Periodic Reporting for period 3 - RESSPICAC (Rational Engineering of Synthetic Systems for Propagation of Information via Catalytic Assembly of Copies)
Reporting period: 2022-11-01 to 2024-04-30
In this project, my team will explore minimal theoretical models of copying, leveraging recent advances in the thermodynamics of small, fluctuating systems and the thermodynamics of information processing, to identify the aforementioned underlying principles. We will then translate this insight, via detailed molecular simulation and experimental characterisation of novel reaction motifs, into the construction of minimal synthetic copying systems.
The project will provide insight into analogous copying processes in living organisms, and shed light on primitive living systems. It will also lay the groundwork for engineering synthetic systems with this key cell-like ability, a step on the road to building synthetic living systems. Additionally, it will be a first step towards using synthetic copying outside of living sytems to produce novel chemicals. Theory and simulation will drive the experiments, making rational design of systems possible whilst providing insight into the fundamental thermodynamics of information processing and computation, and the biophysics of novel nucleic acid interactions. Indeed, designing and building concrete molecular systems based on fundamental theory will enhance our understanding of the theories themselves.
Alongside this experimental work, we have been conducting theory and simulation to guide the next steps of the project. We have simulated the HMSD motif, identifying important differences in the underlying process from similar motifs in DNA nanotechnology [manuscript in preparation]. As part of this process, we produced an extensive review on how the coarse-grained model oxDNA can be used as a simulation tool [A. Sengar et al., Front. Mol. Biosci. 2021]. We have also developed a general theoretical framework that allows us to analyse models of complex molecular copying processes in a much more efficient way than was previously possible [Presented at the 3rd Workshop on Stochastic Thermodynamics (2022) by B. Qureshi, manuscript in preparation].
From now until the end of the project, we expect the following results.
- Completion and publication of the sub-projects noted above, especially: demonstration of dimer copying using HMSD; the first demonstration of kinetic proofreading in a synthetic context; the development of a framework for efficient analysis of complex models of polymer copying; and the detailed molecular simulation of the HMSD process.
- Application of the intial results of the project to demonstrate copying of templates of length 3, 4 and possibly longer.
- Further theoretical/simulation insight into the key features of successful copying processes, in particular the use of HMSD in more complex settings and the adaptation of our theoretical framework to short molecules.
- A modification of the HMSD mechanism to allow it to act as the core of a self-replicating system. Self-replication is a type of copying in which the product can itself act as a template for the production of more templates.