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Abstract
Neurodegenerative diseases threaten human life expectancy, and their pathology remains unclear. These diseases share in-common features that distinctive secondary structural changes are often recognizable along with protein aggregations, which can be used to define whether a lesion has occurred. However, it is difficult to observe the dynamic process by traditional biological methods. In this dissertation, computational approaches are used to model the denaturation of crucial proteins in neurodegenerative diseases and examine different hypotheses with their supporting evidence. Evidence about certain neurodegenerative diseases was validated by representing the structural changes of those features. Alzheimer's disease and human prion diseases are the main subjects of study, and the initial stages of their protein misfolding are simulated and revealed.For Alzheimer's disease, we identified the possibility of endogenous factors that induce misfolding by building a model only containing Amyloid beta (Aβ) peptides and revealing their misfolding process. The Molecular Dynamic (MD) simulations of the Aβ dimers show a misfolding transmission process between a normal Aβ and a misfolded Aβ; misfolding usually starts with I32- L34. Miquelianin was virtually screened out from the drug database as an inhibitor candidate that can prohibit the formation of the beta sheets. Heparin was identified as a stabilizer for maintaining the parallel polymer structure. With heparin in the system, the parallel structure of Aβ will not be disrupted in the MD simulation, which may cause fibrillation Aβ. The electrical charge on the Aβ surface in different pH reveals the active site of Aβ to receive other ligands. Moreover, an exogenous factor that triggers misfolding was also discovered. Herpes Simplex Virus type 1(HSV-1) glycoprotein B was identified as an etiological agent.
Structure prediction algorithms were applied for human prion disease to generate the N- terminus of the whole protein sequence. The formation of beta sheets 129M-130L and 162Y-163Y was regarded as a sign of the start of a misfolding. The predicted structural models reveal that the differences in spatial location between the N-terminus and the primary domain of prion protein may determine whether the misfolding starts. A new misfolding process of prion is proposed based on the simulation results and previous study.