Template Learning: Deep Learning with Domain Randomization for Particle Picking in Cryo-Electron Tomography

Cryo-electron tomography (cryo-ET) enables the three-dimensional visualization of biomolecules and cellular components in their near-native state. Particle picking, a crucial step in cryo-ET data analysis, is traditionally performed by template matching—a method utilizing cross-correlations with available biomolecular templates. Despite the effectiveness of recent deep learning-based particle picking approaches, their dependence on initial data annotation datasets for supervised training remains a significant limitation. Here, we propose a technique that combines the accuracy of deep learning particle identification with the convenience of the model training on biomolecular templates enabled through a tailored domain randomization approach. Our technique, named Template Learning, automates the simulation of training datasets, incorporating considerations for molecular crowding, structural variabilities, and data acquisition variations. This reduces or even eliminates the dependence of supervised deep learning on annotated experimental datasets. We demonstrate that models trained on simulated datasets, optionally fine-tuned on experimental datasets, outperform those exclusively trained on experimental datasets. Also, we illustrate that Template Learning used as an alternative to template matching, can offer higher precision and better orientational isotropy, especially for picking small non-spherical particles. Template Learning software is open-source, Python-based, and GPU and CPU parallelized.