Molecular dynamics studies of Amyloid-β structural dynamics: Effects of pH, protonation states, and platinum (IV) complexes on aggregation behaviour

Alhabradi, Thuraya 2026. Molecular dynamics studies of Amyloid-β structural dynamics: Effects of pH, protonation states, and platinum (IV) complexes on aggregation behaviour. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder strongly associated with the misfolding and aggregation of amyloid-β (Aβ) peptides. The structural dynamics of Aβ are highly sensitive to environmental factors such as pH, protonation states of ionisable residues, and interactions with metal ions. This thesis presents a comprehensive computational investigation into the pH-dependent conformational behaviour and aggregation mechanisms of Aβ peptides, alongside the modulatory effects of platinum(IV) complexes. A multiscale computational approach was employed, integrating quantum mechanics (QM), molecular mechanics (MM), and molecular dynamics (MD) simulations. Theoretical foundations, including density functional theory (DFT), force field development, and constant pH methodologies, were used to accurately describe peptide systems and metal–ligand interactions. Extensive MD simulations were conducted using AMBER-based force fields under explicit and implicit solvent conditions, incorporating both classical and accelerated molecular dynamics (aMD), as well as constant-pH MD to capture protonation equilibria. The pH-dependent structural dynamics of Aβ systems were systematically explored across multiple aggregation states. Accelerated MD simulations of Aβ dimers revealed distinct conformational ensembles and stability profiles as a function of protonation state, highlighting the role of electrostatic interactions in dimer formation and dissociation. In trimer systems, histidine protonation was found to significantly influence structural compactness, intermolecular interactions, and secondary structure content. Constant-pH MD simulations of the Aβ monomer further demonstrated that subtle pH variations modulate conformational flexibility and solvent exposure, with implications for aggregation propensity. In addition, the interaction between Aβ peptides and platinum(IV) complexes was investigated to assess their potential as modulators of aggregation pathways. Molecular dynamics simulations and binding free energy calculations indicate that Pt(IV) complexes interact favourably with Aβ monomers and oligomers, altering peptide conformations and stabilising specific structural states. These interactions suggest a potential inhibitory effect on aggregation, supporting the metal-based therapeutic hypothesis. Overall, this work provides detailed molecular-level insight into the interplay between pH, protonation state, and metal complex interactions in governing Aβ structural dynamics and aggregation behaviour.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Chemistry Schools > Physical, Chemical & Environmental Sciences
Date of First Compliant Deposit:	4 September 2026
Last Modified:	04 Sep 2026 15:54
URI:	https://orca.cardiff.ac.uk/id/eprint/189406

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