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The assembly of ancient informational polymers from nucleotide precursors is the central challenge of life's origin on our planet. Among the possible solutions, dry polymerization of 3',5'-cyclic guanosine monophosphate (3',5'-cGMP) has been proposed as a candidate to create oligonucleotides of 15-20 units in length. However, the reported sensitivity of the reaction to the presence of cations raised questions of whether this chemistry could be relevant in a geological context. The experiments in this study show that the presence of cations is not restrictive as long as the reaction is conducted in an acidic environment, in contrast to previous reports that suggested optimal conditions at pH 9., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

We report that 3',5'-cyclic CMP undergoes nonenzymatic di- and trimerization at 20 °C under dry conditions upon proton or UV irradiation. The reaction involves stacking of the cyclic monomers and subsequent polymerization through serial transphosphorylations between the stacked monomers. Proton- and UV-induced oligomerization of 3',5'-cyclic CMP demonstrates that pyrimidines-similar to purines-might also have taken part in the spontaneous generation of RNA under plausible prebiotic conditions as well as in an extraterrestrial context. The observed polymerization of naturally occurring 3',5'-cyclic nucleotides supports the possibility that the extant genetic nucleic acids might have originated by way of a straight Occamian path, starting from simple reactions between plausibly preactivated monomers., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We outline novel findings on the non-enzymatic polymerization of nucleotides under plausible prebiotic conditions and on the spontaneous onset of informational complexity in the founding molecule, RNA. We argue that the unique ability of 3', 5' cyclic guanosine monophosphate to form stacked architectures and polymerize in a self-sustained manner suggests that this molecule may serve as the 'seed of life' from which all self-replicating oligonucleotides can be derived via a logically complete sequence of simple events. WIREs RNA 2017, 8:e1400. doi: 10.1002/wrna.1400 For further resources related to this article, please visit the WIREs website., (© 2016 Wiley Periodicals, Inc.)

50 years after the historical Miller-Urey experiment, the formamide-based scenario is perhaps the most powerful concurrent hypothesis for the origin of life on our planet besides the traditional HCN-based concept. The information accumulated during the last 15 years in this topic is astonishingly growing and nowadays the formamide-based model represents one of the most complete and coherent pathways leading from simple prebiotic precursors up to the first catalytically active RNA molecules. In this work, we overview the major events of this long pathway that have emerged from recent experimental and theoretical studies, mainly concentrating on the mechanistic, methodological, and structural aspects of this research., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Emergence of the very first RNA or RNA-like oligomers from simple nucleotide precursors is one of the most intriguing questions of the origin of life research. In the current paper, we analyse the mechanism of four non-enzymatic template-free scenarios suggested for the oligomerization of chemically non-modified cyclic and acyclic nucleotides in the literature. We show that amines may have a twofold role in these syntheses: due to their high affinity to bind protons they may activate the phosphorus of the phosphate group via proton transfer reactions, or indirectly they may serve as charge compensating species and influence the self-assembling of nucleotides to supramolecular architectures compatible with the oligomerization reactions. Effect of cations and pH on the reactions is also discussed.

In this review primarily written for non-experts we explain basic methodological aspects and interpretation of modern quantum chemical (QM) computations applied to nucleic acids. We introduce current reference QM computations on small model systems consisting of dozens of atoms. Then we comment on recent advance of fast and accurate dispersion-corrected density functional theory methods, which will allow computations of small but complete nucleic acids building blocks in the near future. The qualitative difference between QM and molecular mechanics (MM, force field) computations is discussed. We also explain relation of QM and molecular simulation computations to experiments., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Knowledge of geometrical and physico-chemical properties of the sugar-phosphate backbone substantially contributes to the comprehension of the structural dynamics, function and evolution of nucleic acids. We provide a side by side overview of structural biology/bioinformatics, quantum chemical and molecular mechanical/simulation studies of the nucleic acids backbone. We highlight main features, advantages and limitations of these techniques, with a special emphasis given to their synergy. The present status of the research is then illustrated by selected examples which include classification of DNA and RNA backbone families, benchmark structure-energy quantum chemical calculations, parameterization of the dihedral space of simulation force fields, incorporation of arsenate into DNA, sugar-phosphate backbone self-cleavage in small RNA enzymes, and intricate geometries of the backbone in recurrent RNA building blocks. Although not apparent from the current literature showing limited overlaps between the QM, simulation and bioinformatics studies of the nucleic acids backbone, there in fact should be a major cooperative interaction between these three approaches in studies of the sugar-phosphate backbone.

