Researchers speed up imaging techniques to capture small molecules’ structures

Pinshane Hung, a University of Illinois Urbana-Champaign Researcher, is working to speed up imaging techniques that allow for clear visualization of the structures of small molecules. It was previously thought impossible. Their discovery unlocks unlimited potential for improving everyday life applications, including plastics and pharmaceuticals.

Associate professor in the Department of Materials Science and Engineering, Blanka Janicek, a ’21 alumna and postdoc at Lawrence Berkeley National Laboratory, Berkeley, Calif., and Pritikharel, a Department of Chemistry graduate student, have teamed up to demonstrate the methodology that allows researchers visualize small molecular structure and speed up current imaging techniques.

Other co-authors include Sang hyun Bae (Graduate Student) and Amanda Loutris (Undergraduate). Nano Letters published the peer-reviewed work of these co-authors.

This team exposed the molecule’s atomic structures, which allowed researchers to study its chemical processes, understand its reactions, and learn how to synthesize it.

Huang said that “the structure of a molecule’s function is so important.” “What we have done in our work was make it possible to directly see that structure.”

It is essential to be able to see the structure of small molecules. Kharel shares the importance of this ability by sharing an example such as the medication thalidomide.

Thalidol was discovered in the 1960s and prescribed to pregnant women as a treatment for morning sickness. However, it was later found that it can cause serious birth defects or even death.

What went wrong? It had a mixed molecular structure, which was responsible for morning sickness treatment and one that caused devastating adverse effects to the fetus.

Huang and her students now realize the importance of proactive science over-reactive science. They are continuing to pursue research that began out of curiosity.

Kharel stated that it is crucial to determine the structure of these molecules accurately.

Molecular structures are usually determined using indirect techniques. These methods can be time-consuming and complicated, as they require nuclear magnetic resonance (X-ray Diffraction) or other difficult approaches. Worse, scientists can get wrong information about a molecule’s structure using indirect methods that can cause them to be inaccurate for years. Direct imaging techniques could eliminate any ambiguity in small molecules’ structure.

Huang has witnessed remarkable advancements in cryogenic electronic microscopy technology over the past decade. In this technology, biologists freeze large molecules to capture images of the structures.

Why aren’t they doing the same for small molecules? Huang said. Huang stated, “If you could do that, then you might be in a position to solve the structure and figure out how to make a natural compound from a plant or an animal.” Huang explained that this could prove to be very important and a great way to fight disease.

It is difficult to detect small molecules because they are often 100-1000 times smaller than large molecules.

Huang’s students became determined and began to use large-molecule imaging methods as a foundation for developing imaging techniques to see the structures of small molecules.

The imaging signals of small molecules are more easily overpowered than those of large molecules. Instead of using ice to protect the electron microscope’s harsh environment, the team developed a new plan that preserves the structure of small molecules.

How can you alter the environment of a molecular? By using graphene.

Graphene, a single carbon atom layer that forms a tightly hexagon-shaped honeycomb structure, is capable of dissipating damaging reactions during imaging.

The Illinois researchers also had to stabilize the small molecule’s environment. To illuminate the molecules, the team had also to limit the use of electrons. This was as low as one-millionth of the usual number of elections.

The researchers can capture images by using low amounts of electrons to ensure that molecules are still moving.

Janicek explained that graphene helps remove some of the charges away from the molecules so we can get a good image.

Unfortunately, once the images were captured, the molecules were almost invisible.

Huang explained that low-dose images look almost like nothing when taken.

The trick was to distinguish the atomic structures and the noise by using a Fourier transformation–a mathematical function that breaks down the small molecules’ image–to see its spatial frequency.

Kharel explained, “We took hundreds of thousands of images and added them together to make a single image.

This averaging method allowed the team creates sharp images of the atoms of the molecule without compromising any individual molecule.

Huang stated, “Monthly after month, the week following week, our resolution has improved.” “Then, one day, my student came in and showed the individual carbon molecules to me. That is a great achievement. This is all after all the knowledge they have gained in order to create an imaging experiment and unlock data from what appears like nothing.

This is the beginning of many structural molecule imaging breakthroughs.

“There is a whole world of small molecules that have been left out in cold. This is our attempt to shine a light on the way we can get there as an entire field. How can we do this? Huang said. “One day it won’t be–that’s the hope.”

The first step to making this dream come true is the work of Illinois researchers.

Huang said, “One day this will be how we solve the structure a small molecular.” “People will simply put the molecule in an electron microscope, take pictures, and then be done.”

Huang and her Illinois team believe that this dream is what motivates them to stay the course.

Huang said, “That could be life-changing, but we’ve made that exist.” “We haven’t made it simple yet, but imaging techniques such as this will transform so much science and technology.”