Amyloidogenic diseases, such as Alzheimer's disease (AD) and Type II Diabetes (T2D), are characterized by the accumulation of amyloid aggregates. Despite having very different amino-acid sequences, the underlying amyloidogenic proteins form similar supramolecular fibril structures that are highly stable and resistant to physical and chemical denaturation. AD is characterized by two toxic lesions: extracellular amyloid β-peptide (Aβ) plaques and intracellular neurofibrillary tangles composed of microtubule-associated protein tau. Similarly, a feature of T2D is the deposition of islet amyloid polypeptide (IAPP) aggregates in and around the pancreas. The mechanisms by which Aβ, tau, and IAPP aggregate, and cause cell death is unknown; thus, gaining greater insight into the stabilizing forces and initial unfolding events is crucial to our understanding of these amyloidogenic diseases. This work uses molecular dynamics (MD) simulations to study the secondary, tertiary, and quaternary structure of Aβ, tau, and IAPP. Specifically, this work used the Drude polarizable force field (FF), which explicitly represents electronic polarization allowing charge distributions to change in response to perturbations in local electric fields. This model allows us to describe the role charge plays on protein folding and stability and how perturbations to the charge state drive pathology. Studies were conducted to address the following questions: 1) What are the stabilizing forces of fibril and oligomeric structures? 2) How do charge-altering mutations modulate the conformational ensemble and thermodynamic properties of Aβ? 3) How do charge-altering post-translational modifications of Aβ and tau modulate changes in the conformational ensembles? These studies establish that shifts in local microenvironments play a role in fibril and oligomer stability. Furthermore, these studies found that changes in protein sequence and charge are sufficient to disrupt and change the secondary and tertiary structure of these amyloidogenic proteins. Overall, this dissertation describes how charge modulates protein unfolding and characterizes the mechanism of those changes. In the long term, this work will help in the development of therapeutics that can target these changes to prevent protein aggregation that leads to cell death. / Doctor of Philosophy / Protein aggregation is the hallmark of many chronic diseases, such as Alzheimer's disease (AD) and Type II Diabetes (T2D). The formation of two toxic aggregates: amyloid β-peptide (Aβ) plaques and neurofibrillary tangles composed of microtubule-associated protein tau are some of the key characteristics of AD. In addition, the formation of islet amyloid polypeptide (IAPP) aggregates in the pancreas is thought to play a role in the development of T2D. The pathways by which the proteins Aβ, tau, and IAPP aggregate are unknown; thus, gaining a greater insight into the properties that may cause these diseases is necessary to develop treatments. By studying these proteins at the atomistic level, we can understand how small changes to these proteins alter how they misfold in a way that promotes toxicity. Herein, we used a computational technique called molecular dynamics (MD) simulations to gain new insights into how protein structure changes. We explored the dynamics of these proteins and investigated the role that charge plays in protein folding and described how charge modulates protein folding and characterized the mechanism of those changes. This work serves as a characterization of protein folding and sets the ground for future structural studies and drug development.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/109669 |
| Date | 14 April 2022 |
| Creators | Davidson, Darcy Shanley |
| Contributors | Biochemistry, Lemkul, Justin A., Brown, Anne M., Slade, Daniel J., Helm, Richard F. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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