For many years, amino acids have been added to medical protein formulations—such as insulin—to keep the proteins stable and prevent them from interacting in harmful ways. Researchers have long understood that amino acids work as stabilizers, but the underlying reason remained unclear.

Now, an international research team led by the Supramolecular Nano-Materials and Interfaces Laboratory at EPFL’s School of Engineering has identified the mechanism behind this effect. Their findings, published in Nature in collaboration with Alfredo Alexander-Katz at MIT and scientists from the Southern University of Science and Technology in China, reveal a fundamental stabilizing role shared by all small molecules in solution. EPFL alumnus Zhi Luo is among the study’s co-authors.

“When proteins are dissolved, they are constantly shifting slightly around a core structure. The common belief was that amino acids prevent proteins from folding incorrectly,” says first author and recent EPFL PhD graduate Ting Mao.

“But our results show that the stabilizing behavior of amino acids is not specific to biological processes. Instead, it reflects a general physical principle that applies to all small molecules and larger particles—known as colloids—in solution.”

How amino acids reduce unwanted interactions

To illustrate the effect, laboratory head Francesco Stellacci offers an analogy: imagine two coworkers walking toward one another in an empty hallway. If they enjoy talking, they will immediately stop to chat. But if the hallway becomes crowded, they may not notice each other in time and pass by without interaction. Here, the crowd plays the role of amino acids, making encounters less likely. This mechanism is known as screening attraction.

Interestingly, scientists already knew that salts have the opposite impact: they screen repulsion. In Stellacci’s hallway analogy, salt prevents two coworkers who would rather avoid each other from successfully doing so.

“Amino acids essentially behave as the opposite of salt,” explains EPFL researcher and co-author Quy Ong. “We even see this in plants—when exposed to salty conditions, plant cells produce more amino acids to compensate and maintain stability.”

Implications for research and medicine

The team stresses that researchers should start reporting amino acid concentrations in their experiments, just as they routinely report salt concentrations.

“In biology, no one would ignore ionic strength when preparing a solution,” Stellacci notes. “Our work shows that amino acid levels can have an equally important effect and should be measured and reported just as carefully.”

The group is now exploring how to predict which small molecules can stabilize specific proteins, and in what amounts—a question currently answered mostly through trial and error. This work is being supported by Stellacci’s recently awarded ERC Advanced Grant.