Cryo-electron microscopy--a primer for the non-microscopist
Open accessAbstract
Cryo‐electron microscopy (cryo‐ EM ) is increasingly becoming a mainstream technology for studying the architecture of cells, viruses and protein assemblies at molecular resolution. Recent developments in microscope design and imaging hardware, paired with enhanced image processing and automation capabilities, are poised to further advance the effectiveness of cryo‐ EM methods. These developments promise to increase the speed and extent of automation, and to improve the resolutions that may be achieved, making this technology useful to determine a wide variety of biological structures. Additionally, established modalities for structure determination, such as X ‐ray crystallography and nuclear magnetic resonance spectroscopy, are being routinely integrated with cryo‐ EM density maps to achieve atomic‐resolution models of complex, dynamic molecular assemblies. In this review, which is directed towards readers who are not experts in cryo‐ EM methodology, we provide an overview of emerging themes in the application of this technology to investigate diverse questions in biology and medicine. We discuss the ways in which these methods are being used to study structures of macromolecular assemblies that range in size from whole cells to small proteins. Finally, we include a description of how the structural information obtained by cryo‐ EM is deposited and archived in a publicly accessible database.
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Cryo-TEM has high resolution (0.02 Å) and easy sample preparation, and has recently emerged as a powerful tool for describing the morphology of micelles.
“Due to the high resolution (0.02 Å) and easy sample preparation [74,164], Cryo-Transmission Electron Microscopy has recently emerged as a powerful tool for describing the morphology of micelles.”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [164]
The sections on imaging and single-particle cryo-electron microscopy describe high-resolution imaging and specimen preparation by plunge-freezing. They do not support the stated resolution of 0.02 Å: the paper reports resolutions of several ångströms even for selected high-resolution structures. The cited passages do not describe cryo-TEM as a tool for micelle morphology or characterize sample preparation as easy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTEM imaging requires complete sample dehydration to ensure high vacuum in the microscope column, whereas cryo-TEM is based on rapid freezing of samples at temperatures of at least -170°C using liquid nitrogen, liquid propane or liquid helium, allowing observation of specimens in their hydrated and native state and reducing artifacts related to water removal.
“However, while TEM imaging requires complete samples dehydration in order to ensure high vacuum in the microscope column, cryo-TEM is based on the rapid freezing of samples at temperatures of at least -170 • C using liquid nitrogen, liquid propane or liquid helium [74,164], allowing for the observation of specimens in their hydrated and native state and reducing artifacts related to water removal”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [164]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAnalysis of samples at cryogenic temperatures remarkably reduces the extent of radiation damage, so imaging resolution can be easily improved by increasing the electron dose used.
“Moreover, as the analysis of samples at cryogenic temperatures remarkably reduces the extent of radiation damage, imaging resolution can be easily improved by increasing the electron dose used [164].”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [164]
In “Imaging with an electron microscope” (page unavailable), the paper says imaging at liquid-nitrogen temperatures can reduce radiation damage by as much as sixfold, permitting a much higher electron dose for the same damage. It does not say that increasing dose easily improves resolution; it also describes damage and other factors that limit high-resolution imaging. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAFM has also been proposed as an innovative tool for studying the mechanisms regulating nanocarrier interaction with cell membrane and their internalization.
“AFM has also been proposed as innovative tool for studying the mechanisms regulating nanocarrier interaction with cell membrane and their internalization, which are quite relevant for ensuring effective drug delivery to the target [161][162][163].”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [163]
The Abstract and the section on cryo-electron tomography discuss cryo-EM imaging of biological structures, not AFM. Searches for AFM, nanocarrier–cell membrane interactions, internalization, and drug delivery found no passage in our copy addressing the attributed proposal. Page numbers were not available. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Self-citationMetallothionein as a clonable high-density marker for cryo-electron microscopy
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Spiral Architecture of the Nucleoid in Bdellovibrio bacteriovorus
Butan, C., Hartnell, L. M., Fenton, A. K., Bliss, D., Sockett, R. E., Subramaniam, S., & Milne, J. L. S. (2010) · Journal of Bacteriology · doi:10.1128/jb.01061-10 · Cited by 40 · see citing works
Self-citationConsensus among flexible fitting approaches improves the interpretation of cryo-EM data
Ahmed, A., Whitford, P. C., Sanbonmatsu, K. Y., et al. (2011) · Journal of Structural Biology · doi:10.1016/j.jsb.2011.10.002 · Cited by 39 · see citing works
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Present and future of membrane protein structure determination by electron crystallography
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The use of trehalose in the preparation of specimens for molecular electron microscopy
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The SIV Surface Spike Imaged by Electron Tomography: One Leg or Three?
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Preservation of high resolution protein structure by cryo-electron microscopy of vitreous sections
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The Orthogonal Tilt Reconstruction Method
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Ghezzi, M., Pescina, S., Padula, C., Santi, P., Del Favero, E., Cantù, L., & Nicoli, S. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.02.031 · Cited by 1,135 · see citing works
Native Mass Spectrometry: What is in the Name?
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“croscopy [7] and small angle scattering [8] excel.”
BackgroundLi, T., Nowell, C. J., Cipolla, D., Rades, T., & Boyd, B. J. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.8b01308 · Cited by 57 · see citing works
Su, Y., Yuan, S., Li, J., Feng, Y., Shen, S., Yan, X., & Zhang, J. (2026) · Renewable and Sustainable Energy Reviews · doi:10.1016/j.rser.2025.116163 · Cited by 3 · see citing works
- Authors
- Milne, J. L. S., Borgnia, M. J., Bartesaghi, A., Tran, E. E. H., Earl, L. A., Schauder, D. M., Lengyel, J., Pierson, J., Patwardhan, A., & Subramaniam, S.
- Affiliations
- National Institutes of Health (US)
- Thermo Fisher Scientific (Japan) (JP)
- European Bioinformatics Institute (GB)
- Corresponding author
- Subramaniam, Sriram
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2012-12-17
- Volume
- 280
- Issue
- 1
- Pages
- 28-45
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- PMC
- PMC3537914
- OpenAlex
- W2047902460
- Cited by
- 277
- References
- 114
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 18 · 2023: 25 · 2022: 21 · 2021: 17 · 2020: 26 · 2019: 17 · 2018: 21 · 2017: 23 · 2016: 23 · 2015: 20 · 2014: 20 · 2013: 7 · 2012: 1
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- University of California, Los Angeles
- Biotechnology and Biological Sciences Research Council (BB/G022577/1)
- National Cancer Institute (ZIABC010826, ZIABC010278)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- cryo-electron microscopy, macromolecular structure determination, protein assembly, virus structure, cellular architecture, cryo-EM density maps, image processing
- MeSH terms
- Animals, Fourier Analysis, Humans, Proteins, Cryoelectron Microscopy, Imaging, Three-Dimensional, Macromolecular Substances, Electron Microscope Tomography
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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