title: Competition between primary nucleation and autocatalysis in amyloid fibril self-assembly.
abstract: Kinetic measurements of the self-assembly of proteins into amyloid fibrils are often used to make inferences about molecular mechanisms. In particular, the lag time--the quiescent period before aggregates are detected--is often found to scale with the protein concentration as a power law, whose exponent has been used to infer the presence or absence of autocatalytic growth processes such as fibril fragmentation. Here we show that experimental data for lag time versus protein concentration can show signs of kinks: clear changes in scaling exponent, indicating changes in the dominant molecular mechanism determining the lag time. Classical models for the kinetics of fibril assembly suggest that at least two mechanisms are at play during the lag time: primary nucleation and autocatalytic growth. Using computer simulations and theoretical calculations, we investigate whether the competition between these two processes can account for the kinks which we observe in our and others' experimental data. We derive theoretical conditions for the crossover between nucleation-dominated and growth-dominated regimes, and analyze their dependence on system volume and autocatalysis mechanism. Comparing these predictions to the data, we find that the experimentally observed kinks cannot be explained by a simple crossover between nucleation-dominated and autocatalytic growth regimes. Our results show that existing kinetic models fail to explain detailed features of lag time versus concentration curves, suggesting that new mechanistic understanding is needed. More broadly, our work demonstrates that care is needed in interpreting lag-time scaling exponents from protein assembly data.
authors: School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: eden.kym@gmail.com.
authors: Kym
authors: K
authors: Eden
authors: School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors: Ryan
authors: R
authors: Morris
authors: School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors: Jay
authors: J
authors: Gillam
authors: School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors: Cait E
authors: CE
authors: MacPhee
authors: School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
authors: Rosalind J
authors: RJ
authors: Allen
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D002384:Catalysis; D002417:Cattle; D003198:Computer Simulation; D008954:Models, Biological; D013997:Time Factors
chemical_list: D000682:Amyloid
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