlsanity.com/paper/2111.05826/) (2021)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [NVAE: A Deep Hierarchical Variational Autoencoder](https://mlsanity.com/paper/2007.03898/) (2020)
- [Score-based Generative Modeling in Latent Space](https://mlsanity.com/paper/2106.05931/) (2021)
- [FFJORD: Free-form Continuous Dynamics for Scalable Reversible Generative Models](https://mlsanity.com/paper/1810.01367/) (2018)
- [Neural Fields in Visual Computing and Beyond](https://mlsanity.com/paper/2111.11426/) (2021)
- [Tackling the Generative Learning Trilemma with Denoising Diffusion GANs](https://mlsanity.com/paper/2112.07804/) (2021)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [Diffusion Autoencoders: Toward a Meaningful and Decodable Representation](https://mlsanity.com/paper/2111.15640/) (2021)
- [Score-based Generative Modeling of Graphs via the System of Stochastic Differential Equations](https://mlsanity.com/paper/2202.02514/) (2022)
- [Very Deep VAEs Generalize Autoregressive Models and Can Outperform Them on Images](https://mlsanity.com/paper/2011.10650/) (2020)
- [Torsional Diffusion for Molecular Conformer Generation](https://mlsanity.com/paper/2206.01729/) (2022)
- [VAE with a VampPrior](https://mlsanity.com/paper/1705.07120/) (2017)
- [Diffusion probabilistic modeling of protein backbones in 3D for the motif-scaffolding problem](https://mlsanity.com/paper/2206.04119/) (2022)
- [Score-Based Generative Modeling with Critically-Damped Langevin Diffusion](https://mlsanity.com/paper/2112.07068/) (2021)
- [Learning Gradient Fields for Molecular Conformation Generation](https://mlsanity.com/paper/2105.03902/) (2021)

## Built on by (most cited first, 6 of 6)

- [Boundary Guided Learning-Free Semantic Control with Diffusion Models](https://mlsanity.com/paper/2302.08357/) (2023)
- [Solving Inverse Problems via Diffusion-Based Priors: An Approximation-Free Ensemble Sampling Approach](https://mlsanity.com/paper/2506.03979/) (2025)
- [Diffusion Models in Bioinformatics: A New Wave of Deep Learning Revolution in Action](https://mlsanity.com/paper/2302.10907/) (2023)
- [CryoFM: A Flow-based Foundation Model for Cryo-EM Densities](https://mlsanity.com/paper/2410.08631/) (2024)
- [Diffusion-driven lensless fiber endomicroscopic quantitative phase imaging towards digital pathology](https://mlsanity.com/paper/2407.18456/) (2024)
- [Denoising diffusion models for high-resolution microscopy image restoration](https://mlsanity.com/paper/2409.12078/) (2024)

## Abstract (arXiv)

Cryo-electron microscopy (cryo-EM) is unique among tools in structural biology in its ability to image large, dynamic protein complexes. Key to this ability is image processing algorithms for heterogeneous cryo-EM reconstruction, including recent deep learning-based approaches. The state-of-the-art method cryoDRGN uses a Variational Autoencoder (VAE) framework to learn a continuous distribution of protein structures from single particle cryo-EM imaging data. While cryoDRGN can model complex structural motions, the Gaussian prior distribution of the VAE fails to match the aggregate approximate posterior, which prevents generative sampling of structures especially for multi-modal distributions (e.g. compositional heterogeneity). Here, we train a diffusion model as an expressive, learnable prior in the cryoDRGN framework. Our approach learns a high-quality generative model over molecular conformations directly from cryo-EM imaging data. We show the ability to sample from the model on two synthetic and two real datasets, where samples accurately follow the data distribution unlike samples from the VAE prior distribution. We also demonstrate how the diffusion model prior can be leveraged for fast latent space traversal and interpolation between states of interest. By learning an accurate model of the data distribution, our method unlocks tools in generative modeling, sampling, and distribution analysis for heterogeneous cryo-EM ensembles.