For decades, the scientific community has known that amino acids play a crucial role in stabilizing proteins within medical formulations like insulin. However, the underlying mechanisms of how these small molecules prevent undesirable interactions between larger particles remained a mystery—until now. An international team of researchers, led by the Supramolecular Nano-Materials and Interfaces Laboratory at EPFL’s School of Engineering, has unveiled the fundamental stabilizing effect of amino acids, publishing their findings in the prestigious journal Nature.
This groundbreaking research, conducted in collaboration with Alfredo Alexander-Katz at MIT and scientists from the Southern University of Science and Technology in China, including EPFL alumnus Zhi Luo, reveals that the stabilizing effect of amino acids is not primarily biological. Instead, it is a general property of all small molecules in relation to larger particles, known as colloids, in solution.
Understanding the Colloidal Effect
Recent EPFL PhD graduate and first author Ting Mao explains, “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.” However, the team’s research shows that this is not the case. Instead, amino acids act as a crowd in a hallway, screening attraction between larger particles, akin to two colleagues missing each other in a crowded corridor.
“What we have discovered is that amino acids are essentially the anti-salt, because they have an opposite ‘screening’ effect,” says EPFL scientist and co-author Quy Ong.
The Role of Salts and Amino Acids
Interestingly, scientists have long understood that salts perform the opposite function by screening repulsion. In the hallway analogy, salt prevents two unfriendly colleagues from avoiding an awkward interaction. This contrast between salts and amino acids highlights the unique role of amino acids in biological systems.
Francesco Stellacci, head of the Supramolecular Nano-Materials and Interfaces Laboratory, elaborates on this phenomenon, suggesting that amino acids’ ability to screen attraction rather than repulsion could have significant implications for understanding molecular interactions in biological systems.
Implications for Scientific Research
The researchers argue that their findings necessitate a change in how scientific studies report amino acid concentrations. Stellacci emphasizes, “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.”
This development represents a significant shift in the approach to studying molecular interactions, with Stellacci already exploring the untapped potential of these effects through his recently funded ERC Advanced Grant. The goal is to predict which molecules can stabilize specific proteins and to what extent, moving beyond the current trial-and-error methods in biomedical research.
Looking Ahead
This discovery opens new avenues for research and application in both medical and biological fields. By understanding the fundamental properties of small molecules like amino acids, scientists can better control and predict molecular interactions, potentially leading to more effective medical formulations and treatments.
As the scientific community absorbs these findings, the potential for innovation in protein stabilization and broader applications in biotechnology appears promising. The work of Stellacci and his team underscores the importance of interdisciplinary collaboration and the continuous quest for deeper understanding in the ever-evolving landscape of scientific discovery.
