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How the fiber surface does this, molecule by molecule, is unknown.","posed_since":"2013","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.","problem_ref":null,"references":"","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.","status_note":"Kinetic analysis established secondary nucleation as the dominant source of new A-beta42 aggregates in 2013; its molecular steps remain unresolved.","title":"Molecular mechanism of secondary nucleation on amyloid 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