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Gustavo González Gaitano, Full Professor of Chemistry Physics in the School of Sciences of the University of Navarra.

Cool is better: seeing molecules coldly

Thu, 05 Oct 2017 13:22:00 +0000 Published in Navarra Newspaper

An architect friend of mine once told me about a principle of design that says that form follows function. On Biochemistry it is usually the other way around. Seen a corkscrew, we intuit how to use it to open a bottle. Once the three-dimensional structure of a biomolecule (such as proteins or DNA) is determined, we can find out what mission statement it is and how it will interact with other molecules. Seeing is knowing, and this year's Nobel Prize for Chemistry , awarded by the Swedish Academy to Jacques Bubochet, Joachim Frank and Richard Henderson for the development of electron cryomicroscopy for high-resolution three-dimensional determination of biomolecules in solution, is precisely about being able to see, in great detail, molecules that are as complicated as they are fundamental.

At Cambridge, the birthplace of biomolecule crystallography, Richard Henderson investigated the structure of certain proteins found in the cell membrane. The problem with these proteins is their immediate deterioration when removed from their environment: they tend to clump together and are reluctant to form crystals, a prerequisite for programs of study with X-rays, the usual technique in these cases. The alternative was to use transmission electron microscopy in which, unlike a conventional microscope, an electron beam is used. However, using electrons literally incinerates the sample, all the more so the higher the resolution desired, and involves applying vacuum, conditions under which biomolecules dehydrate and change their structure completely. The solution was to study a protein in its "juice" (the cell membrane itself) with jets of soft electrons from many different orientations. By combining the information it was possible to obtain, for the first time, the 3D structure of bacteriorhodopsin at an acceptable resolution. This was in 1975, and during the following years electron microscopy increased its resolving power as the possibility of performing the experiments with liquid nitrogen during the measurements(cryomicroscopy) was developed, protecting sample from the aggressive electrons.

Joachim Frank's contribution, on the other side of the Atlantic (NY State Department of Health), was to extend the technique to more complex biomolecules by means of a mathematical procedure capable of extracting information from thousands of photos of the same sample. By combining all the shots, in a sort of molecular photoshop, a well-defined three-dimensional structure could be obtained. Jacques Dubochet, the other laureate (University of Lausanne), brilliantly solved the problem of studying water-soluble biomolecules. While freezing the sample preserves the biomolecules from the action of electrons, the crystalline structure of the ice completely interferes with the biomolecule signal, "veiling" the image. The solution provided was to vitrify the solvent: cooling so fast that the water molecules are unable to organize themselves to form ice, thus producing sharp images.

Subsequent years would see an improvement in instrumentation and computing power of computers, increasing the resolution of cryomicroscopes angstrom by angstrom, so that today researchers can almost routinely obtain three-dimensional Structures of biomolecules. As in other years, it has been a award to a long research, laborious and persevering, that has united science and technique and that, without any doubt, has taken the Biochemistry to a new stage.