Exploring the influence of ph and metal zinc(ii) ion trends on interactions amongst amyloid-β and amylin peptides

Jilani, Oneeb 2025. Exploring the influence of ph and metal zinc(ii) ion trends on interactions amongst amyloid-β and amylin peptides. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The tendency of Aβ to self-assemble into β-rich aggregates is central to the pathology of Alzheimer’s disease. This thesis uses constant-pH molecular dynamics to investigate how protonation equilibria, electrostatics, and zinc coordination jointly influence the structure and oligomerization of Aβ40, amylin, and their mixed assemblies under near-physiological conditions at the nucleation stage. Testing upon a truncated Aβ16 fragment helped validate the implicit-solvent CpHMD approach and identified the pH conditions under which its behaviour best mimics that of full-length Aβ40. Extending the simulations to Aβ40 and amylin monomers at pH 6–8 showed that partial histidine protonation stabilises compact, β-enriched conformations in Aβ40, whereas amylin remains more conformationally flexible and predominantly helix/turn-rich, with both peptides retaining signatures of intrinsic disorder. Building upon this, large ensembles of dimers and trimers were generated for Aβ40 homomers - which consistently formed more β-structured and compact interfaces, and amylin homomers - which adopted semi-ordered but more flexible architectures. Mixed Aβ–amylin dimers adopted the structural patterns of the leading peptide i.e Aβ–led oligomers had greater β sheets and vice versa. The heterodimers produced cooperative but poor intermediates, in which amylin dampens excessive β structuring by Aβ, whereas trimeric assemblies marked the first point at which consistent, aggregation-competent β-core architectures appeared, largely independent of initial peptide orientation. Finally, Zn(II) coordination was examined in Aβ40 homodimers – to validate native-like compactness and β-content of unprotonated structures, particularly near His13 and Aβ40–amylin heterodimers – to highlight changes in local protonation and charge distribution, weakening β-sheets and favouring more helical, moderately flexible conformations, particularly in dual metal systems. These results indicate that early Aβ–amylin co-aggregation, and its modulation by Zn(II), is controlled by a subtle balance between protonation state, electrostatics, and metal coordination, providing atomistic insight into the earliest nucleation events that link Alzheimer’s disease with metabolic dysfunction.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Chemistry
Date of First Compliant Deposit:	9 March 2026
Last Modified:	10 Mar 2026 10:14
URI:	https://orca.cardiff.ac.uk/id/eprint/185627

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