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Author Notes:

David G. Lynn, Email: dlynn2@emory.edu

We thank John Bacsa for the powder XRD which was performed by the X-ray Crystallography Center at Emory University. We are grateful to Jeannette Taylor and Hong Yi in the Emory Robert P. Apkarian Microscopy Core for TEM advice and training. We also acknowledge the Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences of the U.S. Department of Energy through Grant DE-FG02-02ER15377 (D.G.L.) for some of the peptide synthesis and analyses, and initial support from the NSF and NASA Astrobiology Program, under the NSF Center for Chemical Evolution, CHE-1004570. We thank Matthew Sheldon, and Justin Hill from the Freeman team, for help with the graphic illustrations included in the manuscript.

The manuscript was written with contributions and approval from all authors. S.J.K. characterized all peptides with the assistance of co-authors, designed and executed all experiments for phenylalanine-based peptides, and assisted with writing the manuscript. M.L. assisted with synthesis and characterization of KLVFFA(E), (L), and (V) peptides and assisted with drafting the manuscript. T.J. and Q.W. contributed to peptide synthesis and purification. K.D.R. and S.B. performed cell treatments and analysis and assisted with writing. Y.G. assisted with electron diffraction of nanotubes and SEM imaging. M.L.D. performed FTIR analysis of Fmoc-FFFF-PEG2 peptide. W.S.C., T.O.O., and A.K.M. contributed to the initial characterization of nanotubes with CD, SAXS, NMR, and TEM. D.G.L. and R.F. supervised the research, procured funding, and assisted with writing the manuscript.

The authors declare no competing interests.

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Research Funding:

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:

  • neurodegenerative disease
  • polymorphism
  • supramolecular assembly
  • β-sheet amyloids
  • Self-assembly
  • Bioinspired materials
  • Peptides

Uncovering supramolecular chirality codes for the design of tunable biomaterials

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Journal Title:

Nature Communications

Volume:

Volume 15

Publisher:

, Pages 788-None

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author(s) 2024

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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