By achieving atomic resolution using cryogenic-electron microscopy (cryo-EM), researchers will be able to understand, in unprecedented detail, the workings of proteins that cannot easily be examined by other imaging techniques, such as X-ray crystallography.
Cryo-EM has been around for decades. It has long been able to determine the shape of flash-frozen samples by firing electrons at them and recording the resulting images. Advances in technology for detecting the ricocheting electrons and in image-analysis software catalyzed a ‘resolution revolution’ that started around 2013. This led to protein structures that were sharper than ever before — and nearly as good as those obtained from X-ray crystallography, an older technique that infers structures from diffraction patterns made by protein crystals when they are bombarded with X-rays.
The best resolution with Cryo-EM dropped from 9 angstroms in 2002 to 4 angstroms in 2008 to 2 angstroms in 2014 and now to 1.2 angstroms. An angstrom is 0.1 nanometers.
Different proteins have different stability. The best resolutions are reached on the most stable proteins like an iron-storing protein called apoferritin. The protein has become a testbed for cryo-EM. A resolution of 1.54 ångströms was the previous record and now it is 1.2 angstroms. Further improvements will push this to a limit with Cryo-EM of about 1.0 angstroms. Less stable proteins are currently at 1.7 to 2 angstroms. The researchers expect a further 20% resolution improvement.
They used an instrument that ensures that the electrons travel at about the same speed before hitting a sample which enhances the resolution of the resulting images. Scheres and team used a different technology to fire electrons traveling at similar speeds. They reduced the noise generated after some electrons careen off the protein sample and had a more sensitive electron-detecting camera. Their 1.2-ångström structure could pick detect individual hydrogen atoms, both in the protein and in surrounding water molecules. Combining all of the methods for reducing variance in electron speed and reducing noise will help them to get to about 1.0 angstrom resolution in the most stable protein images.
Written by Brian Wang, Nextbigfuture.com
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