For decades, scientists have known that adding small molecules such as amino acids to medical formulations—like insulin—helps stabilize the proteins they contain. These small molecules prevent larger protein particles from interacting in unwanted ways. While this stabilizing effect has been widely used, the mechanism behind it has remained unclear—until now.

An international research team led by the Supramolecular Nano-Materials and Interfaces Laboratory at EPFL’s School of Engineering has uncovered how this process works. Their findings, published in Nature, involved collaboration with Alfredo Alexander-Katz at MIT and researchers from the Southern University of Science and Technology in China, including EPFL alumnus Zhi Luo.

“When suspended in solution, proteins are constantly changing shape around a central form, and so the prevailing theory has been that amino acids help keep proteins from misfolding,” explains recent EPFL PhD graduate and first author Ting Mao.

“Now, we show that this is not the case. In fact, the stabilizing effect of amino acids has little to do with biology but is rather a general property of all small molecules in relation to larger particles, known as colloids, in solution.”

Balancing Attraction and Repulsion

The team demonstrated that amino acids stabilize proteins not by influencing their folding, but by affecting how particles interact in solution.

To illustrate this effect, Supramolecular Nano-Materials and Interfaces Laboratory head Francesco Stellacci offers a simple analogy:
“Imagine these two colleagues get along really well and always want to stop and chat. If the hallway is empty, they will immediately spot each other and come together. But if the hallway suddenly becomes crowded, they may not see each other until they have already walked past, or even miss each other entirely,” Stellacci explains. “This phenomenon, called screening attraction, is how amino acids affect larger particles: they play the role of the crowd in the hallway, discouraging passing interactions.”

Interestingly, scientists have long known that salts have the opposite effect: they screen repulsion.
In Stellacci’s analogy, salt is like a crowd that forces two unfriendly colleagues to collide rather than avoid each other.

“What we have discovered is that amino acids are essentially the anti-salt, because they have an opposite ‘screening’ effect. You can even see this in nature: it has been shown that when a plant is watered with salty water, its cells will produce more amino acids to help stabilize them as they become stressed by the increased salt concentration,” says EPFL scientist and co-author Quy Ong.

Implications for Biomedical Research

According to the researchers, this discovery highlights the need to consider amino acid concentrations in experimental work just as rigorously as salt concentrations.

“In biology, one would never do an experiment without reporting the ionic (salt) concentration of a solution. Our work shows that amino acid concentrations have just as much impact, and should therefore be reported just as rigorously,” Stellacci says.

Building on this insight, Stellacci has launched a new project supported by a recently awarded ERC Advanced Grant.
“We want to understand how small molecules like amino acids are central to healthy biological function. With the support of our ERC grant, our goal is ultimately to predict which molecules can stabilize which proteins, and how much – something that is currently done by trial and error in biomedical research.”

Original Publication
Authors: Ting Mao, Xufeng Xu, Pamina M. Winkler, Cécilia Siri, Ekaterina Poliukhina, Paulo Jacob Silva, Nan Xu, Yu Hu, Karim Al Zahabi, Rémi La Polla, Zhi Luo, Quy Ong, Alfredo Alexander-Katz and Francesco Stellacci.
Journal: Nature
DOI: 10.1038/s41586-025-09506-w
Method of Research: Experimental study
Article Title: Stabilizing effect of amino acids on protein and colloidal dispersions
Article Publication Date: 10-Sep-2025

Original Source: https://actu.epfl.ch/news/scientists-uncover-key-stabilizing-role-of-small-m

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