Date of Award


Document Type

Thesis campus only



First Advisor

Kwan K Cheng

Second Advisor

Kah-Chung Leong

Third Advisor

Gerard Beaudoin


Self-aggregation and misfolding of two major amyloidogenic proteins, tau and human islet amyloid polypeptide (hIAPP), have been implemented in the pathogenesis of Alzheimer’s disease, yet the exact mechanisms remain unknown. It has been suggested that the small oligomers are more toxic than mature fibrils, but the mechanisms of membrane disruption are unknown. Using molecular dynamics (MD) simulations, the membrane-binding and protein-folding behaviors of these amyloidogenic proteins were investigated. Using both coarse-grained (CG) and atomistic MD simulations, we successfully model protein oligomers binding to specific and non-specific lipid rafts and the subsequent surface-induced protein folding. The tau simulations revealed that the membrane binding deficient mutant k18 fragment experienced surface-induced helical conformations while the wild type k18 fragment did not, which may speak to the difference in toxicity. With hIAPP, we found that there was a significant difference in protein folding between the different model membranes, suggesting that nonspecific membranes are most likely to promote helical conformations. In addition, monomeric hIAPP is less likely to experience formation of ordered structures when bound to GM1. The hybrid system did not demonstrate any preferential folding based on model membrane or size of oligomer. In general, this study provides new mechanistic insights about the protein folding of membrane-bound amyloidogenic proteins.