Resolving compositional and conformational heterogeneity in cryo-EM with deformable 3D Gaussian representations

TL;DR

GaussianEM introduces a novel Gaussian-based framework for cryo-EM data analysis, effectively resolving protein heterogeneity and conformational dynamics at atomic detail, enhancing understanding of protein flexibility.

Contribution

The paper presents GaussianEM, a new pseudo-atomic method that explicitly models conformational variability in cryo-EM data using Gaussian components, enabling continuous and detailed structural reconstructions.

Findings

Successfully reconstructs complex heterogeneity in cryo-EM datasets

Captures atomic-scale conformational landscapes

Resolves previously unobserved structural details

Abstract

Understanding protein flexibility and its dynamic interactions with other molecules is essential for studying protein function. Although cryogenic electron microscopy(cryo-EM) provides an opportunity to observe macromolecular dynamics directly, computational analysis of datasets mixing continuous and discrete structural states remains a formidable challenge. Here we introduce GaussianEM, a Gaussian-based pseudo-atomic framework that simultaneously resolves compositional and conformational heterogeneity from cryo-EM images. GaussianEM employs a dual-encoder-single-decoder architecture to decompose images into learnable Gaussian components, with variability encoded through modulated parameters. This explicit parameterization yields a continuous, intuitive representation of conformational dynamics that inherently preserves local structural integrity. By modeling displacements in Gaussian space, we capture atomic-scale conformational landscapes, bridging density maps and all-atom models. In comprehensive experiments, GaussianEM successfully reconstructs complex compositional and conformational variability,and resolves previously unobserved details in public datasets. Quantitative evaluations further confirm its ability to capture broader conformational diversity without sacrificing structural fidelity.