Nucleation of amyloid fibrils

TL;DR

This paper develops a theoretical model for amyloid fibril nucleation, revealing how fibrils grow and transform structure to minimize formation work, with explicit relations for nucleus size and nucleation rate based on concentration and temperature.

Contribution

It introduces a classical nucleation theory-based expression for amyloid fibril formation, detailing the transition from one- to two-dimensional structures during growth.

Findings

Fibrils transition from 1D to 2D structures as they grow.

Explicit formulas for nucleus size and nucleation rate.

Nucleation rate depends on concentration and temperature.

Abstract

We consider nucleation of amyloid fibrils in the case when the process occurs by the mechanism of direct polymerization of practically fully extended protein segments, i.e. beta-strands, into beta-sheets. Applying the classical nucleation theory, we derive a general expression for the work to form a nanosized amyloid fibril (protofilament) constituted of successively layered beta-sheets. Analysis of this expression reveals that with increasing its size, the fibril transforms from one-dimensional into two-dimensional aggregate in order to preserve the equilibrium shape corresponding to minimal formation work. We determine the size of the fibril nucleus, the fibril nucleation work and the fibril nucleation rate as explicit functions of the concentration and temperature of the protein solution. The results obtained are applicable to homogeneous nucleation which occurs when the solution is sufficiently pure and/or strongly supersaturated.