Abstract
Amyloid fibrils have long been associated with many neurodegenerative diseases. The conventional picture of the formation and proliferation of fibrils from unfolded proteins comprises primary and secondary nucleation of oligomers followed by elongation and fragmentation thereof. In this work, we first employ extensive all-atom molecular dynamics (MD) simulations of short peptides to investigate the governing processes of fibril growth at the molecular scale. We observe that the peptides in the bulk solution can bind onto and subsequently diffuse along the fibril surface, which leads to fibril elongation via either bulk- or surface-mediated docking mechanisms. Then, to guide the quantitative interpretation of these observations and to provide a more comprehensive picture of the growth kinetics of single fibrils, a continuum model which incorporates the key processes observed in the MD simulations is formulated. The model is employed to investigate how relevant physical parameters affect the kinetics of fibril growth and identify distinct growth regimes. In particular, it is shown that fibrils which strongly bind peptides may undergo a transient exponential growth phase in which the entire fibril surface effectively acts as a sink for peptides. We also demonstrate how the relevant model parameters can be estimated from the MD trajectories. Our results provide compelling evidence that the overall fibril growth rates are determined by both bulk and surface peptide fluxes, thereby contributing to a more fundamental understanding of the growth kinetics of amyloid-like fibrils.