Graduation Date

Spring 5-5-2018

Document Type


Degree Name

Doctor of Philosophy (PhD)


Pharmaceutical Sciences

First Advisor

Yuri L. Lyubchenko


Protein misfolding followed by the formation of aggregates, is an early step in the cascade of conformational changes in a protein that underlie the development of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Efforts aimed at understanding this process have produced little clarity and the mechanism remains elusive.

Here, we demonstrate that the hairpin fold, a structure found in the early folding intermediates of amyloid b, induces morphological and stability changes in the aggregates of Aβ(14-23) peptide. We structurally characterized the interactions of monomer and hairpin using extended molecular dynamics (MD) simulations, which revealed a novel intercalated type complex. These finding suggest that folding patterns of amyloid proteins define the aggregation pathway.

Computational analysis was then used to characterize the dimerization of full-length Aβ peptide and reveal their dynamic properties. Aβ dimers did not show β-sheet structures, as one may expect based on the known structures of Aβ fibrils, rather dimers are stabilized by hydrophobic interactions in the central hydrophobic regions. Comparison between Aβ40 and Aβ42 showed that overall, the dimers of both alloforms exhibit similar interaction strengths. However, the interaction patterns are significantly different.

A novel aggregation pathway, able to describe aggregation at physiologically relevant concentrations, was elucidated when aggregation of amyloid proteins was performed in presence of surfaces. Computational analysis revealed that interaction of a monomer with the surface is accompanied by the structural transition of the monomer; which can then facilitate binding of another monomer and form a dimer. Compared to our previous data we observed an almost five-fold faster dimer formation.

Further investigation of the surface-mediated aggregation revealed that lipid membranes promote aggregation of a-syn protein. MD simulations demonstrate that a-syn monomers change conformation upon interaction with the bilayers. On POPS, a-syn monomer protrudes from the surface. This conformation on POPS dramatically facilitates assembly of a dimer that remains stable over the entire simulation period. These findings are in line with experimental data.

Overall, the studies described in this thesis provide the structural basis for the early stages of the misfolding and aggregation process of amyloid proteins.

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