For a long time, amino acids have been added to medical formulations like insulin as stabilizers: these small molecules preserve proteins (i.e. bigger particles) from interacting in undesirable methods. And for many years, scientists have recognized that this works – however not why.
Now, a global workforce of scientists, led by the Supramolecular Nano-Materials and Interfaces Laboratory in EPFL’s School of Engineering, has lastly defined the ‘why’ – and within the course of, unearthed a elementary stabilizing impact of all small molecules in answer. The discovery has been revealed in Nature in collaboration with Alfredo Alexander-Katz at MIT and researchers on the Southern University of Science and Technology in China, together with 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 current EPFL PhD graduate and first creator 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
To perceive this colloidal impact of small molecules, Supramolecular Nano-Materials and Interfaces Laboratory head Francesco Stellacci suggests imagining two colleagues strolling towards one another on reverse sides of a hallway.
“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.”
“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.” Supramolecular Nano-Materials and Interfaces Laboratory head Francesco Stellacci.
Interestingly, scientists have recognized for over a century that salts do the alternative: they display screen repulsion. In the hallway instance, salt additionally performs the function of the group, solely on this case it prevents two unfriendly colleagues from avoiding an ungainly interplay.
“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.
Better management of molecular interactions
The researchers say that their work offers a powerful argument for reporting amino acid concentrations in scientific research going ahead. “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.
Indeed, Stellacci is already pursuing the untapped potential of those molecular results as a part of his recently funded 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.”
Reference: Mao T, Xu X, Winkler PM, et al. Stabilizing impact of amino acids on protein and colloidal dispersions. Nature. 2025. doi: 10.1038/s41586-025-09506-w
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