Defining Chemical Reaction Mechanisms Associated with Threshold Phenomena in Conformational Diseases.

Abstract

Conformational diseases arise from the failure of a protein to fold or remain in its native conformational state. The resulting misfolded protein isomers are prone to aggregation, a hallmark of conformational diseases. In some conformational diseases, there is an observed threshold behavior characterized by a sudden shift from nontoxic to toxic misfolded protein concentrations. Evidence suggests that basal protein isomer concentrations, protein isomer interactions, pH, and temperature impact protein aggregation but the mechanism(s) underlying threshold behavior are unknown. Identifying the factors underlying the sudden toxic shift in misfolded protein concentration is a key to controlling conformational disease. The central hypothesis of this research is that a limited number of protein isomer interaction reaction mechanisms drive threshold behavior in conformational disease. In this work, I apply mathematical and computational modeling techniques to identify reaction mechanisms associated with threshold behavior in conformational diseases. First, I present a mathematical model of native and misfolded protein isomer interactions and define the model conditions under which threshold behavior occurs. Second, I apply a novel computational approach to characterize known models of protein aggregation based on reaction mechanisms and dynamical behavior. Finally, I organize these characterizations into AggMod, an online repository of known models of protein aggregation.