Minimal molecular mechanisms for autonomous template copying
File(s)
Author(s)
Juritz, Jordan
Type
Thesis
Abstract
In this thesis, I develop models of chemical reactions in which a template copolymer directs the synthesis of new copolymers (copies). I use the models to inform the design of synthetic analogues of the information-copying molecular machines found in nature.
Template copying processes, like DNA replication, transcription, and translation, are the basis of living systems’ ability to produce, maintain and evolve a diverse set of complex biomolecules using a small set of molecular building blocks. Biological copying processes can operate in constant environments driven by chemical fuel molecules and typically use each template many times over, as the copies eventually separate. To date, no synthetic systems have been created that can achieve the same feat under the same ``life-like’’ conditions. Experimental attempts have been hindered by product inhibition, the tendency for long copies to bind to the template instead of spontaneously separating. Furthermore, few theoretical models have considered the effects of the separation of copies from the templates or the effects of product inhibition on the copy-length distributions.
In Chapter 2, I identify a lack of suitable metrics to compare template copying reactions, and argue that, if we are to build them, the time-averaged turnover frequency (TATF) - a measure of the average copy production rate per unit template - should serve this purpose.
The patterns of product inhibition are more complex on longer templates. In Chapter 3, I present a coarse-grained stochastic simulation of copolymerisation on a finite-length template and use it to identify reaction mechanisms that could overcome product inhibition.
In Chapter 4, I explore how the mechanisms identified in Chapter 3 should be implemented in a model system, a DNA strand-displacement reaction network. Through simulation, I identify optimal designs to characterise experimentally.
Template copying processes, like DNA replication, transcription, and translation, are the basis of living systems’ ability to produce, maintain and evolve a diverse set of complex biomolecules using a small set of molecular building blocks. Biological copying processes can operate in constant environments driven by chemical fuel molecules and typically use each template many times over, as the copies eventually separate. To date, no synthetic systems have been created that can achieve the same feat under the same ``life-like’’ conditions. Experimental attempts have been hindered by product inhibition, the tendency for long copies to bind to the template instead of spontaneously separating. Furthermore, few theoretical models have considered the effects of the separation of copies from the templates or the effects of product inhibition on the copy-length distributions.
In Chapter 2, I identify a lack of suitable metrics to compare template copying reactions, and argue that, if we are to build them, the time-averaged turnover frequency (TATF) - a measure of the average copy production rate per unit template - should serve this purpose.
The patterns of product inhibition are more complex on longer templates. In Chapter 3, I present a coarse-grained stochastic simulation of copolymerisation on a finite-length template and use it to identify reaction mechanisms that could overcome product inhibition.
In Chapter 4, I explore how the mechanisms identified in Chapter 3 should be implemented in a model system, a DNA strand-displacement reaction network. Through simulation, I identify optimal designs to characterise experimentally.
Version
Open Access
Date Issued
2023-04
Date Awarded
2024-05
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Ouldridge, Thomas
Sponsor
Royal Society (Great Britain)
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)