A computational study of interactions between amyloid-β and transition metals via molecular dynamics

Kennedy-Britten, Oliver 2022. A computational study of interactions between amyloid-β and transition metals via molecular dynamics. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The aggregational properties of Aβ are crucial in understanding the causes of the neurodegenerative Alzheimer’s disease. Coordination of transition metal centres to these peptides have been shown to have differing effects on the mechanism and rate of aggregation of Aβ into characteristic neurotoxic deposits. Within this work, the interaction of Aβ alloforms and various metal ions are investigated computationally via use of molecular dynamics. Initially, genetic mutations of truncated N-terminus Aβ peptides were bound to Cu(II) to replicate effects of metal coordination on the full-length structure compared to wild-type unaltered Aβ. This study showed effects of these variants were marked and varied affecting secondary structure, stability and conformations adapted. Some mutants showed more consistent compact conformations whereas some formed more flexible structures. Contrasts between comparable mutations at similar sites, such as A2T/A2V and D7H/D7N, show the location as well as the type of mutation have effects on protein structure. Notable changes in peptide structure at residues remote to the site of substitution showed these mutations influence the entirety of Aβ. Effects on secondary structure differ between mutations, most notably a change in incidence of β-strand, which has been linked to enhanced aggregational properties for the peptide. Next, accelerated molecular dynamics (aMD) simulations of four different lengths of Aβ and their complexes when bound to Cu(II), Fe(II), or Zn(II) were reported. The presence of a metal ion leads to reduced size and decreased mobility relative to the free peptide due to the anchoring effect of the ions. The reduced mobility was shown largely to be due to the restricted movement in N-terminal residues, most notably Asp1 and His6 that are involved in the metal-ion coordination in all cases. Similarities were noted between results for Zn(II) and Fe(II), whereas results for Cu(II) are more comparable to that of the free peptides. Finally, dimers of full-length Aβ42 were simulated via aMD, with free structures compared to those connected via a Zn(II) bridge. The zinc-bound structures adopted more compact configurations shown via Rg, SASA and cluster data compared to the free Aβ dimers. Differences in secondary structures were observed with free dimers forming higher frequencies of helical structures, compared to zinc-bound dimers. The metal-ion bridge between monomers allowed greater amounts of intermolecular interactions than those seen in the free Aβ, meaning inferences can be made on its propensity for enhanced aggregation.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Chemistry
Date of First Compliant Deposit:	9 January 2023
Last Modified:	10 Jan 2023 12:14
URI:	https://orca.cardiff.ac.uk/id/eprint/155570

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