Abstract
The classical nucleation theory finds the rate of nucleation proportional to the monomer concentration raised to the power, which is the "critical nucleus size," nc. 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 β-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 Aβ1-42 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 ∼7-8 for Aβ1-42).
Highlights
As more evidence emerges that oligomers produced at the early stages of amyloid aggregation could be the most toxic species,5–7 researchers have been keen on understanding the details of the nucleation mechanism of fibrils, in particular, determining the critical nucleus size nc of primary nucleation: the minimum size that enables the extension of amyloid fibrils
An important quantity, called the lag time tlag,18,19 can be extracted; it is defined as the waiting time before a sharp increase of fibril mass appears in the sigmoidal plot
We find it is sufficient to use a two-state simplification to capture the essence of the amyloid aggregation mechanism, as has been suggested in molecular simulations:28,29 we denote the soluble monomer as “α-mer”, while the β-mer is the monomeric unit of mature amyloid fibrils
Summary
Amyloid fibrils are insoluble linear ordered aggregates of misfolded proteins or peptides, which are closely connected with neurodegenerative disorders. As more evidence emerges that oligomers produced at the early stages of amyloid aggregation could be the most toxic species, researchers have been keen on understanding the details of the nucleation mechanism of fibrils, in particular, determining the critical nucleus size nc of primary nucleation: the minimum size that enables the extension of amyloid fibrils. An important quantity, called the lag time tlag, can be extracted; it is defined as the waiting time before a sharp increase of fibril mass appears in the sigmoidal plot. This lag time approximately holds a power-law relationship to the initial monomer concentration C1, as originally suggested by the Oosawa model, which considers only primary nucleation and irreversible elongation in aggregation kinetics. The power-law exponent in tlag ∼ C1γ is approximately γ = − nc/2, which should enable experimental determination of nc by plotting ln tlag against ln C1 or through a global fitting scheme of the total fibril mass plots against time with different initial monomer concentrations as used in Ref. 23. The validity of such methods of obtaining the critical nucleus size nc depends on how closely the assumed microscopic aggregation mechanisms and kinetic equations match the actual ones in experiments
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
