Mechanisms and rates of nucleation of amyloid fibrils

The classical nucleation theory finds the rate of nucleation proportional to the monomer concentration raised to the power, which is the critical nucleus 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(1-42) amyloidogenic peptide for illustration, to find theoretical expressions for the effective rate of amyloid nucleation. We find that at low monomer concentrations 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 concentrations, 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 similar to 7- 8 for A beta(1-42)). (C) 2017 Author(s).