The RNA kink-turn is an important recurrent RNA motif, an internal loop with characteristic consensus sequence forming highly conserved three-dimensional structure. Functional arrangement of RNA kink-turns shows a sharp bend in the phosphodiester backbone. Among other signature interactions, kink-turns form A-minor interaction between their two stems. Most kink-turns possess extended A-minor I (A-I) interaction where adenine of the second A•G base pair of the NC-stem interacts with the first canonical pair of the C-stem (i.e., the receptor pair) via trans-sugar-edge/sugar-edge (tSS) and cis-sugar-edge/sugar-edge (cSS) interactions. The remaining kink-turns have less compact A-minor 0 (A-0) interaction with just one tSS contact. We show that kink-turns with A-I in ribosomal X-ray structures keep G═C receptor base pair during evolution while the inverted pair (C═G) is not realized. In contrast, kink-turns with A-0 in the observed structures alternate G═C and C═G base pairs in sequences. We carried out an extended set (~5 μs) of explicit-solvent molecular dynamics simulations of kink-turns to rationalize this structural/evolutionary pattern. The simulations were done using a net-neutral Na(+) cation atmosphere (with ~0.25 M cation concentration) supplemented by simulations with either excess salt KCl atmosphere or inclusion of Mg(2+). The results do not seem to depend on the treatment of ions. The simulations started with X-ray structures of several kink-turns while we tested the response of the simulated system to base substitutions, modest structural perturbations and constraints. The trends seen in the simulations reveal that the A-I/G═C arrangement is preferred over all three other structures. The A-I/C═G triple appears structurally entirely unstable, consistent with the covariation patterns seen during the evolution. The A-0 arrangements tend to shift toward the A-I pattern in simulations, which suggests that formation of the A-0 interaction is likely supported by the surrounding protein and RNA molecules. A-0 may also be stabilized by additional kink-turn nucleotides not belonging to the kink-turn consensus, as shown for the kink-turn from ribosomal Helix 15. Quantum-chemical calculations on all four A-minor triples suggest that there is a different balance of electrostatic and dispersion stabilization in the A-I/G═C and A-I/C═G triples, which may explain different behavior of these otherwise isosteric triples in the context of kink-turns., (© 2011 American Chemical Society)

The RNA-world theory hypothesizes that early Earth life was based on the RNA molecule. However, the notion that ribose, the sugar in RNA, is unstable still casts a serious doubt over this theory. Recently, it has been found that the silicate-mediated formose reaction facilitates the stabilization of ribose. Using accurate quantum chemical calculations, we determined the relative stability of the silicate complexes of arabinose, lyxose, ribose, and xylose with the intent to determine which would form predominantly from a formose-like reaction. Five stereoisomers were investigated for each complex. The stereoisomers of 2:1 ribose-silicate are the more stable ones, to the extent that the least stable of these is even more stable than the most stable stereoisomer of the other 2:1 sugar-silicate complexes. Thus, thermodynamically, a formose-like reaction in the presence of silicate minerals should preferentially form the silicate complex of ribose over the silicate complex of arabinose, lyxose, and xylose., (© Mary Ann Liebert, Inc.)

In this feature article, we provide a side-by-side introduction for two research fields: quantum chemical calculations of molecular interaction in nucleic acids and RNA structural bioinformatics. Our main aim is to demonstrate that these research areas, while largely separated in contemporary literature, have substantial potential to complement each other that could significantly contribute to our understanding of the exciting world of nucleic acids. We identify research questions amenable to the combined application of modern ab initio methods and bioinformatics analysis of experimental structures while also assessing the limitations of these approaches. The ultimate aim is to attain valuable physicochemical insights regarding the nature of the fundamental molecular interactions and how they shape RNA structures, dynamics, function, and evolution.

