Thermodynamics and kinetics analysis of lipid-assisted transport of intrinsically disorder proteins.

Abstract

Intrinsically disordered proteins (IDPs) are implicated in numerous neurodegenerative diseases, including Alzheimer's, Parkinson's, and type 2 diabetes. Although the amyloid and toxic oligomer hypotheses have provided significant molecular insights into these diseases, they are incomplete in fully explaining the complexity of the observed phenomena. In this study, we propose a new quantitative hypothesis, the lipid-chaperone hypothesis, which postulates a central role for the interaction between IDPs and lipids in the pathogenesis of these diseases. The resulting lipid-protein complex facilitate protein transfer into the cell membrane and the subsequent formation of pores, compromising cellular integrity. To experimentally test this hypothesis, we developed a mathematical model describing the kinetics of pore formation. The model was calibrated using experimental data and allowed us to estimate the kinetic constants and Gibbs free energy associated with the formation of the lipid-protein complex. These results support the hypothesis that the interaction between IDPs and lipids is a crucial event in the pathogenesis of IDP-related diseases and suggest that modulating this interaction could represent a promising therapeutic strategy.