Synthetic polymer that mimics protein folding paves the way for new applications

In the cell, proteins naturally fold into specific shapes, such as helices, which are essential for their function. Now, NCCR Bio-Inspired Materials researchers have designed a synthetic polymer that can mimic this helical shape by incorporating alternating water-attracting and water-repelling groups along the polymer chain. These functional groups prompt the polymer to fold into a stable, tube-like structure when exposed to water, much like how proteins fold in cellular environments.

The work provides researchers with a simpler model to study folding mechanics, which is otherwise challenging due to the complexity of real proteins. Recent advancements, such as the Nobel Prize-winning work on protein folding, have shown that computers can now predict complex protein structures with remarkable accuracy, says NCCR PI and study co-author Andreas Kilbinger, professor of polymer chemistry at the University of Fribourg. “Yet, our understanding of folding processes hasn’t improved much,” he says.

To study molecular folding, Kilbinger and his colleagues combined three distinct approaches: synthetic chemistry, computer simulations and physical measurements. First, the researchers synthesized water-attracting and water-repelling building blocks using a series of chemical reactions, then polymerized them under controlled conditions.

In water, the water-attracting sections of the polymer naturally orient toward the solvent, while the water-repelling segments orient away from it. This self-organization creates a rod-like helical structure with an inner cavity. Using computer simulations, the team had a real-time look at how folding occurred at the molecular level. These simulations revealed that water acts as a “folding trigger,” causing the polymers to coil in a stable helical shape. Physical measurements such as nuclear magnetic resonance, small-angle X-ray scattering and atomic force microscopy confirmed the polymer’s helical structure.

This collaborative approach was crucial, as each method on its own would have offered only a partial picture of the folding mechanism, says study co-author and NCCR PI Stefan Salentinig, professor of physical chemistry at the University of Fribourg. The researchers published their findings in the Journal of the American Chemical Society.

Beyond the fundamental insights into molecular folding, this research has promising applications. One key area is antimicrobial design. Traditional antibiotics are often broken down by enzymes in the body, which limits their effectiveness. However, Salentinig says, these synthetic polymers are much more durable and can resist enzymatic breakdown, which could make them a promising candidate for developing new antimicrobial treatments.

Another potential application is in water purification and membrane technology. The polymer’s tube-like structure could enable selective transport of molecules, which might be used to trap and filter specific contaminants from water or control transport through thin membranes.

Looking ahead, this work could lead to further innovations, such as creating complex molecular structures similar to “molecular Tetris,” Kilbinger says, where specific shapes and functionalities are assembled in a controlled manner.

 Reference: Molliet, A.; Doninelli, S.; Hong, L.; Tran, B.; Debas, M.; Salentinig, S.; Kilbinger, A. F. M.; Casalini, T. Solvent Dependent Folding of an Amphiphilic Polyaramid. J. Am. Chem. Soc. 2023, 145 (50), 27830–27837. https://doi.org/10.1021/jacs.3c11026.