Theses

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Included in the Research Theses collection are Masters, PHD and Professional Doctorate theses.
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Browsing Theses by Advisors "Abell, Andrew D."

Now showing 1 - 3 of 3
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    Advanced Engineering of Nanoporous Anodic Alumina Photonic Crystals for Optical Sensing Applications
    (2019) Law, Cheryl Suwen; Santos, Abel; Abell, Andrew D.; School of Chemical Engineering
    Conventional analytical systems have intrinsic limitations that restrict their applicability, including high costs, bulkiness, time-consuming processing, and require highly trained personnel. This triggers an increasing demand of optical sensing technologies that can address these limitations, while offering enhanced sensing capabilities over benchmark analytical techniques. Current progress in nanotechnology is enabling development of rapid, sensitive, user-friendly, and cost-competitive optical sensors integrated into lab-on-a-chip platforms with broad applicability across different disciplines, including medicinal, industrial and environmental applications. This thesis presents the development of cutting-edge optical sensing systems based on the combination of nanoporous anodic alumina photonic crystals (NAA-PCs) and reflectometric interference spectroscopy (RIfS). Fundamental and applied advances of the proposed sensing systems towards ultrasensitive and selective detection of target analytes are achieved through rational structural engineering of NAA-PCs and surface chemistry architectures. A collection of NAA-PCs was generated by innovative pulse-like anodisation methods aimed at engineering the optical properties of these photonic crystals to harness light–matter interactions at the nanoscale. The sensing characteristics of these optical sensing systems in terms of selectivity and sensitivity were further optimised by engineering the surface chemistry architecture of NAA-PC platforms with multiple functional molecules. The sensitivity and reliability of the proposed sensing systems were demonstrated through real-time detection of heavy metal ions (i.e. gold (III) and mercury (II) ions) and other analytes. The work completed in this thesis advances both fundamental understanding and applied knowledge on the sensing performance of NAA-PCs with optimised geometrical, chemical and optical properties integrated with RIfS, pushing the boundaries of science a step closer to fully functional and marketable analytical tools for real-life medical, environmental, industrial and defence applications.
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    Advanced Photonic Crystals for Efficient Light-Trapping in Photocatalytic Applications
    (2020) Lim, Siew Yee; Santos, Abel; Abell, Andrew D.; School of Chemical Engineering and Advanced Materials
    Despite advances in solar technologies, there is still a growing and urgent demand for light-harnessing materials that enable efficient utilisation of solar energy for solar-to-fuel conversion and environmental remediation applications. Existing photocatalytic technologies present inherent limitations to achieve these goals due to wide energy bandgap and poor electrochemical properties of conventional materials. A combination of fundamental and applied materials science, nanotechnology, chemistry, photonics and applied physics offers a way forward for developing new light-confining photocatalyst platforms with improved capabilities, versatilities, cost-effectiveness and sustainability to address global energy and environmental issues. This thesis presents the development of rationally engineered composite photocatalyst platforms based on nanoporous anodic alumina photonic crystals (NAA-PCs) and photoactive materials. The fabrication of these photocatalytic systems with enhanced performances is achieved through structural engineering and chemical modification of NAA-PCs. Various forms of NAA-PCs were produced by pulse-like anodisation strategies with a view to optimising optical properties to harness light–matter interactions at the nanoscale efficiently, within high-irradiance spectral regions. The essential photocatalytic properties of these PC structures, well-defined energy bandgap capable of photogeneration of charge carriers, were provided by chemical functionalisation, using photoactive layers of titanium dioxide (TiO₂) deposited onto the inner surface of NAA-PCs through sol-gel method. Photocatalytic performances of photo-active NAA-PCs as well as photocatalytic enhancements associated with distinct forms of light–matter interactions were demonstrated through photodegradation of model organics such as methylene blue, methyl orange, rhodamine B and 4-chlorophenol, under simulated solar light irradiation conditions. Photocatalytic enhancements associated with slow photons, light confinement, and plasmonic effects in noble metal nanostructures with and without NAA-PCs were also analysed. This thesis demonstrated that: (i) high-quality nanoporous anodic alumina gradient-index filters (NAA-GIFs) and hybrid NAA-PCs can be developed with tunable optical properties across the UV-visible-NIR spectrum, (ii) various forms of photo-active NAA-PCs with and without noble metal nanostructures are found to have superior performances to benchmark photocatalyst materials in many cases due to “slow photon” effect and light confinement, and (iii) 2D gold nanodot plasmonic single-lattices show outstanding performances due to efficient utilisation of solar energy at high-irradiance spectral regions and harnessing plasmonic light-matter interactions. The studies completed in this thesis advance both fundamental understanding and applied knowledge on the photocatalytic performance of chemically-modified NAA-PCs with optimised structural, optical, chemical and photocatalytic properties. These advanced materials could potentially be integrated into fully functional and marketable real-life photocatalytic devices for addressing global energy challenges and environmental pollution remediation.
