Atomic insights into fibril elongation: beyond dock-and-lock mechanisms

An amyloid fibril can grow for several micrometers in length while preserving the structure of its tips with atomic fidelity. This phenomenon, which determines the fate of almost all amyloid peptides in diseases like Alzheimer’s, is poorly understood. In particular, it remains unknown how sticky regions of the fibril surface affect the kinetics of growth and what are molecular forces enabling peptides to target the fibril tip with high fidelity. Here, we perform all-atom molecular dynamics simulations of the amphipathic Ac-(FKFE)₂-NH₂ peptide in explicit solvent to study the atomic mechanisms accounting for fibril growth. In these large-scale simulations, peptides are attracted to either non-polar regions at the surface of a pre-formed fibril or to the tip of this fibril. When the peptide binds to the fibril tip, it remains bound for several microseconds, never detaching from it during the simulation. However, with increasing temperature, peptides desorb more promptly from non-polar regions of the fibril surface. At high temperatures, these detached peptides always end up locked onto the fibril tip in less than one μs. In simulations performed with several peptides (conc. ~ 19 mM), peptides accumulate at non-polar regions of the fibril surface, where they nucleate new fibrils. The latter phenomena, known as secondary nucleation, gives rise to fibrils that tend to grow perpendicularly to the pre-formed fibril. A detailed description of the pathways and forces driving these phenomena will be discussed in this presentation.