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| Title | Overcoming the preferred-orientation problem in cryo-EM with self-supervised deep learning. |
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| Journal, issue, pages | Nat Methods, Vol. 22, Issue 1, Page 113-123, Year 2025 |
| Publish date | Nov 18, 2024 |
 Authors | Yun-Tao Liu / Hongcheng Fan / Jason J Hu / Z Hong Zhou /  |
| PubMed Abstract | While advances in single-particle cryo-EM have enabled the structural determination of macromolecular complexes at atomic resolution, particle orientation bias (the 'preferred' orientation problem) ...While advances in single-particle cryo-EM have enabled the structural determination of macromolecular complexes at atomic resolution, particle orientation bias (the 'preferred' orientation problem) remains a complication for most specimens. Existing solutions have relied on biochemical and physical strategies applied to the specimen and are often complex and challenging. Here, we develop spIsoNet, an end-to-end self-supervised deep learning-based software to address map anisotropy and particle misalignment caused by the preferred-orientation problem. Using preferred-orientation views to recover molecular information in under-sampled views, spIsoNet improves both angular isotropy and particle alignment accuracy during 3D reconstruction. We demonstrate spIsoNet's ability to generate near-isotropic reconstructions from representative biological systems with limited views, including ribosomes, β-galactosidases and a previously intractable hemagglutinin trimer dataset. spIsoNet can also be generalized to improve map isotropy and particle alignment of preferentially oriented molecules in subtomogram averaging. Therefore, without additional specimen-preparation procedures, spIsoNet provides a general computational solution to the preferred-orientation problem. |
 External links | Nat Methods / PubMed:39558095 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.45 - 4.14 Å |
| Structure data |  EMDB-45551: CryoEM structure of HA trimer from EMPIAR10096, processed with spIsoNet  EMDB-45555: CryoEM structure of HA trimer from EMPIAR10097, processed with spIsoNet |
| Source |
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Influenza A virus (A/Hong Kong/1/1968(H3N2))