Prebiotically Plausible Activation Chemistry Compatible with Nonenzymatic RNA Copying

ABSTRACT The nonenzymatic replication of ribonucleic acid (RNA) oligonucleotides may have enabled the propagation of genetic information during the origin of life. RNA copying can be initiated in the laboratory with chemically activated nucleotides, but continued copying requires a source of chemical energy for in situ nucleotide activation. Recent work has illuminated a potentially prebiotic cyanosulfidic chemistry that activates nucleotides, but its application to nonenzymatic RNA copying remains a challenge. Here we report a novel pathway that enables the activation of RNA nucleotides in a manner that is compatible with template-directed nonenzymatic polymerization. We show that this pathway selectively yields the reactive imidazolium-bridged dinucleotide intermediate required for nonenzymatic template-directed RNA copying. Our results will enable more realistic prebiotic chemical simulations of RNA copying based on continuous in situ nucleotide activation.