Multivalent macromolecules redirect nucleation-dependent fibrillar assembly into discrete nanostructures

Area of Science:

• Supramolecular Chemistry
• Polymer Science
• Biophysics

Background:

• Controlling the size and shape of noncovalent multivalent assemblies is a significant challenge in supramolecular polymer science.
• Nucleation-elongation kinetics offers potential for controlled growth, dependent on critical nucleus formation dynamics.
• Amyloid-beta (Aβ) peptide fibrillar assembly serves as a model for nucleation-dependent supramolecular polymerization.

Purpose of the Study:

• To investigate the use of multivalent polymer-peptide conjugates (mPPCs) to control the self-assembly of Aβ peptides.
• To redirect the fibrillar assembly of Aβ into discrete nanostructures by targeting pre-nucleation intermediates.
• To demonstrate a prototypical molecular design for controlling supramolecular polymer shape via nucleation-dependent mechanisms.

Main Methods:

• Design and synthesis of multivalent polymer-peptide conjugates (mPPCs).
• Utilizing atomic force microscopy (AFM) and transmission electron microscopy (TEM) to visualize nanostructure formation.
• Employing Thioflavin T (ThT) fluorescence assays to monitor fibrillogenesis kinetics.

Main Results:

• Aβ peptides self-assembled into discrete zero-dimensional nanostructures (5-35 nm) in the presence of mPPCs.
• Aβ peptides alone formed one-dimensional fibrils (micrometer length) in the absence of mPPCs.
• Thioflavin T assays confirmed that mPPCs effectively suppress Aβ fibrillogenesis.

Conclusions:

• Multivalent polymer-peptide conjugates (mPPCs) can effectively redirect Aβ self-assembly from fibrillar to discrete nanostructures.
• This study demonstrates a novel strategy for controlling supramolecular polymer morphology by targeting nucleation-dependent pathways.
• The findings present a prototypical molecular design for creating shape-controlled macromolecules in supramolecular chemistry.