Self-replicating molecules catalyze multiple reactions

Three hallmarks of life are that it can replicate, metabolize molecules to build and power itself, and compartmentalize these different reactions. Sijbren Otto and coworkers at the University of Groningen now report a chemical system that can do simple versions of the first two. The work represents a step on the path to developing synthetic life.

The researchers started with a previously reported, synthetic, self-replicating system. The self-replicators in this system are made of hexameric macrocycles built from peptides containing an aromatic dithiol at one end.

These macrocycles stack on top of each other and assemble into fibers that continue growing as long as enough precursors are available to outrun any breakage in the chain. Like living systems, which can synthesize their own building blocks from simple starting materials, these self-replicators can make their own precursors by oxidizing the peptide’s aromatic dithiols to form disulfides that hold the macrocycles together.

To give the self-replicators this rudimentary metabolism, the researchers added photosensitive molecules, such as rose bengal or tetraphenylporphyrin, that bind to the macrocycle fibers and act as cofactors (Nat. Chem. 2020, DOI: 10.1038/s41557-020-0494-4). Exciting the cofactors with light leads to the production of singlet oxygen, which in turn leads to disulfide formation.

Otto and his team have also found that the same self-replicators can catalyze other chemistry such as a retro-aldol reaction and the cleavage of fluorenylmethoxycarbonyl (FMOC) groups (Nat. Catal. 2020, DOI: 10.1038/s41929-020-0463-8). “The FMOC cleavage was a chance discovery,” Otto says. “We were trying to do phosphodiester cleavage, and we happened to have FMOC on the substrate.”

The researchers are trying to find other reactions that the self-replicator can catalyze. They’re having limited success, but Otto is hopeful. “It would be very weird if we already had reached the limits, given that the things that they do are so different,” he says. The reactions found so far all use different mechanisms involving different amino acid side chains on the peptides, he notes.

“These papers describe systems that beautifully mimic, or capture, some of the properties of living systems,” says Wilhelm T. S. Huck, a chemist at Radboud University who is working on developing synthetic cells. “Are they steps towards a synthetic form of life? I guess this depends what definition of life you would like to use. If I compare these systems to the only life we know, even the most minimal cells are infinitely more complex.”

The next step is to get the system to catalyze the formation of compartments, Otto says. “We’re by no means there yet, but the ability to catalyze reactions suddenly opens up a path that might get us there.”