Comparison between HEMNMA-3D and Traditional Classification Techniques for Analyzing Biomolecular Continuous Shape Variability in Cryo Electron Subtomograms

Cryogenic electron tomography (cryo-ET) allows studying biological macromolecular complexes in cells by three-dimensional (3D) data analysis. The complexes continuously change their shapes (conformations) to achieve biological functions. The shape heterogeneity in cryo-ET is a bottleneck for comprehending biological mechanisms and developing drugs. Cryo-ET data suffer from a low signal-to-noise ratio and spatial anisotropies (missing wedge artefacts), making it particularly challenging for resolving the shape variability. Other shape variability analysis techniques simplify the problem by consid-ering discrete rather than continuous conformational changes of complexes. Recently, HEMNMA-3D was introduced for cryo-ET continuous shape variability analysis, based on elastic and rigid-body 3D registration between simulated shapes and cryo-ET data using normal mode analysis and fast rotational matching with missing wedge compensation. HEMNMA-3D provides a visual insight into molecular dynamics by grouping and aver-aging subtomograms of similar shapes and by animating movies of registered motions. This article reviews HEMNMA-3D and compares it with existing literature on a simulated dataset for nucleosome shape variability.