Date of Award
5-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Physics and Astronomy
Committee Chair/Advisor
Feng Ding
Committee Member
Emil Alexov
Committee Member
Hugo Sanabria
Committee Member
Xian Lu
Abstract
The buildup of protein in tissues and organs plays a major role in unfunctional several serious diseases, including Alzheimer’s disease, Parkinson’s disease, and Type 2 diabetes, each tied to specific proteins that form harmful amyloid deposits. Amyloid aggregation typically follows a sigmoidal kinetic curve, beginning with a slow lag phase, followed by rapid fibril growth, and eventually reaching a plateau where mature, stable fibrils are formed. However, the early stage of aggregation remains particularly difficult to capture experimentally due to the highly dynamic nature and low abundance of small oligomeric species. In this dissertation, we employed discrete molecular dynamics (DMD) simulations to investigate these early aggregation events (Chapter 3-5) and provide molecular insights into the inhibition mechanisms of several amyloid aggregation inhibitors (Chapter 6-7).
Multiple studies have highlighted the connection between liquid–liquid phase separation (LLPS) and amyloid aggregation. Using a simplified coarse-grained model, we successfully captured the LLPS process and further demonstrated that the nanodroplet/oligomer morphology is influenced by the hydrophobic/hydrophilic distribution within peptide sequences. This published work offers valuable insight into how sequence features shape oligomer structures, providing a molecular foundation for understanding amyloidosis and guiding the development of peptide-based therapeutic strategies. Full details of this study are presented in Chapter 3.
Additionally, we employed all-atom simulations to investigate the early-stage assembly of two amyloidogenic Bri23 variants, ADan and ABri, which arise from mutations in the Bri2 gene. ADan and ABri are associated with amyloid deposits across the central nervous system and are linked to two rare familial dementias, familial Danish dementia and familial British dementia. Our simulations captured the formation of parallel in-register β-sheets—hallmarks of mature fibrils—within oligomeric intermediates. Notably, ADan formed longer β-sheets than ABri, suggesting a lower nucleation barrier and offering a possible explanation for the earlier onset of FDD compared to FBD. This study introduces a new criterion for evaluating amyloidogenicity: the ability to form extended parallel β-sheets during early aggregation. Full details are provided in Chapter 4.
While many amyloids such as Aβ and IAPP are associated with human diseases, the functional bacterial amyloid FapC from Pseudomonas aeruginosa also warrants attention. FapC plays a key role in bacterial biofilm formation, but growing evidence suggests it may exacerbate human conditions via the gut-brain axis following infection. Our study indicates that FapC can promote Aβ fibril formation, highlighting a potential link between bacterial infections and the progression of amyloid-related diseases. The full details of this published study are presented in Chapter 5.
Building on the above findings, a promising strategy to inhibit Pseudomonas aeruginosa bacterial activity focuses on disrupting extracellular connections between cells—specifically by preventing the aggregation of the functional bacterial amyloid FapC. One promising approach involves non-toxic silver nanoparticles and nanoclusters (AgNPs and AgNCs) capped with cationic branched polyethylenimine (bPEI), which have demonstrated antimicrobial potential by reducing FapC aggregation and disrupting biofilm formation. In this study, we employed discrete molecular dynamics (DMD) simulations to provide molecular insights into how nano silver particles prevent FapC from forming β-sheet-rich aggregates, thereby blocking fibril growth and subsequently reducing biofilm development. This published work is presented in detail in Chapter 6.
Although nano silver particles have shown effectiveness in inhibiting amyloid aggregation, their exogenous nature raises concerns about potential immune responses. As a result, the exploration of endogenous inhibitors remains an active area of research. A key example is the BRICHOS domain from the Bri2 gene, which has been experimentally demonstrated to delay Aβ and IAPP fibril formation even at low molar ratios. Our all-atom simulations revealed that the BRICHOS domain preferentially binds to the weakly populated fibril seeds rather than to amyloid monomers. When bound to a fibril seed, the BRICHOS domain tends to remain on the elongation surface, thereby preventing fibril extension by occupying unsaturated hydrogen donors and acceptors. The ability of BRICHOS to inhibit multiple amyloids highlights its potential as a therapeutic candidate. This work has been published and the details are provided in Chapter 7.
Together, these investigations provide a comprehensive view of amyloid formation and potential strategies to prevent aggregation. They span the liquid–liquid phase separation, nucleation dynamics, human amyloid interactions with bacterial amyloids, and both exogenous (nano silver particles) and endogenous (BRICHOS domain) approaches to inhibiting fibril growth. These insights contribute to a deeper understanding of amyloid-related diseases and offer promising directions for therapeutic development.
Recommended Citation
Zhang, Zhenzhen, "Amyloid Aggregation and Mitigation" (2025). All Dissertations. 3955.
https://open.clemson.edu/all_dissertations/3955
Author ORCID Identifier
0009-0009-5756-3027