Using various physical-chemical tools and perturbation parameters, the effects of temperature, pressure as well as lipid interfaces, confining geometries and cosolvents on the various stages of the aggregation and fibrillation reaction of amyloidogenic peptides have been studied. First we show data on the experimentally derived static structure factor obtained for the protein insulin which has been analyzed with a statistical mechanical model based on the DLVO potential. The data reveal that the protein self-assembles into equilibrium clusters already at low concentrations in the pre-nucleation phase. Then, mechanistic details about the nucleation process and concurrent aggregation pathways of disease-related amyloidogenic peptides, such as IAPP, and the differential stability of the aggregate structures formed are discussed. Also solvational perturbations, accomplished by the addition of various salts and cosolvents have been explored. They exert pronounced and diversified effects on the unfolding, non-native assembly and fibril formation, which ultimately manifest in morphological variations of mature aggregates and fibrils. Finally, the presence of lipid interfaces, soft-matter confinement and protein chaperons will be discussed, which drastically change the aggregation pathway as well as the kinetics of peptide aggregation.

Exploring the free energy and conformational landscape of amyloidogenic peptides upon aggregation and amyloid formation

249th National Meeting (2015)

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