title: Inherent variability in the kinetics of autocatalytic protein self-assembly.
abstract: In small volumes, the kinetics of filamentous protein self-assembly is expected to show significant variability, arising from intrinsic molecular noise. This is not accounted for in existing deterministic models. We introduce a simple stochastic model including nucleation and autocatalytic growth via elongation and fragmentation, which allows us to predict the effects of molecular noise on the kinetics of autocatalytic self-assembly. We derive an analytic expression for the lag-time distribution, which agrees well with experimental results for the fibrillation of bovine insulin. Our expression decomposes the lag-time variability into contributions from primary nucleation and autocatalytic growth and reveals how each of these scales with the key kinetic parameters. Our analysis shows that significant lag-time variability can arise from both primary nucleation and from autocatalytic growth and should provide a way to extract mechanistic information on early-stage aggregation from small-volume experiments.
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JZ, United Kingdom.
authors.forename: Juraj
authors.initials: J
authors.lastname: Szavits-Nossan
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JZ, United Kingdom.
authors.forename: Kym
authors.initials: K
authors.lastname: Eden
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JZ, United Kingdom.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Morris
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JZ, United Kingdom.
authors.forename: Cait E
authors.initials: CE
authors.lastname: MacPhee
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JZ, United Kingdom.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Evans
authors.affiliation: SUPA, School of Physics and Astronomy, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JZ, United Kingdom.
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Allen
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D002417:Cattle; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D008956:Models, Chemical; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013269:Stochastic Processes
chemical_list: D000682:Amyloid; D007328:Insulin; D011506:Proteins