"Self-replicating molecules have most likely played an important role in the origin of life. This proposal explores the use of dynamic combinatorial chemistry for identifying new self-replicating molecules. We will make dynamic combinatorial libraries of macrocyclic molecules of different ring sizes that can exchange building blocks through reversible covalent chemistry. The building blocks are equipped with peptides that are predisposed to form beta-sheets. The building blocks, which carry only one peptide, do not self-associate, while sufficiently large macrocycles, which display multiple peptides, will self-assemble into extended tubular structures.
The self-assembly process will drive the synthesis of the very macrocycle that assembles by shifting the equilibrium in favour of its formation. There is also a kinetic effect: the ends of the resulting fibres promote the formation of more of the constituent macrocycles. Breaking fibres through agitation is an efficient way of generating more fibre ends, which allows for exponential growth of the replicator. The dependence of growth on mechanical energy translates into a selection criterion when multiple replicators compete for the same building block. The replicator that forms fibres that fragment most readily under a given set of agitation conditions will win.
We have already identified the first building block that shows the behaviour described above. We now propose to investigate in detail:
(1) The mechanism of replication. We aim to find out what exactly happens at the molecular level at the fibre end during fibre growth.
(2) The influence of the peptide sequence and aromatic core of the building blocks. We expect to be able to tune the size of the replicating macrocycle by altering the strength of the interactions between the peptides.
(3) The competition between replicators in an ""open system""; i.e. with a continuous influx of building block and ""death"" of some of the replicators through an outflux of a fraction"
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