Scientists at the University of Wisconsin-Madison have developed a new, highly sensitive method to detect and analyze single molecules without the use of fluorescent labels; This method potentially transforms research in drug development and materials science.

Researchers at the University of Wisconsin-Madison have developed the most sensitive method yet to detect and profile a single molecule; They have uncovered a new tool that has the potential to better understand how the building blocks of matter interact with each other. The new method could have implications for a wide range of pursuits, from drug discovery to the development of advanced materials.

A technical achievement described in an article published in a magazine Nature, It marks a major advance in the growing field of observing single molecules without the aid of fluorescent labels. While these tags are useful in many applications, they alter molecules in ways that obscure their natural interactions with each other. The new label-free method makes it possible to detect molecules as easily as if they had labels.

“We’re very excited about this,” says Randall Goldsmith, a chemistry professor at the University of Madison who led the study. “Capturing behavior at the single-molecule level is a highly informative way to understand complex systems, and if you can create new tools that provide better access to this insight, those tools can be really powerful.”

While researchers can gain useful information by studying materials and biological systems at a large scale, Goldsmith says observing the behaviors and interactions between individual molecules is important to contextualize that information, sometimes leading to new insights.

“When you see how nations interact with each other, it all depends on the interaction between individuals,” Goldsmith says. “You can’t even think of understanding how groups of people interact with each other by ignoring how individuals interact with each other.”

The importance of observing a single molecule

Goldsmith had been looking for the appeal of single molecules since working at Stanford University more than a decade ago. There he worked under the guidance of chemist WE Moerner, who won the 2014 Nobel Prize in Chemistry for developing the first method of using light to observe a single molecule.

Following Moerner’s initial success, researchers around the world invented and perfected new ways to observe these tiny particles of matter.

The method developed by the UW-Madison team relies on a device called an optical microcavity, or microcavity. As the name suggests, a microcavity is an extremely small area in which light can be trapped in space and time (at least for a few nanoseconds) and interact with a molecule. Microcavities are more common in physics or electrical engineering laboratories than in chemistry. Goldsmith’s background in combining concepts from different scientific fields was rewarded with Schmidt Futures’ Polymath Prize in 2022.

Microcavities are made of incredibly small mirrors created just above the fiber optic cable. These fiber optic mirrors reflect light back and forth very quickly many times inside the microcavity.

Potential applications and future developments

Researchers allow molecules to fall into the void, allow light to pass through them, and not only detect the molecule’s presence, but also obtain information such as how fast the molecule is moving in water. This information can be used to determine the shape or conformation of the molecule.

“Co-occurrence at the molecular level is incredibly important, especially for thinking about how biomolecules interact with each other,” says Goldsmith. “Let’s say you have a protein and a low molecular weight drug. You want to see if the protein interacts with the drug, meaning if the drug has a significant interaction with the protein? One way to see this is if it makes a conformational change.”

There are other ways to do this, but they require large amounts of sample material and lengthy analyses. With the newly developed microcavity technique, “We have the potential to create a black box instrument that will give us an answer in tens of seconds,” says Goldsmith.

The team, which included former PhD student Lisa-Maria Needham, who is now director of the laboratory at the University of Cambridge, has applied for a patent for the device. Goldsmith says the device and methods will be improved over the next few years. In the meantime, she says, she and her team are already thinking about how this could be useful.

“We are excited about many other applications in spectroscopy,” he says. “We hope we can use this as a stepping stone to other ways of learning about molecules.”