Kinetics of Irreversible Protein Aggregation: Analysis of Extended Lumry−Eyring Models and Implications for Predicting Protein Shelf Life

Abstract

A general phenomenological kinetic model of irreversible protein aggregation in aqueous solution proceeding via non-native conformations is examined with a view toward the development of techniques to predict in vitro protein shelf life quantitatively. Approximate analytical solutions are derived for interpreting experimental data and agree with explicit numerical simulations over a broad range of physically relevant conditions. Results are presented in terms of the observed kinetics of monomer loss to provide a basis for direct comparison with typical experimental measures of aggregation as well as to provide a basis for quantitative prediction of protein shelf life. Similar to classic Lumry−Eyring models, experimentally observed aggregation kinetics are described as a combination of reversible conformational transitions and the intrinsic kinetics of aggregation via non-native states. However, in contrast to classic models, the extended Lumry−Eyring model developed here includes a detailed description of...