All ETDs from UAB

Advisory Committee Chair

James C Patterson

Advisory Committee Members

Aaron L Lucius

Jamil S Saad

Jianhua Zhang

Tracy P Hamilton

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences


α-Synuclein (αS) is a cytosolic protein expressed at high levels in the human brain and concentrated in presynaptic nerve terminals. Although the precise nature of αS in vivo remains unclear, the aggregation of αS, from its soluble, functional forms into highly organized amyloid fibrils, has been substantially implicated in the pathology of a number of neurodegenerative diseases collectively known as synucleinopathies. The long-term goal of this project is to understand the molecular mechanisms that initiate αS oligomerization in aqueous solution. A novel computational methodology involving protein modeling and atomistic molecular dynamics (MD) simulations is used in this work. The objective included in this dissertation is to produce an ensemble of small soluble αS species, and then identify aggregation-prone species with a characterization of their dynamic structures in explicit water. In Chapter 2, based on the results from currently available experimental studies on tetrameric αS, we develop a systematic computational methodology to create tetramer models. With such models, we simulate their dynamic conformations and identified the hydrophobic core and important salt-bridges that stabilize the tetramers. In Chapter 3, we simulate the most hydrophobic region in αS sequence with strong tendency of self-assembly, also known as the non-amyloid β component (NAC) of amyloid plaques in Alzheimer’s disease at both room and near-boil temperatures. From the ensemble of monomer species, the one with high tendency of forming β-sheet is identified and then used to generate the dimeric species. The simulations with those dimer species suggest that the N- and C-terminal regions of NAC are likely to be the regions where initial β-sheet structure forms in small oligomers of αS. In Chapter 4, simulations with the monomeric wild-type αS and three missense mutations at various temperatures suggest that all three mutations induce the loss of helix of αS, which might promote formation of β-sheet structure. Additionally, the results support in vitro studies of αS’s thermal behavior that suggest wild-type αS is a heat-resistant protein, and further predict that some missense mutations might cause faster changes of secondary structure of αS upon heat treatment.



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