Mechanisms and Rates of Nucleation of Amyloid Fibrils

TL;DR

This paper develops a theoretical framework to understand amyloid fibril nucleation, revealing conditions under which classical or two-step mechanisms dominate, and providing expressions for nucleation rates based on peptide interactions and concentrations.

Contribution

It introduces a comprehensive model combining classical and two-step nucleation theories, specifically applied to Aβ1-42, to predict nucleation rates and mechanisms based on interaction parameters.

Findings

Classical nucleation dominates at low monomer concentrations.

Two-step aggregation-conversion mechanism prevails at higher concentrations.

Effective nucleation rate depends on complex interaction parameters, not just nucleus size.

Abstract

The classical nucleation theory finds the rate of nucleation proportional to the monomer concentration raised to the power, which is the `critical nucleaus size', ${n_c}$. The implicit assumption, that amyloids nucleate in the same way, has been recently challenged by an alternative two-step mechanism, when the soluble monomers first form a metastable aggregate (micelle), and then undergo conversion into the conformation rich in ${\beta}$-strands that are able to form a stable growing nucleus for the protofilament. Here we put together the elements of extensive knowledge about aggregation and nucleation kinetics, using a specific case of A${\beta_{1\mathrm{-}42}}$ amyloidogenic peptide for illustration, to find theoretical expressions for the effective rate of amyloid nucleation. We find that at low monomer concentration in solution, and also at low interaction energy between two peptide conformations in the micelle, the nucleation occurs via the classical route. At higher monomer concentration, and a range of other interaction parameters between peptides, the two-step `aggregation-conversion' mechanism of nucleation takes over. In this regime, the effective rate of the process can be interpreted as a power of monomer concentration in a certain range of parameters, however, the exponent is determined by a complicated interplay of interaction parameters and is not related to the minimum size of the growing nucleus (which we find to be ${\sim}$ 7-8 for A${\beta_{1-42}}$).