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Home / Science / From the cup to the dissolved 3D structure in minutes – ScienceDaily

From the cup to the dissolved 3D structure in minutes – ScienceDaily



A joint study by UCLA / Caltech has shown that it is possible to preserve the structure of small molecules such as certain hormones and drugs in just 30 minutes. That's hours and even days less than before.

The team used a technique called MicroED (MicroED), which was previously used to learn the 3D structures of larger molecules, especially proteins. In this new study, the researchers show that the technique can be applied to small molecules and that the process requires much less preparation time than expected. Unlike related techniques – which sometimes require the growth of crystals in the size of grains of salt – this method can, as the new study shows, work with normal starting samples, sometimes even with powders scraped off the side of a cup

"We quickly took the lowest samples that you can get and get the highest quality structures," says Brian Stoltz, a professor of chemistry at Caltech, who has collaborated on the new study Journal ACS Central Science . "When I saw the results for the first time, my chin hit the floor." The article originally published on the pre-print Chemrxiv server in mid-October was viewed more than 35,000 times.

The reason why the method works so well on low-molecular weight samples is that while the samples appear as simple powders they actually contain tiny crystals, each about one billion times smaller than a speck of dust. The researchers already knew about these hidden microcrystals but did not realize they could easily identify the molecular structures of the crystals using MicroED. "I do not think people have realized how common these microcrystals are in the powdered samples," says Stoltz. "It's like science fiction, I did not think that would happen in my life ̵

1; that you could see structures made of powders."

The results have implications for chemists who want to determine the structures of defined small molecules such as those weighing less than about 900 daltons. (A dalton is about the weight of a hydrogen atom.) These tiny compounds include certain naturally occurring chemicals, some biological substances such as hormones, and a range of therapeutics. Possible applications of the MicroED structure finding methodology include drug discovery, crime analysis, medical testing, and more. For example, according to Stoltz, the method might be useful for testing the latest performance-enhancing drugs in athletes who may only have traces of a chemical.

"The slowest step in producing new molecules is determining the structure. This may not be the case anymore as this technique promises to revolutionize organic chemistry," says Robert Grubbs, Caltech's Victor and Elizabeth Atkins Professor for chemistry and a prize winner of the Nobel Prize for Chemistry of 2005, in which he was not involved in the research. "The last big break in the structure determination before that was the nuclear magnetic resonance spectroscopy, which was introduced at the end of the 60's by Jack Roberts at Caltech."

Like other synthetic chemists, Stoltz and his team are trying to figure out how to assemble chemicals in the lab from basic raw materials. Their laboratory focuses on natural small molecules such as the fungus-derived beta-lactam family of compounds, which is related to penicillins. In order to build these chemicals, they must determine the structures of molecules in their reactions – both the intermediate molecules and the final products – to see if they are on the right path.

One technique for this is X-ray crystallography, in which a chemical sample is hit with X-rays that deflect its atoms; The pattern of these diffractive X-rays shows the 3D structure of the target chemical. This method is often used for solving the structures of really large molecules, such as complex membrane proteins, but it can also be applied to small molecules. The challenge is that a chemist needs to produce crystals of good size from a sample for this method, which is not always easy. "I spent months finding the right crystals for one of my samples," says Stoltz.

Another reliable method is NMR (Nuclear Magnetic Resonance), which does not require crystals, but a relatively large amount of a requires a sample that is difficult to collect. NMR also provides only indirect structural information.

Previously, MicroED, which is similar to X-ray crystallography but uses electrons instead of X-rays, was mainly used in crystallized proteins rather than small molecules. Co-author Tamir Gonen, an expert in electron crystallography at UCLA, who began developing the MicroED technique for proteins at the Howard Hughes Medical Institute in Virginia, said he would only join after moving to UCLA and working with UCLA the use of this method was thought with Caltech.

"Tamir had used this technique on proteins and just happened to mention that sometimes they can only get powdered protein samples working," says Hosea Nelson (PhD & # 39; 13), assistant professor of chemistry and biochemistry at UCLA. "My thoughts were blown away that you did not have to grow crystals, at which time the team realized we could apply this method to a whole new class of molecules that had far-reaching effects on all types of chemistry."

The Team tested several samples of varying quality without ever trying to crystallize, and was able to determine their structures thanks to the large microcrystals of the samples. They were able to obtain sample base structures for the branded drugs Tylenol and Advil, and they were able to identify different structures from a powdered mixture of four chemicals.

The UCLA / Caltech team hopes this method will do so "In our labs, we have students and postdocs who make completely new and unique molecular entities every day," says Stoltz. "Now we have the power to quickly find out what they are, which will change synthetic chemistry."


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