Uncovering supramolecular chirality codes for the design of tunable biomaterials

Stephen J. Klawa, Michelle Lee, Kyle D. Riker, Tengyue Jian, Qunzhao Wang, Yuan Gao, Margaret L. Daly, Shreeya Bhonge, W. Seth Childers, Tolulope O. Omosun, Anil K. Mehta, David G. Lynn () and Ronit Freeman ()
Additional contact information
Stephen J. Klawa: University of North Carolina
Michelle Lee: Emory University
Kyle D. Riker: University of North Carolina
Tengyue Jian: University of North Carolina
Qunzhao Wang: University of North Carolina
Yuan Gao: University of North Carolina
Margaret L. Daly: University of North Carolina
Shreeya Bhonge: University of North Carolina
W. Seth Childers: Emory University
Tolulope O. Omosun: Emory University
Anil K. Mehta: Emory University
David G. Lynn: Emory University
Ronit Freeman: University of North Carolina

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract In neurodegenerative diseases, polymorphism and supramolecular assembly of β-sheet amyloids are implicated in many different etiologies and may adopt either a left- or right-handed supramolecular chirality. Yet, the underlying principles of how sequence regulates supramolecular chirality remains unknown. Here, we characterize the sequence specificity of the central core of amyloid-β 42 and design derivatives which enable chirality inversion at biologically relevant temperatures. We further find that C-terminal modifications can tune the energy barrier of a left-to-right chiral inversion. Leveraging this design principle, we demonstrate how temperature-triggered chiral inversion of peptides hosting therapeutic payloads modulates the dosed release of an anticancer drug. These results suggest a generalizable approach for fine-tuning supramolecular chirality that can be applied in developing treatments to regulate amyloid morphology in neurodegeneration as well as in other disease states.

Date: 2024
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DOI: 10.1038/s41467-024-45019-2

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