Date of Award

12-31-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Applied Physics - (Ph.D.)

Department

Physics

First Advisor

Cristiano L. Dias

Second Advisor

Treena Livingston Arinzeh

Third Advisor

Edgardo Tabion Farinas

Fourth Advisor

Gordon A. Thomas

Fifth Advisor

Tao Zhou

Abstract

Compared to globular proteins that have a stable native structure, intrinsically disordered peptides (IDP) sample an ensemble of structures without folding into a native conformation.One example of IDP is the amyloid-beta(Abeta) protein which is the main constituent of senile plaques in the brain of Alzheimer's patients.Understanding the process by which IDPs undergo structural changes to form oligomers that eventually aggregate into senile plaques/amyloid fibrils may significantly advance the development of novel therapeutic methods to treat neurodegenerative diseases, for which there is no cure to date. This dissertation has two main objectives. The first one is to investigate and identify structural conformations of Abeta monomer which are precursor to aggregation. The second objective is to understand the underlying mechanisms of amyloid fibril stability using atomistic molecular dynamics simulations in explicit water.

The aggregation of Abeta peptides into amyloid fibrils in Alzheimer's patients depends on the spectrum of conformations adopted by monomers of this peptides. These conformations are strongly affected by properties of the aqueous environment. In the first part of this dissertation, conformations of Abeta in environments that promote and inhibit fibril formation are studied. Micro-second Replica Exchange Molecular Dynamics (REMD) simulations are performed for that purpose. A comparative study of the set of conformations in each environment is performed using contact maps, cluster analysis and by studying the network of the backbone hydrogen bonds of Abeta. A specific in-register strand-loop-strand conformation is found in the environment that promotes fibril formation, which is not observed in environments that inhibit fibril formation. It is proposed here that this conformation may act as intermediate structure in fibril formation. Inhibiting the formation of this conformation might be helpful in developing drugs for Alzheimer's disease.

In the second part of this dissertation, the molecular mechanisms of amyloid fibril stability are investigated using a thermodynamic framework. Understanding the atomic interactions responsible for fibril stability may be useful in designing novel therapeutic methods to disrupt fibrils and plaques in neurodegenerative diseases. However, despite numerous studies on amyloid fibrils, a thorough understanding of fibril stability is still missing. A combination of enhanced sampling methods is used to simulate all-atom models in explicit solvent in order to investigate the stability of non-polar (Abeta16-21) and polar (IAPP28-33) amyloid fibrils. Umbrella sampling is performed jointly with replica exchange molecular dynamics to determine the free energy of peptide addition to a pre-formed amyloid fibril at different temperatures.Results from these simulations show that the non-polar fibril becomes more stable with increasing temperature and its stability is dominated by entropy. In contrast, the polar fibril becomes less stable as temperature increases while it is stabilized by enthalpy. These findings suggest that the stability of fibrils can be customized by the choice of amino acid sequence in the dry core of the amyloid fibrils, e.g., proteins can be modified to transition between fibril and monomer state at a designated temperature. Such fine-tuned amyloid fibrils can be used as scaffolds for drug delivery and other biomaterials.

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