Urea and Acetamide Rich Solutions Circumvent the Strand Inhibition Problem to Allow Multiple Rounds of DNA and RNA Copying

For decades prebiotic chemists have attempted to achieve replication of RNA under prebiotic conditions with only limited success. One of the long‐recognized impediments to achieving true replication of a duplex (copying of both strands) is the so‐called strand inhibition problem. Specifically, while the two strands of an RNA (or DNA) duplex can be separated by heating, upon cooling the strands of a duplex will reanneal before mononucleotide or oligonucleotide substrates can bind to the individual strands. Here we demonstrate that a class of plausible prebiotic solvents, when coupled with thermal cycling and varying levels of hydration, circumvents the strand inhibition problem, and allows multiple rounds of information transfer from both strands of a duplex (replication). Replication was achieved by simultaneous ligation of oligomers that bind to their templates with the aid of the solvents. The solvents used consisted of concentrated solutions of urea and acetamide in water (UAcW), components that were likely abundant on the early Earth. The UAcW solvent system favors the annealing of shorter strands over the re‐annealing of long strands, thereby circumventing strand inhibition. We observed an improvement of DNA and RNA replication yields by a factor of 100× over aqueous buffer. Information transfer in the UAcW solvent system is robust, being achieved for a range of solvent component ratios, various drying conditions, and in the absence or presence of added salts. Copying of nucleic acids under prebiotic conditions has been hard to achieve because of a problem known as strand inhibition. This problem can be overcome using solvents composed of molecules abundant in the early Earth, allowing for multiple rounds of information transfer of DNA and RNA duplexes under simulated prebiotic conditions through temperature and hydration cycles.