Stimulus-Induced Relief of Intentionally Incorporated Frustration Drives Refolding of a Water-Soluble Biomimetic Foldamer

• Published in: Journal of the American Chemical Society Vol. 145; no. 50; pp. 27672 - 27679
• Main Authors: Henriksen, Hanne C., Sowers, Adam J., Travis, Christopher R., Vulpis, Troy D., Cope, Thomas A., Ouslander, Sarah K., Russell, Alexander F., Gagné, Michel R., Pophristic, Vojislava, Liu, Zhiwei, Waters, Marcey L.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.12.2023; Amer Chemical Soc
• Subjects: Biomimetics; Chemistry; Chemistry, Multidisciplinary; Molecular Conformation; Molecular Dynamics Simulation; Physical Sciences; Science & Technology; RECEPTOR; MODULATION; SOLVENT; ALLOSTERY
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.3c09883

Frustrated, or nonoptimal, interactions have been proposed to be essential to a protein’s ability to display responsive behavior such as allostery, conformational signaling, and signal transduction. However, the intentional incorporation of frustrated noncovalent interactions has not been explored as a design element in the field of dynamic foldamers. Here, we report the design, synthesis, characterization, and molecular dynamics simulations of the first dynamic water-soluble foldamer that, in response to a stimulus, exploits relief of frustration in its noncovalent network to structurally rearrange from a pleated to an intercalated columnar structure. Thus, relief of frustration provides the energetic driving force for structural rearrangement. This work represents a previously unexplored design element for the development of stimulus-responsive systems that has potential application to materials chemistry, synthetic biology, and molecular machines.