Can Cyanuric Acid and 2,4,6-Triaminopyrimidine Containing Ribonucleosides be Components of Prebiotic RNA? Insights from QM Calculations and MD Simulations.

As a step toward assessing their fitness as pre-RNA nucleobases, we employ DFT and MD simulations to analyze the noncovalent interactions of cyanuric acid (CA) and 2,4,6-triaminopyrimidine (TAP), and the structural properties of the associated ribonucleosides (rNs) and oligonucleotides. Our calculations reveal that the TAP : CA pair has a comparable hydrogen-bond strength to the canonical A : U pair. This strengthens the candidature of CA and TAP as prebiotic nucleobases. Further, the stacking between two canonical nucleobases is stronger than those between TAP or CA and a canonical base, as well as those between two TAP and/or CA, which indicates that enhanced stacking may have served as a driving force for the evolution from prebiotic to canonical nucleobases. Similarities in the DFT-derived anti/syn rotational barriers and MD-derived (anti) glycosidic conformation of the CA and TAP rNs and canonical rNs further substantiate their candidature as pre-RNA components. Greater deglycosylation barriers (as obtained by DFT calculations) for TAP rNs compared to canonical rNs suggest TAP rNs indicate higher resistance to environmental factors, while lower barriers indicate that CA rNs were likely more suitable for less-challenging locations. Finally, the tight packing in narrow CA:TAP-containing helices suggests that the prebiotic polymers were shielded from water, which would aid their evolution into self-replicating systems. Our calculations thus support proposals that CA and TAP can act as nucleobases of pre-RNA.