Uncovering supramolecular chirality codes for the design of tunable biomaterials

• Type of Material: Article
• Authors: 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 Gaoo, 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 Mehta, Emory University; David Lynn, Emory University; Ronit Freeman, University of North Carolina
• Language: English
• Date: 2024
• Publisher: Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2024
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038%2Fs41467-024-45019-2
• Title of Journal or Parent Work: Nature Communications
• Volume: 15
• Start Page: 788
• Grant/Funding Information: This work was supported by the University of North Carolina at Chapel Hill (UNC-CH) and Emory University. Mass spectrometry was performed at the UNC Mass Spectrometry Core Laboratory supported in part by the University of North Carolina’s School of Medicine Office of Research. Transmission electron microscopy, FRAP, heating videos, and fluorescent cell images were taken at UNC Hooker Imaging Core Facility, supported in part by P30CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Imaging studies were also supported by Robert P. Apkarian Integrated Electron Microscopy Core (IEMC) at Emory University, which is subsidized by the School of Medicine and Emory College of Arts and Sciences. Additional support for IEMC was provided by the Georgia Clinical and Translational Science Alliance of the National Institutes of Health under award number UL1TR000454. Circular Dichroism was performed at UNC Macromolecular Interactions Facility supported by the National Cancer Institute of the National Institutes of Health under award number P30CA016086. Confocal microscopy of DOX structures was performed at UNC Microscopy Services Laboratory, supported in part by P30CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. SEM and electron diffraction was performed at the Chapel Hill Analytical and Nanofabrication Laboratory, CHANL, a member of the North Carolina Research Triangle Nanotechnology Network, RTNN, which is supported by the National Science Foundation, Grant ECCS-2025064, as part of the National Nanotechnology Coordinated Infrastructure, NNCI. R.F. and S.J.K. acknowledge financial support from the Alfred P. Sloan Foundation grant G-2021-14197 (R.F.). R.F. also acknowledges additional support from the Cottrell Scholar Award #CS-CSA-2023-033 (R.F.) sponsored by Research Corporation for Science Advancement. We are further grateful for support from NSF DMR-2004846 BMAT (D.G.L.) in collaboration with BSF 2019745 (D.G.L.) for some of the peptide synthesis resources accessed from NIH Alzheimer’s Disease Research Center P50AG025688.
• Keywords: Bioinspired materials; Self-assembly; supramolecular assembly; neurodegenerative disease; polymorphism; Peptides; β-sheet amyloids
• Research Categories: Biology, Neuroscience

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.