Computational examination of biomolecular systems related to Alzheimer’s and Parkinson’s diseases

Savva, Loizos 2023. Computational examination of biomolecular systems related to Alzheimer’s and Parkinson’s diseases. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The aggregation of proteins has long been implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, through their deposition in amyloid plaques and Lewy bodies. The interaction of metal ions with these proteins has attracted signif- icant attention due to their potential role in accelerating protein aggregation and neurotoxicity. In this thesis, Amyloid-β (Aβ) and α-Synuclein (αS) were studied using molecular dynamics (MD), to investigate the effect of metal ions on their structure and folding. Given the wide array of force fields available, the first part of this thesis focused on the evaluation of force fields and solvent models in simulating the average structure of Aβ16 in complexation with Zn(II), derived from an NMR study. The parameterisation of the metal ion and coordinating atoms was performed using quantum mechanic (QM) calculations on the metal-binding site (His6, His13, His14, Glu11), and incorporated into the force field to allow for the description of the metal ion and coordinating residues. The conformational landscape explored during the MD was expanded using accelerated MD (aMD), through the introduction of an energy bias to permit the crossing of energy barriers. The simulations revealed the ff14SB force field with the GBSA implicit solvent model to be the most accurate in reproducing the experimental structure. The parameterisation described above was thus applied to a more disordered system, look- ing at the coordination of Cu(II) to αS. The simulations revealed that the force field was less ideal in reproducing the experimental characteristics of the protein, with better representation instead coming from ff03ws with the OBC continuum model. The aMD simulations revealed that the Cu(II) coordination to αS increased the stability of β-hairpins, while decreasing the N-terminal helical content, which has the potential to increase the rate of secondary nucleation. The Cu(I) coordination to αS was also investigated, due to the copper ions’ interconversion during the catalytic release of reactive oxygen species. The system’s average structure was suggestive of an intermediary state between the Cu(II) and apo forms. Following that, a differ- ent way of simulating the metal ion was implemented, through the use of cationic dummy atom models, eliminating the need for pre-defined bonded interactions with the coordinating atoms. This allowed the calculation of relative binding affinities to the metal ion. The model was also applied to study the αS-dimer in the presence and absence of Cu(II). The simulations on these systems, suggests the metal ion is a stabilising factor in the aggregation of αS, facilitating the formation of β-strand interlinkages between the chains. The last part of this thesis, looked at two of the modifications often described in PD patients, in particular the phosphorylation at S129 (pS129) and the A53T mutation. The former systems suggested a protective effect to the aggregation of the protein, while the A53T mutation, espe- cially in the case of the Cu(II)-bound system, presented longer-lasting β-characteristics, which could be indicative of a more stable aggregation with other peptides. Taken together, the results provide an understanding of the structural changes elicited by the association of these metal ions with the proteins, along with their influence on the aggregation process.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Chemistry
Date of First Compliant Deposit:	12 December 2023
Last Modified:	12 Dec 2023 16:41
URI:	https://orca.cardiff.ac.uk/id/eprint/164734

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