The Conformational Dynamics of the Polymorphic Amyloid β Protofilaments
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Authors
Armbruster, Matthew Alan
Issue Date
2014-05-12
Volume
Issue
Type
Thesis
Language
en_US
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Abstract
My research combined methodologies of physics and chemistry to understand biological processes. Specifically, I focused on understanding the interaction between amyloid β (Aβ) protofilaments and model bilayers.|The community, as a whole, does not know the 3D structure of the Aβ protofilament. Therefore, we studied two polymorphic Aβ (9-40) structures [1] as likely conformations. We relaxed the structures through normal mode analysis. In normal mode analysis, we approximated around a thermal equilibrium and treated every atom-to-atom interaction like a spring.|Once we obtained the most likely conformations, we coarse-grained the protofilament. Coarse-grained simulations greatly reduced the number of degrees of freedom, and thus the computational cost of the simulations.|With the coarse-grained conformations, we performed molecular dynamics simulations to further relax the protofilaments. We prepared the relaxed structures for simulations in the presence of coarse-grained bilayers. I self-assembled multiple coarse-grained lipid bilayers to study the effects of the protofilament on multiple membrane environments.|Once we prepared both the protofilament and the model bilayer, I exposed the protofilament to the lipid environment. The simulations mimicked the protofilament in an environment similar to that found in the membrane of neurons in the central nervous system. We examined the thermodynamic interactions of the protofilament and the bilayer through molecular dynamics simulations to identify the mechanisms for toxicity.
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Publisher
Creighton University
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Copyright is retained by the Author.
A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.