Nucleation of polymorphic amyloid fibrils

Area of Science:

• Biochemistry
• Biophysics
• Materials Science

Background:

• Proteins can self-assemble into amyloid fibrils with varying morphologies (polymorphism).
• Fibril polymorphism is biologically significant due to differing toxicities of polymorphs.
• Currently, no tools exist to predict fibril polymorph formation or conditions.

Purpose of the Study:

• To develop a predictive tool for amyloid fibril polymorphism.
• To understand the nucleation process of polymorphic amyloid fibrils.
• To link fibril formation to protein concentration and solubility.

Main Methods:

• Application of a newly developed nonstandard nucleation theory.
• Analysis of the concentration dependence of nucleation rates for different fibril polymorphs.
• Modeling the relationship between nucleation rate, protein solubility, and binding energies.

Main Results:

• The theory predicts the concentration-dependent nucleation rate for various fibril polymorphs.
• Nucleation rate is closely linked to protein solubility and a critical threshold concentration.
• A lower threshold monomer concentration renders fibril formation biologically irrelevant.

Conclusions:

• The developed theory provides a framework for predicting amyloid fibril polymorphism.
• Understanding the relationship between nucleation, solubility, and binding energies is key.
• This approach may guide experimental design for controlling specific fibril polymorph formation.