Stability of 2′,3′ and 3′,5′ cyclic nucleotides in formamide and in water: a theoretical insight into the factors controlling the accumulation of nucleic acid building blocks in a prebiotic pool

Abstract

Synthesis of the first RNAs represents one of the cornerstones of the emergence of life. Recent studies demonstrated powerful scenarios of prebiotic synthesis of cyclic nucleotides in aqueous and formamide environments. This raised a question about their thermodynamic stability, a decisive factor determining their accumulation in the prebiotic pool. Here we performed ab initio molecular dynamics simulations at various temperatures in formamide and water to study the relative stabilities of the 2',3' and 3',5' isomers of cyclic nucleotides. The computations show that in an aqueous environment 2',3' cyclic nucleotides are more stable than their 3',5' counterparts at all temperatures up to the boiling point. In contrast, in formamide higher temperatures favor accumulation of the 3',5' cyclic form, whereas below about 400 K the 2',3' cyclic form becomes more stable. The latter observation is consistent with a formamide-based origin scenario suggesting that 3',5' cyclic nucleotides accumulated at higher temperatures subsequently allowed oligomerization reactions after fast cooling to lower temperatures. A statistical analysis of the geometrical parameters of the solutes indicates that thermodynamics of cyclic nucleotides in aqueous and formamide environments are dictated by the floppiness of the molecules rather than by the ring strain of the cyclic phosphodiester linkages.

Integrated synthesis of nucleotide and nucleosides influenced by amino acids

“…In addition to AMP, glycosidic bond-containing products, including cyclic nucleotides (i.e. cAMP) 27 , and nucleosides (i.e. adenosine), were detected using RP-HPLC-MS, MS/MS, and tested for 1,N6-etheno derivative formation 28,29 , confirmed by comparison to standards (Fig.…”

Geological and Geochemical Constraints on the Origin and Evolution of Life

“…The presence of formamide as a solvent has a major role in prebiotic experiments and, hence, hypotheses for the origin of life (Š poner et al, 2016;Cassone et al, 2017;Costanzo et al, 2017;Saladino et al, 2017). Such hypotheses differ from geologically viable hypotheses that merely involve the expected presence of ammonia, cyanides, sulfides, and formamide dissolved in water during transient reducing conditions, including cyanosulfidic protometabolism (Patel et al, 2015) and the aqueous media with dissolved formamide hypothesis of Rotelli et al (2016).…”

Nonenzymatic Oligomerization of 3′,5′‐Cyclic CMP Induced by Proton and UV Irradiation Hints at a Nonfastidious Origin of RNA

“…As discussed in refs. and , liquid formamide would have been able to form and accumulate on the early Earth in volcanic environments at temperatures far above the boiling point of water as the thermal dissociation product of ammonium formate. Formamide is part of other prebiotic scenarios, such as the “discontinuous synthesis scenario” of the origin of life, suggested by Benner and co‐workers .…”