Research team accelerates imaging techniques to capture structures of small molecules

A research effort from the University of Illinois at Urbana-Champaign led by Pinshane Huang is accelerating imaging techniques to clearly visualize the structures of small molecules – a process once considered impossible. Their discovery unlocks endless potential in improving everyday life applications, from plastics to pharmaceuticals.

The associate professor in the Department of Materials Science and Engineering joined co-lead authors Blanka Janicek, a 21-year-old alumnus and post-doctoral fellow at Lawrence Berkeley National Laboratory in Berkeley, Calif., and Priti Kharel, a graduate student at Department of Chemistry, to prove the methodology that allows researchers to visualize small molecular structures and accelerate current imaging techniques.

Additional co-authors include graduate student Sang hyun Bae and undergraduate students Patrick Carmichael and Amanda Loutris. Their peer-reviewed research was recently published in Nano-letters.

The team’s efforts expose the atomic structure of the molecule, allowing researchers to understand how it reacts, learn its chemical processes, and see how to synthesize its chemical compounds.

“The structure of a molecule is so fundamental to its function,” Huang said. “What we’ve done in our work is allow this structure to be seen directly.”

The ability to see the structure of a small molecule is vital. Kharel shares how vital it is by giving the example of a drug known as thalidomide.

Discovered in the 1960s, thalidomide was prescribed to pregnant women to treat morning sickness and was later found to cause serious birth defects or, in some cases, even death.

What went wrong? The drug had mixed molecular structures, one responsible for treating morning sickness and the other unfortunately causing devastating adverse effects on the fetus.

The need for proactive, not reactive science drove Huang and his students to continue this research effort that originally began out of sheer curiosity.

“It’s so crucial to accurately determine the structures of these molecules,” Kharel said.

Typically, molecular structures are determined with indirect techniques, a time-consuming and difficult approach that uses nuclear magnetic resonance or X-ray diffraction. Worse still, indirect methods can produce incorrect structures that give scientists the wrong understanding. of the composition of a molecule for decades. The ambiguity surrounding the structures of small molecules could be eliminated by using direct imaging methods.

Over the past decade, Huang has seen significant advances in cryogenic electron microscopy technology, where biologists freeze large molecules to capture high-quality images of their structures.

“The question I had was, what’s stopping them from doing the same for small molecules?” Huang said. “If we could do that, you might be able to figure out the structure (and) figure out how to synthesize a natural compound made by a plant or animal. It could turn out to be very important, like an excellent disease fighter,” Huang said.

The challenge is that small molecules are often 100 or even 1,000 times smaller than large molecules, which makes their structures difficult to detect.

Determined, Huang’s students began to use existing large molecule methodology as a starting point to develop imaging techniques to reveal the structures of small molecules.

Unlike large molecules, imaging signals from small molecules are easily overwhelmed by their surroundings. Instead of using ice, which typically serves as a protective layer against the harsh environment of the electron microscope, the team devised another plan to keep the small molecule structures intact.

How to temper the environment of a molecule? Using graphene.

Graphene, a single layer of carbon atoms that form a tight, hexagon-shaped honeycomb network, dissipates damaging reactions during imaging.

Stabilizing the small molecule’s environment was just one of the problems the Illinois researchers had to manage. The team also had to limit its use of electrons, to as low as one millionth the number of normally used elections, to illuminate the molecules.

Low doses of electrons ensure that the molecules are still moving enough for researchers to capture an image.

“The way I like to think about it is that the molecule doesn’t like to be bombarded by higher energy elections, but we have to be able to see the structure, and the graphene helps to dissipate some of that charge away of the molecule so we can get a nice picture of it,” Janicek said.

Unfortunately, once captured, the molecules were almost invisible in the image.

“When they take a low-dose image, it initially looks like noise or static TV – almost like nothing is there,” Huang said.

The trick was to isolate the atomic structures from this noise using a Fourier transform – a mathematical function that breaks down the image of the small molecule – to see its spatial frequency.

“We took images of hundreds of thousands of molecules and added them together to create a single, clear image,” Kharel said.

This averaging approach allowed the team to create sharp images of molecule atoms without damaging the integrity of an individual molecule.

“Month by month, week by week, our resolve has improved,” Huang said. “And then one day my students came and showed me the individual carbon atoms – that’s a major achievement. imagery and how to unlock data from what looks like nothing.”

This collective discovery paves the way for many other structural molecule imaging discoveries.

“There’s been this whole field of small molecules that have been left out, so to speak. We’re highlighting how to get there as a field? How do we do this thing that for us right now is very difficult? ” Huang said. “One day it won’t – that’s the hope.”

The efforts of the Illinois researchers are the first major step in turning this dream into reality.

“One day this will be how we solve the structure of a small molecule,” Huang said. “People will just throw the molecule into the electron microscope, take a picture, and be done.”

This dream inspires Huang and his Illinois team to stay the course.

“It’s potentially life-changing, and we made it happen,” Huang said. “We haven’t made it simple yet, but imaging techniques like this are going to change science and technology so much.”

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