John W. Smith, Xing Jiang, Hyosung An, Alexander M. Barclay, Giuseppe Licari,
Emad Tajkhorshid, Edwin G. Moore, Chad M. Rienstra, Jeffrey S. Moore, and
Qian Shen.
Polymer-peptide conjugates convert amyloid into protein nanobundles
through fragmentation and lateral association.
ACS Applied Materials and Interfaces, 3:937-945, 2020.
(PMC: PMC7059651)
SMIT2019-ET
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 beta-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.
