Kinetic selection in the out-of-equilibrium autocatalytic reaction networks that produce macrocyclic peptides.

Autocatalytic reaction networks are instrumental for validating scenarios for the emergence of life on Earth and for synthesizing life de novo . It is well understood how the selection of specific molecules occurs in reaction networks driven by template-assisted ligation; however how selection could occur in strongly interconnected, nonselective, autocatalytic networks is less clear. Here, we demonstrate that dimeric thioesters of tripeptides with the general structure (Cys-Xxx-Gly-SR) 2 form strongly interconnected autocatalytic reaction networks that predominantly generate macrocyclic peptides up to 69 amino acids long. Some macrocycles of 6-12 amino acids were isolated from the product pool and were characterized by NMR spectroscopy and single-crystal X-ray analysis. We studied the autocatalytic formation of macrocycles in a flow reactor in the presence of acrylamide, whose conjugate addition to thiols served as a model "removal" reaction. These results indicate that autocatalytic production and competing removal of molecular species in an open compartment could be a feasible route for selecting functional molecules during the pre-Darwinian stages of molecular evolution.