Polymer-Peptide Conjugates Convert Amyloid into Protein Nanobundles through Fragmentation and Lateral Association

John W. Smith, Xing Jiang, Hyosung An, Alexander M. Barclay, Giuseppe Licari, Emad Tajkhorshid, Edwin G. Moore, Chad M. Rienstra, Jeffrey S. Moore, Qian Chen

Research output: Contribution to journalArticle

Abstract

The assembly of proteins into amyloid fibrils has become linked not only with the progression of myriad human diseases, but also with important biological functions. Understanding and controlling the formation, structure, and stability of amyloid fibrils are therefore major scientific goals. Here we utilize electron microscopy-based approaches combined with quantitative statistical analysis to show how a recently developed class of amyloid modulators - multivalent polymer-peptide conjugates (mPPCs) - can be applied to control the structure and stability of amyloid fibrils. In doing so, we demonstrate that mPPCs are able to convert 40-residue amyloid β-fibrils into ordered nanostructures through a combination of fragmentation and bundling. Fragmentation is shown to be consistent with a model where the rate constant of fragmentation is independent of the fibril length, suggesting a local and specific interaction between fibrils and mPPCs. Subsequent bundling, which was previously not observed, leads to the formation of sheetlike nanostructures that are surprisingly much more uniform than the original fibrils. These nanostructures have dimensions independent of the molecular weight of the mPPC and retain the molecular-level ordering of amyloid fibrils. Overall, we reveal a quantitative and nanoscopic understanding of how mPPCs can be applied to control the structure and stability of amyloid and demonstrate approaches to elucidate nanoscale amyloid phase behavior in the presence of functional macromolecules and other modulators.

Original languageEnglish (US)
Pages (from-to)937-945
Number of pages9
JournalACS Applied Nano Materials
Volume3
Issue number2
DOIs
StatePublished - Feb 28 2020

Keywords

  • amyloid
  • functional polymers
  • polymer-peptide conjugates
  • protein electron microscopy
  • protein nanomaterials

ASJC Scopus subject areas

  • Materials Science(all)

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