Conformational landscapes in cryo-electron tomography data based on molecular dynamics simulations

Cryo-electron tomography (cryo-ET) provides a unique window into molecular organization in cellular environments (in situ). However, the interpretation of molecular structural information is complicated by several intrinsic properties of cryo-ET data, such as noise, missing wedge, and continuous conformational variability of the molecules. These challenges shift the emphasis from high-resolution structure determination toward validation and interpretation of low-resolution density maps and analysis of conformational flexibility. Molecular dynamics (MD) simulations are particularly well suited to this task, as they provide a physically grounded way to explore continuous conformational transitions consistent with both experimental data and molecular energetics. This review focuses on the roles of MD simulations in cryo-ET, emphasizing their use in emerging methods for conformational landscape determination.