The presence of self-assembled protein aggregates known as Amyloid fibrils are associated with an increasing number of human conditions such as type-II Diabetes, Parkinson’s, Huntington’s and Alzheimer’s disease. A link has been made between the fragility of these normally robust structures and an enhancement of their toxic effects. This highlights a need for a firm understanding of the factors that govern their mechanical properties if effective therapeutic strategies are to be developed. The main aims of this thesis are to probe, at a molecular level, the key interactions that contribute to the mechanical stability generically exhibited by amyloid fibril systems and then explore ways in which these may be modulated. A variety of atomistic detailed fibrils are computationally mod- elled and then subjected to molecular dynamics steering forces from a variety of directions that characterise their fragmentation through disruption of the stabilising interactions. This work focuses on models of proto-fibrils associated with type-II Diabetes and mature fibres linked with Alzheimer’s disease. Three separate investigations were undertaken to examine firstly the role played by the peptide sequence in mechanical resistance, then ways of modulating mechanical failure in polymorphic fibril arrangements and finally the mechanical effects of heterologous cross-seed interfaces. The presence of structural defects in the otherwise highly ordered protein aggregates were consistently found to be able to dominate the overall mechanical characteristics of the fibrils. The results of the simulations give further insights into the fracture mechanisms as well as have wider implications for both therapeutic and potential nano-technological applications.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:581712 |
| Date | January 2013 |
| Creators | Ndlovu, Hlengisizwe |
| Contributors | Ashcroft, A. ; Radford, S. ; Harris, S. |
| Publisher | University of Leeds |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.whiterose.ac.uk/4592/ |
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