Rational Engineering of Synthetic Systems for Propagation of Information via Catalytic Assembly of Copies

Copying of information-bearing polymer templates is vital to life. The central dogma of molecular biology describes how a sequence of nucleotides in DNA is copied into a sequence of nucleotides in a newly-assembled RNA polymer, and then into a sequence of amino acids in a protein. These processes involve sophisticated machinery in extant organisms, but even the ribosome is bound by the same physical principles as simpler systems that must have operated in early life. Despite the fundamental importance of copying, and its potential for the engineering of complex molecular systems, we do not understand these basic principles that enable accurate and reliable copies to be made of polymer templates, and cannot build minimal synthetic copying systems.I propose to explore minimal models of copying, leveraging recent advances in the thermodynamics of small, fluctuating systems and the thermodynamics of information processing, to identify these principles. I will translate this insight, via detailed molecular simulation and experimental characterisation of novel reaction motifs, into the construction of minimal synthetic copying systems. I will construct these systems from non-biological synthetic DNA.The project will provide insight into analogous processes in living organisms, and shed light on primitive living systems. It will also lay the groundwork for engineering synthetic systems with key cell-like functionalities, providing a mechanism for the production of complex assemblies that is fundamentally distinct from traditional self-assembly. 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.