title: Stability analysis of 4-species Aβaggregation model: A novel approach to obtaining physically meaningful rate constants.
abstract: Protein misfolding and concomitant aggregation towards amyloid formation is the underlying biochemical commonality among a wide range of human pathologies. Amyloid formation involves the conversion of proteins from their native monomeric states (intrinsically disordered or globular) to well-organized, fibrillar aggregates in a nucleation-dependent manner. Understanding the mechanism of aggregation is important not only to gain better insight into amyloid pathology but also to simulate and predict molecular pathways. One of the main impediments in doing so is the stochastic nature of interactions that impedes thorough experimental characterization and the development of meaningful insights. In this study, we have utilized a well-known intermediate state along the amyloid-βpeptide aggregation pathway calledprotofibrilsas a model system to investigate the molecular mechanisms by which they form fibrils using stability and perturbation analysis. Investigation of protofibril aggregation mechanism limits both the number of species to be modeled (monomers, and protofibrils), as well as the reactions to two (elongation by monomer addition, and protofibril-protofibril lateral association). Our new model is a reduced order four species model grounded in mass action kinetics. Our prior study required 3200 reactions, which makes determining the reaction parameters prohibitively difficult. Using this model, along with a linear perturbation argument, we rigorously determine stable ranges of rate constants for the reactions and ensure they are physically meaningful. This was accomplished by finding the ranges in which the perturbations dieout in a five-parameter sweep, which includes the monomer and protofibril equilibrium concentrations and three of the rate constants. The results presented are a proof-of-concept method in determining meaningful rate constants that can be used as a bonafide way for determining accurate rate constants for other models involving complex biological reactions such as amyloid aggregation.
authors.affiliation: Department of Chemistry and Biochemistry, University of Southern Mississippi, 118 College Dr, # 5043, Hattiesburg, MS 39406, United States.
authors.forename: G
authors.initials: G
authors.lastname: Ghag
authors.affiliation: Department of Computer Science, Virginia Commonwealth University, Richmond, VA 23220, United States.
authors.forename: P
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States.
authors.forename: A
authors.initials: A
authors.lastname: Mauro
authors.affiliation: Department of Chemistry and Biochemistry, University of Southern Mississippi, 118 College Dr, # 5043, Hattiesburg, MS 39406, United States.
authors.forename: V
authors.initials: V
authors.lastname: Rangachari
authors.affiliation: Department of Mathematical Science, Montclair State University, Montclair, NJ 07043, United States.
authors.forename: A
authors.initials: A
authors.lastname: Vaidya
keywords: Aβ; Mathematical model; Protein aggregation; Rate constants; Stability