美国麻省理工学院Barrett M. Powell和Joseph H. Davis利用tomoDRGN从低温电子子断层图像中学习结构异质性。2024年3月8日，国际知名学术期刊《自然—方法学》在线发表了这一成果。

研究人员将最初为单光子冷冻电镜分析而创建的高表达性cryoDRGN（深度重构生成网络）深度学习架构，扩展到了低温电子断层成像（cryo-ET）。该新工具tomoDRGN可以学习cryo-ET数据集中结构异质性的连续低维表示，同时还能学习重建由底层数据支持的异质性结构集合。利用模拟和实验数据，研究人员描述了tomoDRGN中的架构选择，并对其进行了基准测试，这些选择是cryo-ET所必需的，也是其所支持的。

此外，研究人员还展示了tomoDRGN在分析不同数据集方面的功效，用它揭示了组装在类病毒颗粒中的人类免疫缺陷病毒（HIV）噬菌体复合物的高级组织结构，并解决了原位成像核糖体之间的广泛结构异质性。

据了解，cryo-ET技术可以观察到大分子复合物在细胞环境中的原生空间环境。通过迭代配准和平均化在纳米分辨率下，可视化此类复合物的冷冻电镜处理软件已得到很好的开发，但依赖于对相关复合物结构同质性的假设。最近开发的工具可以对结构多样性进行一定程度的评估，但在表现高度异质结构（包括正在发生持续构象变化的结构）方面能力有限。

附：英文原文

Title: Learning structural heterogeneity from cryo-electron sub-tomograms with tomoDRGN

Author: Powell, Barrett M., Davis, Joseph H.

Issue&Volume: 2024-03-08

Abstract: Cryo-electron tomography (cryo-ET) enables observation of macromolecular complexes in their native, spatially contextualized cellular environment. Cryo-ET processing software to visualize such complexes at nanometer resolution via iterative alignment and averaging are well developed but rely upon assumptions of structural homogeneity among the complexes of interest. Recently developed tools allow for some assessment of structural diversity but have limited capacity to represent highly heterogeneous structures, including those undergoing continuous conformational changes. Here we extend the highly expressive cryoDRGN (Deep Reconstructing Generative Networks) deep learning architecture, originally created for single-particle cryo-electron microscopy analysis, to cryo-ET. Our new tool, tomoDRGN, learns a continuous low-dimensional representation of structural heterogeneity in cryo-ET datasets while also learning to reconstruct heterogeneous structural ensembles supported by the underlying data. Using simulated and experimental data, we describe and benchmark architectural choices within tomoDRGN that are uniquely necessitated and enabled by cryo-ET. We additionally illustrate tomoDRGN’s efficacy in analyzing diverse datasets, using it to reveal high-level organization of human immunodeficiency virus (HIV) capsid complexes assembled in virus-like particles and to resolve extensive structural heterogeneity among ribosomes imaged in situ.

DOI: 10.1038/s41592-024-02210-z

Source: https://www.nature.com/articles/s41592-024-02210-z