Scientists uncover how amino acids stabilize proteins in resolution

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 basic stabilizing impact of all small molecules in resolution. The discovery has been printed 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 latest 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 alongside very well and all the time wish to cease and chat. If the hallway is empty, they may instantly spot one another and are available collectively. But if the hallway out of the blue turns into crowded, they could not see one another till they’ve already walked previous, and even miss one another solely. This phenomenon, referred to as screening attraction, is how amino acids have an effect on bigger particles: they play the function of the group within the hallway, discouraging passing interactions.”

Francesco Stellacci, Head, Supramolecular Nano-Materials and Interfaces Laboratory

Interestingly, scientists have recognized for over a century that salts do the alternative: they display repulsion. In the hallway instance, salt additionally performs the function of the group, solely on this case it prevents two unfriendly colleagues from avoiding a clumsy 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 gives 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 lately 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.”