Using reverse micelles to explore the effects of confinement and hydration on peptide folding and aggregation
Martinez-Saltzberg, Anna Victoria
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Knowledge of how intermolecular interactions of amyloidogenic proteins cause protein aggregation and how those interactions are affected by sequence and solution conditions is essential to our understanding of the onset of many degenerative diseases. Of particular interest is the aggregation of the amyloid-β (Aβ) peptide, linked to Alzheimer's disease, and the aggregation of the Sup35 yeast prion peptide, which resembles the mammalian prion protein (PrP) linked to spongiform encephalothopies. To facilitate the study of these important peptides, experimentalists have identified small peptide congeners of the full-length proteins that exhibit amyloidogenic behavior, including the KLVFFAE sequence of the Aβ protein, and the GNNQQNY sequence of Sup35. Reverse micelles provide an important environment for the study of protein folding and aggregation. In a reverse micelle, it is possible to observe the effects that confinement and water activity, believed to play a critical role in an in vivo cellular environment, have on protein folding, misfolding, and aggregation. We employed molecular dynamics simulations of reverse micelles as well as peptides encapsulated in reverse micelles in order to characterize the reverse micelle environment and identify fundamental principles that inform how sequence and solution environment influence protein aggregation. The peptides studied include the alanine-rich peptide AKA2 as well as the amyloidogenic KLVFFAE and GNNQQNY peptide fragments. The results of these studies suggest that substantial fluctuations in reverse micelle shape away from an idealized spherical geometry enables significant interaction between peptides and the surfactant interface. Analysis these results, including evaluation of water dynamics and calculated IR spectra of the amide I vibration of the peptides, indicate that our model of the reverse micelle is a robust one which captures essential features of this complex system. Moreover, our studies provide critical insight into the complex role played by a heterogeneous cellular environment in the earliest stages of protein aggregation and amyloid formation.