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

Abstract

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.

On the prebiotic selection of nucleotide anomers: A computational study

“…Finally, the assembled structure of TAP-CA-containing helices suggests that this type of pre-RNA could have been shielded from water allowing its evolution and self-replication. The results in that paper, ( Kaur et al, 2019 ), place TAP and CA as plausible candidates for a pre- or proto-RNA.…”

“…In their first paper, KSW report that the potential energy hypersurface of breaking the glycosidic bond is consistent with a stronger bond in TAP nucleosides compared to canonical nucleosides. Interestingly, in the case of the CA the opposite result is obtained ( Kaur et al, 2019 ). KSW found larger deglycosylation barriers for the C-C glycosidic bond of BA-ribonucleosides compared to canonical nucleobases while the reverse occurs in the case of MM ( Kaur et al, 2017 ).…”

“…Kaur, Sharma, and Wetmore (KSW) have proposed barbituric acid and melamine ( Kaur et al, 2017 ) and cyanuric acid (CA) and 2,4,6-triaminopyrimidine (TAP) ( Kaur et al, 2019 ) as precursors of prebiotic RNA on the basis of quantum mechanical calculations and molecular dynamics (MD) simulations. In their more recent paper ( Kaur et al, 2019 ), KSW use density functional theory (DFT) calculations to obtain potential energy surfaces describing the rotation around the glycosidic bonds of β - and α -ribonucleosides of the non-canonical nucleobases TAP and CA as well as their complementary base pairing TAP:CA and stacking energies.…”

“…Kaur, Sharma, and Wetmore (KSW) have proposed barbituric acid and melamine ( Kaur et al, 2017 ) and cyanuric acid (CA) and 2,4,6-triaminopyrimidine (TAP) ( Kaur et al, 2019 ) as precursors of prebiotic RNA on the basis of quantum mechanical calculations and molecular dynamics (MD) simulations. In their more recent paper ( Kaur et al, 2019 ), KSW use density functional theory (DFT) calculations to obtain potential energy surfaces describing the rotation around the glycosidic bonds of β - and α -ribonucleosides of the non-canonical nucleobases TAP and CA as well as their complementary base pairing TAP:CA and stacking energies. Additionally, these authors studied the base pairing of these nucleobases with the canonical nucleobases (A, G, C, T and U) and compared the canonical 10-mer A-form of RNA duplexes 5′-AAAAAAAAAA-3' paired with 5′-UUUUUUUUUU-3′ and 5′-AAAGCGCAAA-3′ paired with its complementary 5′-UUUCGCGUUU-3′ with the non-canonical duplexes 5′-AAAXXYYAAA-3′ paired with 3′-UUUYYXXUUU-5', where X = CA and Y = TAP.…”

Automated Exploration of Prebiotic Chemical Reaction Space: Progress and Perspectives

“…Automated approaches like AutoMeKin combine molecular dynamics (MD), graph theory algorithms and Monte Carlo simulations to discover likely relevant reaction mechanisms [52]. Quantum mechanics/molecular mechanics (QM/MM) and MD simulations have been combined to study prebiotic nucleic acid analogues [53] and lipids [54]. Kua et al [55], benchmarked thermochemical estimations for compounds thought to be important in protometabolism derived from eQuilibrator to those derived from more accurate yet computationally demanding DFT quantum chemical methods, and found them to be remarkably similar.…”