Alageel, Amal (2024) Macromolecules For Protein Binding Using Dendrimer and Graphene Oxide. PhD thesis, University of Sheffield.
Abstract
This research explored non-covalently functionalized dendrimers and graphene oxide as macromolecular ligands for protein binding. Their structures were functionalized with amino acids to modulate protein recognition and binding.
Developing macromolecular ligands to target large protein-binding surfaces is a promising approach for inhibiting protein-protein interactions. Although covalently functionalized macromolecules have shown potential, challenges arise in their synthesis and the precise positioning of binding groups.
Consequently, this research explores dendrimers functionalized through non-covalent methods. Neutral PAMAM dendrimers, unable to bind α-chymotrypsin (Chy), were synthesized alongside a series of linear chains that could interact with the protein.
Originally, these chains were synthesized using a Boc protection strategy involving extensive aqueous workup, which led to low yields and purity. This thesis presents an improved Cbz protection method, eliminating aqueous workup to achieve excellent yields and high purity. Linear chains with tyrosine or valine were synthesized, with up to 6 encapsulated in a G3.5 hydroxyl ended dendrimer, while an additional 4 to 5 dissolved in bulk water. The resulting complexes were assessed for binding to cytochrome-c. For quantitative analysis, zinc-tetra(4-hydroxyphenyl) porphyrin (Zn-THPP) was
co-encapsulated as a quencher. Fluorescence titration revealed a dissociation constant (Kd) of 33 nM for the tyrosine-chain-encapsulated G3.5 dendrimer, while no binding was observed for the dendrimer alone or with valine chains.
The next part of this project explored a “dynamic” approach to protein binding by functionalizing graphene oxide through covalent and non-covalent methods. This involved synthesizing anthracenes modified with various amino acids. These were covalently added to GO via a Diels Alder reaction, with fixed functional group positions, limiting binding efficiency due to protein mobility constraints. Alternatively, anthracenes could non-covalently attach to GO using π-π interactions, allowing greater functional group mobility and maximum binding efficiency. Mixed covalent and non-covalent systems with different amino acids showed improved binding to chymotrypsin, highlighting benefits of diverse functionalization.
Metadata
Supervisors: | Dr.Lance J, Twyman |
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Keywords: | Protein Binding, Dendrimer, Graphene Oxide |
Awarding institution: | University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > Chemistry (Sheffield) The University of Sheffield > Faculty of Science (Sheffield) |
Depositing User: | Amal Alageel |
Date Deposited: | 28 Apr 2025 08:28 |
Last Modified: | 28 Apr 2025 08:28 |
Open Archives Initiative ID (OAI ID): | oai:etheses.whiterose.ac.uk:36672 |
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