title: A minimal conformational switching-dependent model for amyloid self-assembly.
abstract: Amyloid formation is associated with various pathophysiological conditions like Alzheimer's and Parkinson's diseases as well as many useful functions. The hallmark of amyloid assemblies is a conformational transition of the constituent proteins into a β - sheet rich filament. Accounting for this conformational transition in amyloidogenic proteins, we develop an analytically solvable model that can probe the dynamics of an ensemble of single filaments. Using the theory and Monte Carlo simulations, we show the presence of two kinetic regimes for the growth of a self-assembling filament - switching-dependent and -independent growth regimes. We observe a saturation in fibril elongation velocities at higher concentrations in the first regime, providing a novel explanation to the concentration-independence of growth velocities observed experimentally. We also compute the length fluctuation of the filaments to characterize aggregate heterogeneity. From the early velocities and length fluctuation, we propose a novel way of estimating the conformational switching rate. Our theory predicts a kinetic phase diagram that has three distinct phases - short oligomers/monomers, disordered aggregates and β-rich filaments. The model also predicts the force generation potential and the intermittent growth of amyloid fibrils evident from single molecular experiments. Our model could contribute significantly to the physical understanding of amyloid aggregation.
authors.affiliation: Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India.
authors.forename: Srivastav
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India.
authors.forename: Dhiman
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Maji
authors.affiliation: Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Padinhateeri
mesh_terms: D000465:Algorithms; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008958:Models, Molecular; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D066329:Protein Aggregates