Modeling Protein Aggregation Kinetics from NMR Data

We provide an overview of the practical aspects of using NMR spectroscopy to follow the time course of protein fibril formation (aggregation) and quantitatively model the kinetics of aggregation processes. Following a brief survey of the theoretical foundations of the kinetics of protein aggregation and its inhibition, the modeling of aggregation kinetics, from data acquired by a series of fast two-dimensional ¹H-¹⁵N correlation NMR spectra, is described. Examples are drawn from our recent NMR-based studies of (1) the aggregation kinetics of a pathogenic huntingtin exon-1 protein whose fibrillization in neurons is responsible for Huntington's disease, and (2) the kinetics of amyloid β42 fibril formation and the mechanism of its inhibition by the chaperone Hsp104.