Molecules move in the 4th dimension

The movement within supramolecular assemblies is critical to their biological activity, including their ability to regenerate cartilage and repair spinal cord damage. The finding suggests that scientists should consider molecules’ behavior beyond the three physical dimensions of space when they design systems for medical use.

“The fourth dimension is time. It’s not just the three-dimensional structure but what molecules are doing in time,” said Samuel I. Stupp, a chemist at Northwestern University who spoke about the work during a presentation Monday in the Division of Polymer Chemistry at the American Chemical Society’s Fall 2024 meeting.

Stupp has been working on systems for regenerative medicine for more than 2 decades. The system developed in his lab uses peptide amphiphiles—molecules with a hydrophilic peptide on one end and a hydrophobic alkyl chain on the other. These molecules assemble into fibers that Stupp’s group has been exploring as a way to treat lost cartilage, repair spinal cord injuries, and grow bone in spinal fusion. But the importance of molecular movement in these systems has emerged only in the past few years, Stupp said.

In recent experiments, the group made peptide amphiphiles with a cyclic peptide structure that mimics transforming growth factor-β1 (TGF-β1)—a protein that plays an important role in cellular processes. They then dialed movement into their supramolecular assemblies by using the TGF-β1 mimetic molecules alongside some peptide amphiphiles designed to have dynamic motion and some designed to move less. The assemblies with more movement proved to be better than sluggish assemblies at prompting human cartilage cells in test tubes to make collagen—an important step in regenerating cartilage (J. Am. Chem. Soc. 2024, DOI: 10.1021/jacs.4c05170).

Stupp’s group previously reported that assemblies with dynamic movement are better than slowpoke ones at repairing damaged spinal cords in mice. Because both systems have different components, Stupp thinks the dynamic movement is general phenomenon for molecular interaction with proteins. “There isn’t just one mechanism to enhance motion. There probably are many, and we are now enjoying the discovery of all the possible mechanisms that we could use to do this,” Stupp said.

Bert Meijer, an expert in supramolecular systems at Eindhoven University of Technology, told C&EN in an email that Stupp’s work offers insight on developing biomaterials. The finding “is the next step in bioactive synthetic materials based on peptide amphiphiles and brings these materials a step closer to clinical applications.”