title: Kinetics of fragmentation and dissociation of two-strand protein filaments: Coarse-grained simulations and experiments.
abstract: While a significant body of investigations have been focused on the process of protein self-assembly, much less is understood about the reverse process of a filament breaking due to thermal motion into smaller fragments, or depolymerization of subunits from the filament ends. Indirect evidence for actin and amyloid filament fragmentation has been reported, although the phenomenon has never been directly observed either experimentally or in simulations. Here we report the direct observation of filament depolymerization and breakup in a minimal, calibrated model of coarse-grained molecular simulation. We quantify the orders of magnitude by which the depolymerization rate from the filament ends koff is larger than fragmentation rate k- and establish the law koff/k- = exp[(ε‖ - ε⊥)/kBT] = exp[0.5ε/kBT], which accounts for the topology and energy of bonds holding the filament together. This mechanism and the order-of-magnitude predictions are well supported by direct experimental measurements of depolymerization of insulin amyloid filaments.
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Zaccone
authors.affiliation: Granta Design, 62 Clifton Rd, Cambridge CB1 7EG, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Terentjev
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: T W
authors.initials: TW
authors.lastname: Herling
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: T P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Aleksandrova
authors.affiliation: Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, United Kingdom.
authors.forename: E M
authors.initials: EM
authors.lastname: Terentjev
mesh_terms: D000199:Actins / Q000737:chemistry* / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013696:Temperature
chemical_list: D000199:Actins; D000682:Amyloid