Lanphere, Conor Joshua;
(2021)
Controlling Assembly and Activity of Biomimetic DNA Nanopores.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Biological channels control the transport of vital biomolecular cargo across the cellular membrane. Reflecting the channels’ critical role, replicating their structure and improving on their function is of significant biomedical and scientific interest. However, de novo design of pores with the typical biological building material of polypeptides is challenging. DNA, by contrast, offers unrivalled structural control due to the simplicity and specificity of Watson-Crick base-pairing. Taking advantage of these properties, DNA membrane pores have been rationally designed with tuneable dimensions. The overall aim of this thesis is to advance on the simple barrel-like synthetic pores and create higher-order function to control pore formation and transport by means of exogenous triggers. The first aim of this thesis was the development of a model system to probe DNA hybridisation under steric constraints. By exploring the effect of DNA hybridisation under steric constraints, such as at membranes and on DNA nanostructures, greater insight was provided for the design of DNA nanopore that assemble in situ and respond to exogenous triggers. The second aim was to design a DNA nanopore that would mimic protein pore formation by undergoing triggered assembly. To transition the inactive pre-pore monomers to an active membrane-spanning oligomeric pore, the locked monomers can be unlocked in the presence of keys to trigger pore assembly. The pore advances functional DNA nanotechnology and synthetic biology by imparting targeted selectivity for pore activity and by serving as a synthetic mimic. The third aim was to build a DNA nanopore that functions as a synthetic protein-gate, allowing the transport of molecular cargo only in the presence of a target exogenous trigger. To function as a protein-gate, a DNA nanopore was designed with a lid featuring an aptamer sequence. In the rational designed structure, the binding of a target protein to the aptamer actuates the lid to open the pore into a transport-active state. A pore with such selective control could then be used in targeted drugdelivery.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Controlling Assembly and Activity of Biomimetic DNA Nanopores |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10138399 |
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