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Title: Molecular mechanism of secondary nucleation on amyloid fibrils
Plain: Some proteins stack into long fibers called amyloids, and the surface of an existing fiber speeds up the birth of new ones, which drives the self-amplifying aggregation seen in neurodegenerative disease. How the fiber surface does this, molecule by molecule, is unknown.
Precise: For A-beta42 at neutral pH and $\alpha$-synuclein at mildly acidic pH (about 5 to 6) in vitro, aggregation kinetics fit a master equation in which secondary nucleation on fibril surfaces, at rate $k_{2}$ m^$n_{2}$ M (m = monomer concentration, M = fibril mass concentration), dominates the formation of new aggregates. Determine the microscopic steps (adsorption, conformational conversion on the surface, detachment) and compute k_2 and the reaction order n_2 from a molecular model, matching measured values within a factor of 3.
Settled by: A molecular simulation or structural-kinetic model that predicts $k_{2}$ and $n_{2}$ and their dependence on sequence mutations, confirmed by bulk kinetics and single-fibril imaging.
Kind: well-posed
Answer type: mechanism
References: (empty)
Literature status: open
Status note: Kinetic analysis established secondary nucleation as the dominant source of new A-beta42 aggregates in 2013; its molecular steps remain unresolved.
Posed since: 2013