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    Approaches to study protein interactions
    (2021) Horsfall, Aimee Jade; Abell, Andrew D.; Bruning, John B.; School of Physical Sciences : Chemistry
    This thesis presents studies on series of modified peptides to study protein-protein interactions. Specifically, the use of new fluorescent peptide modifications to influence secondary structure and secondly, development of a peptidomimetic scaffold to target Proliferating Cell Nuclear Antigen (PCNA). Chapter 1 introduces the importance of protein-protein interactions, their role in disease, and the difficulty in targeting these large-surface-area interactions. Peptides present as an ideal compromise between the large size of proteins and the drug-like properties of small molecules, to study such interactions. The importance of secondary structure and methods to stabilise a conformation favourable to binding specific proteins are outlined in order to address limitations associated with the use of peptides as therapeutics. Methods used to prepare such peptides, and determine the resulting conformations are outlined, along descriptions of techniques to characterise biological activity of peptides and their interaction with proteins. Chapter 2 details studies on the synthesis of peptide macrocycles that are constrained by a bimane group that covalently links two cysteine residues. The methodology allows preparation of nine macrocycles that range in size from 16 to 31 atoms. These peptides are cell permeable, where blue fluorescence corresponding to the bimane is present in the cell cytosol. CD and NMR secondary shift analysis revealed that the i-i+4 bimane-constrained pentapeptide is α-helical. Chapter 3 extends the investigation presented in Chapter 2 and demonstrates the i-i+4 bimane constraint introduces 310-helical structure into a 12 amino-acid sequence known to target Estrogen Receptor alpha (ERα). This same peptide adopts an α-helical geometry in the presence of 20% TFE, and when the peptide is bound to ERα as shown by computational modelling. This demonstrates sufficient flexibility in the bimane-constrained macrocycles to adopt α-helical conformation. Interestingly, helical structure is also adopted in acyclic peptides, where a bimane-modified cysteine is six amino-acids away from a tryptophan or phenylalanine residue. The fluorescence properties of the bimane-modified peptides are also presented. The methodology to introduce the bimane constraint into peptides and define helical structure is summarised in a mini-review-style Focus article in Appendix 1. Chapter 4 reviews the structure-activity relationship of peptides and molecules that bind PCNA, and summarises the current knowledge of features that allow specific and high affinity interaction with PCNA. Chapter 5 presents a series of 51 modified p21-derived peptides (141-155) with sequence modifications to the PCNA-interacting motif (known as the PIP-box). SPR analysis identified seven peptides that bind PCNA with higher affinity than the native p21 sequence (12.3 nM). The PCNA-binding affinity was correlated to the binding conformation of these peptides bound to PCNA, as studied by X-ray crystallography and computational modelling, and highlights a series of important hydrogen bonding networks that modulate PCNA binding affinity. Collectively, these data elucidate the rational design of a new PCNA-binding peptide that binds with the highest affinity reported to date (1.21 nM). A series of five macrocyclic p21 peptides is presented in Chapter 6, where a range of covalent constraints were installed by dithiol bis-alkylation in a p21 peptide (143-154) containing two cysteines at positions 146 and 149. The binding affinity of the resulting i-i+4 constrained macrocycles for PCNA was determined by SPR to reveal the bimane-constrained p21 peptide as the most potent at 570 nM. The secondary structure adopted by the macrocycles bound to PCNA was studied by X-ray crystallography and computational modelling, and indicated that the bimane-constrained peptides are the only macrocycle to adopt the key 310-helical binding conformation. Additionally, the bimane peptide was cell permeable, in comparison to a linear fluorescein-tagged p21 peptide of the same length, where confocal microscopy revealed blue fluorescence corresponding to the bimane in the cell cytosol. Chapter 7 examines the role of the peptide sequence flanking PCNA-binding motif of the p21 peptide, and reveals that a short p21 peptide of 12 amino-acids (143-154) can bind PCNA with 102 nM affinity. These short p21 peptides, however, are not cell permeable and a series of nuclear locating sequence (NLS)-tags were appended to a p21 peptide in an endeavour to improve cell and nuclear uptake, but were unsuccessful. Albeit, nuclear permeability was achieved when the NLS-tags were instead appended to the macrocyclic p21 bimane-constrained peptide presented in Chapter 6. Only the bimane-constrained p21 macrocycle appended to a SV40 NLS-tag via a thiol-maleimide linkage was nuclear permeable. Interestingly, nuclear entry was only permitted when a fluorescein was coupled to the N-terminus of the SV40-tag. Chapter 8 explores the use of solvatochromic amino-acids in a p21 sequence (141-155), at the positions known to insert into the hydrophobic cleft on the PCNA surface (147, 150 and 151), to determine whether a peptide could be utilised as a selective turn-on fluorescent PCNA sensor. Two different solvatochromic amino-acids were utilised, 4-DMNA and 4-DMAP, and the fluorescence properties and affinity of the six resulting peptides for PCNA was characterised. This revealed that only the peptides with 4-DMNA or 4-DMAP at position 150 maintained high affinity binding to PCNA. A 10-fold increase in fluorescence intensity, relative to the peptide alone, was achieved in the presence of 2.5 equivalents of PCNA for the 151-substituted 4-DMNA peptide. The 151-substituted 4-DMAP peptide only produced a 3.5-fold change in fluorescence under the same conditions. Chapter 9 provides an overall summary of this thesis, including the methodology to introduce a bimane modification into short peptides and the optimal configurations to introduce helical structure. It also details key mutations presented in Chapter 5 to improve binding affinity of peptides for PCNA, along with the importance of stabilising a 310-helical binding conformation (Chapter 6). Chapter 9 presents a new series of nine i-i+4 constrained macrocyclic peptidomimetics that include the high affinity sequence modifications, in order to consolidate these distinct achievements. The binding affinity of these macrocycles for PCNA, and corresponding linear analogues, was determined by SPR and revealed that in all except for one case, the binding affinity of the macrocycle was greater than the linear analogue. The position of a polar group (e.g. amide or acyl thioether) in asymmetric constraints alters PCNA binding affinity, where higher affinity for PCNA was observed when the polar group is nearer the C-terminal end of the constraint. The most potent peptide of this series is a Lys/Glu lactam macrocycle which binds PCNA with 8.16 nM affinity, the highest affinity peptidomimetic that binds PCNA to date. Finally, this chapter outlines future directions to build on this work and develop a peptidomimetic that targets PCNA for application as a cancer therapeutic.