Scientists discover a whole new world. The revolutionary microscopic technique allows you to view individual atoms in proteins

A revolutionary new particle imaging technique called cryoelectron microscopy produced the most accurate images to date, allowing scientists to separate individual atoms in proteins for the first time.

By achieving atomic resolution levels using cryogenic electron microscopy, researchers will be able to see at an unprecedented resolution the action of proteins that has not been seen with any other imaging technique, such as X-ray crystallography.

The breakthrough, reported by two laboratories last month, strengthens the position of cryo-EM as the best tool for mapping three-dimensional protein shapes. It will help scientists understand how proteins work in health and disease, and therefore lead to the development of better drugs with fewer side effects.

This is a real milestone. There is no next stage to which we can go. This was the last barrier to resolution, says Holger Stark, biochemist and electron microscopy specialist at the Institute of Biophysical Chemistry. Max Planck in Göttingen.

True atomic resolution is a huge leap forward, adds John Rubinstein, a biologist at the University of Toronto, Canada.

However, this does not change the fact that getting a picture of the atomic structure of many proteins will still be quite a challenge, if only because of the flexibility of proteins, but the papers published now clearly show what level of accuracy can be reduced if scientists deal with other limitations.

Breaking the boundaries

Cryo-EM is a technique with a long history. For many decades, it has been able to determine the shape of frozen samples by shooting electrons at them and recording the resulting images. Advances in the technology for detecting reflected electrons and the development of image analysis software enabled a sort of "resolution revolution" that began around 2013. It was then that people began to obtain sharper images than before, almost as good as X-ray crystallography, which allows to study the internal structure of protein crystals by bombarding them with X-rays.

The problem, however, is that it sometimes takes months or years to crystallize a protein, and many medically important proteins do not form useful crystals. Meanwhile, the cryoelectron microscopy technique requires only placing the protein in a purified solution.

More precise drugs

Maps with atomic resolution are so precise that they allow to clearly determine the position of individual atoms in a protein with a resolution of 1.2 angstroms. Such detailed pictures will allow scientists to study how enzymes work, and this in turn will allow the development of drugs that will inhibit their activity.

In an attempt to go down to the atomic level, researchers worked with apoferritin, a protein that transports iron ions. Due to the amazing stability of this protein, it has become a kind of guinea pig for cryo-EM.

Record resolution

Before using the new technique, the record resolution was achieved at 1.54 angstroms. Now, thanks to an instrument that makes the electrons move at similar speeds before hitting the sample, Stark's team has dropped to 1.25 angstrom, improving image sharpness. In this way, sufficiently accurate images of the protein structure were achieved that it was possible to see individual hydrogen atoms in them, both in the protein and in the surrounding water molecules.

Stark notes that this is already the limit. Yes, you could go down to level 1 angstrom, but not below. Obtaining a more accurate image of the protein structure with current technologies would require hundreds of years of data collection and an unrealistic amount of computing power.

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Scientists discover a whole new world. The revolutionary microscopic technique allows you to view individual atoms in proteins