CryoCCD: Conditional Cycle-consistent Diffusion with Biophysical Modeling for Cryo-EM Synthesis

Abstract: Cryo-electron microscopy (cryo-EM) offers near-atomic resolution imaging of macromolecules, but developing robust models for downstream analysis is hindered by the scarcity of high-quality annotated data. While synthetic data generation has emerged as a potential solution, existing methods often fail to capture both the structural diversity of biological specimens and the complex, spatially varying noise inherent in cryo-EM imaging. To overcome these limitations, we propose CryoCCD, a synthesis framework that integrates biophysical modeling with generative techniques. Specifically, CryoCCD produces multi-scale cryo-EM micrographs that reflect realistic biophysical variability through compositional heterogeneity, cellular context, and physics-informed imaging. To generate realistic noise, we employ a conditional diffusion model, enhanced by cycle consistency to preserve structural fidelity and mask-aware contrastive learning to capture spatially adaptive noise patterns. Extensive experiments show that CryoCCD generates structurally accurate micrographs and enhances performance in downstream tasks, outperforming state-of-the-art baselines in both particle picking and reconstruction.