Cryogenic Electron Microscopy

Cryogenic electron microscopy (cryo-EM) is a technique for determining the three-dimensional structure of biological molecules by imaging them with an electron microscope after flash-freezing them in a thin layer of ice. Jacques Dubochet, Joachim Frank and Richard Henderson shared the 2017 Nobel Prize in Chemistry for developing it.

A small droplet of solution containing the molecule is spread on a grid and plunged into liquid ethane so that the water freezes as glass-like ice rather than crystals, which preserves the shape of the molecules. The electron microscope records many thousands of images of single particles in different orientations. Computers then align and average them to rebuild a 3D map, much as in X-ray crystallography but without the need to grow crystals.

Around 2013, direct electron detectors and better software greatly improved image quality, moving cryo-EM to near-atomic resolution, and by 2020 a structure of the protein apoferritin was resolved to about 1.2 angstroms. It is especially valuable for large, flexible or membrane-bound complexes, such as the ribosome, ion channels and ATP synthase, that are hard to crystallize.

The technique revealed the spike protein of coronaviruses within weeks of the sequence being published, helping the design of vaccines. A variant, cryo-electron tomography, images structures inside intact cells. Cryo-EM complements computational predictions from artificial intelligence and its results feed into biochemistry and biophysics, and reveal how proteins function.

• X-ray Crystallography — the older method it complements
• Ribosome — a complex solved by cryo-EM
• Biophysics — the field that uses it