From the beaker to the 3D structure solved in minutes – ScienceDaily

The team used a technique called microelectron diffraction (MicroED), which had been used in the past to learn 3D structures of larger molecules, particularly proteins. In this new study, the researchers showed that the technique could be applied to small molecules and that the process required much less preparation time than expected. Unlike related techniques – some of which involve the growth of salt-size crystals – this method, as shown in the new study, can work with starting samples, sometimes scraped powders on the side of one's body. beaker.

"We took the lowest possible samples and obtained the highest quality structures at almost any time," says Brian Stoltz, professor of chemistry at Caltech, co-author of the new study published in the newspaper. ACS Central Science. "When I saw the results for the first time, my jaw hit the ground." Originally published on the Chemrxiv pre-print server in mid-October, the article has been viewed more than 35,000 times.

The method works so well on small molecule samples because they may seem like simple powders, they actually contain tiny crystals, each about a billion times smaller than a speck of dust. The researchers knew these previously hidden microcrystals, but did not realize that they could easily reveal the molecular structures of the crystals with the help of MicroED. "I do not think people have realized how common these microcrystals are in pulverulent samples," says Stoltz. "It's like science fiction, I did not think it would happen in my lifetime – that we can see structures from powders."

The results have implications for chemists wishing to determine small molecule structures, defined as those weighing less than about 900 daltons. (A dalton has about the weight of a hydrogen atom.) These tiny compounds include some natural chemicals, some biological substances such as hormones and a number of therapeutic drugs. Possible applications of the MicroED structure search methodology include drug discovery, laboratory analysis of crime, medical tests, and so on. For example, says Stoltz, the method could be useful for testing the latest performance-enhancing drugs in athletes, where only traces of a chemical may be present.

"The slowest step in making new molecules is determining the structure of the product, which may not be the case anymore, because this technique promises to revolutionize organic chemistry," says Robert. Grubbs, professor of chemistry at the Victor and Elizabeth Atkins Training Center in Caltech. the 2005 Nobel Prize in Chemistry, who was not involved in the research. "The last big break in determining the structure before that was nuclear magnetic resonance spectroscopy, introduced by Jack Roberts at Caltech in the late 1960s."

Like other synthetic chemists, Stoltz and his team spend their time trying to figure out how to assemble chemicals in the lab from basic materials. Their laboratory focuses on small natural molecules such as the family of beta-lactams derived from fungi, which are related to penicillins. To make these chemicals, they must determine the structures of the molecules in their reactions – both the intermediate molecules and the finished products – to see if they are on the right track.

One technique to do this is X-ray crystallography, in which a chemical sample is struck by X-rays that diffract its atoms; the pattern of these diffractive X-rays reveals the 3D structure of the targeted chemical. Often, this method is used to solve the structures of very large molecules, such as complex membrane proteins, but it can also be applied to small molecules. The challenge is that to perform this method, a chemist must create large pieces of crystal from a sample, which is not always easy. "I spent months trying to get the right crystals for one of my samples," Stoltz says.

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

Until now, MicroED – which looks like X-ray crystallography but uses electrons instead of X-rays – was mainly used on crystallized proteins and not on small molecules. The co-author Tamir Gonen, an expert in electronic crystallography at UCLA who began developing the MicroED technique for proteins while he was at the Howard Hughes Medical Institute in Virginia, said that he He had begun thinking about using the small molecule method after being installed at UCLA and teaming up with Caltech.

"Tamir used this technique on proteins, and just mentioned that it's sometimes possible to use it only with protein powder samples," says Hosea Nelson (PhD & # 39; 13), professor chemistry and biochemistry assistant at UCLA. "I thought that there was no need to grow crystals, and it was about that time that the team began to realize that we could apply this method has a whole new class of molecules with broad implications for all types of chemistry. "

The team tested several samples of various qualities, without ever trying to crystallize them, and was able to determine their structures thanks to the many microcrystals of the samples. They managed to obtain structures for crushed samples of Tylenol and Advil brand medications, and were able to identify separate structures from a powder mix of four chemicals.

The UCLA / Caltech team hopes that this method will become common in chemistry labs in the future.

"In our labs, students and post-docs are creating new and unique molecular entities every day," said Stoltz. "We now have the power to quickly determine what they are, that will change the synthetic chemistry."