Simulation-based inference provides a powerful framework for cryo-electron microscopy, employing neural networks in methods like CryoSBI to infer biomolecular conformations via learned latent representations. This latent space represents a rich opportunity, encoding valuable information about the physical system and the inference process. Harnessing this potential hinges on understanding the underlying geometric structure of these representations. We investigate this structure by applying manifold learning techniques to CryoSBI representations of hemagglutinin (simulated and experimental). We reveal that these high-dimensional data inherently populate low-dimensional, smooth manifolds, with simulated data effectively covering the experimental counterpart. By characterizing the manifold's geometry using Diffusion Maps and identifying its principal axes of variation via coordinate interpretation methods, we establish a direct link between the latent structure and key physical parameters. Discovering this intrinsic low-dimensionality and interpretable geometric organization not only validates the CryoSBI approach but enables us to learn more from the data structure and provides opportunities for improving future inference strategies by exploiting this revealed manifold geometry.
View on arXiv@article{evans2025_2504.11249,
title={ Cryo-em images are intrinsically low dimensional },
author={ Luke Evans and Octavian-Vlad Murad and Lars Dingeldein and Pilar Cossio and Roberto Covino and Marina Meila },
journal={arXiv preprint arXiv:2504.11249},
year={ 2025 }
}