For the emergence of life, the abiotic synthesis of RNA from its monomers is a central step. We found that in alkaline, drying conditions in bulk and at heated air‐water interfaces, 2′,3′‐cyclic nucleotides oligomerised without additional catalyst, forming up to 10‐mers within a day. The oligomerisation proceeded at a pH range of 7–12, at temperatures between 40–80 °C and was marginally enhanced by K+ ions. Among the canonical ribonucleotides, cGMP oligomerised most efficiently. Quantification was performed using HPLC coupled to ESI‐TOF by fitting the isotope distribution to the mass spectra. Our study suggests a oligomerisation mechanism where cGMP aids the incorporation of the relatively unreactive nucleotides C, A and U. The 2′,3′‐cyclic ribonucleotides are byproducts of prebiotic phosphorylation, nucleotide syntheses and RNA hydrolysis, indicating direct recycling pathways. The simple reaction condition offers a plausible entry point for RNA to the evolution of life on early Earth. [ABSTRACT FROM AUTHOR]

50 years after the historical Miller-Urey experiment, the formamide-based scenario is perhaps the most powerful concurrent hypothesis for the origin of life on our planet besides the traditional HCN-based concept. The information accumulated during the last 15 years in this topic is astonishingly growing and nowadays the formamide-based model represents one of the most complete and coherent pathways leading from simple prebiotic precursors up to the first catalytically active RNA molecules. In this work, we overview the major events of this long pathway that have emerged from recent experimental and theoretical studies, mainly concentrating on the mechanistic, methodological, and structural aspects of this research. [ABSTRACT FROM AUTHOR]

The origin of the catalytic activity of ancient oligonucleotides is a largely unexplored field of contemporary science. In the current work we use molecular dynamics simulations to investigate the plausibility of tetraloop-like overhang geometries to initiate transphosphorylation reactions that lead to ligation and terminal cleavage in simple, Watson-Crick (WC) complementary oligoC/oligoG sequences observed experimentally. We show a series of examples of known tetraloop architectures, which can be adopted by the unpaired overhangs of short oligonucleotide sequences for a sufficiently long time to enable chemical reactions that lead to simple ribozyme-like catalytic activity. Thus, our computations demonstrate that the role of non-WC interactions at the emergence of the most ancient catalytic oligonucleotides could be more significant than ever believed. [ABSTRACT FROM AUTHOR]

3',5'-Cyclic GMP spontaneously nonenzymatically polymerizes in a base-catalyzed reaction affording G oligonucleotides. When reacted with fully or partially sequence-complementary RNA (oligo C), the abiotically generated oligo G RNA displays a typical ribozyme activity consisting of terminal ligation accompanied by cleavage of an internal phosphate site of the donor oligonucleotide stem upon attack of the acceptor 3' terminal OH. This reaction is dubbed Ligation following Intermolecular Cleavage (LIC). In a prebiotic perspective, the ability of oligo G polynucleotides to react with other sequences outlines a simple and possible evolutionary scenario based on the autocatalytic properties of RNA. [ABSTRACT FROM AUTHOR]

Oligonucleotides In their Full Paper on page 3596 ff., J. E. Šponer et al. report on the results of molecular dynamics (MD) simulations used to investigate whether tetraloop ‐ like overhang geometries might give rise to ribozyme ‐ like activity in short Watson – Crick complementary oligoG/oligoC sequences. Their results demonstrate that the studied tetraloop ‐ like overhang geometries are able to stabilize the 2′ ‐ and 3′ ‐ OH groups of the acceptor ribose in the vicinity of the phosphate of the donor strand for several tens to hundreds of nanoseconds, which is entirely sufficient for the required transphosphorylation reactions to proceed. [ABSTRACT FROM AUTHOR]

RNA molecules are stabilized by a wide range of noncanonical interactions that are not present in DNA. Among them, the recently classified base--phosphate (BPh) interactions belong to the most important ones. Twelve percent of nucleotides in the ribosomal crystal structures are involved in BPh interactions. BPh interactions are highly conserved and provide major constraints on RNA sequence evolution. Here we provide assessment of the energetics of BPh interactions using MP2 computations extrapolated to the complete basis set of atomic orbitals and corrected for higher-order electron correlation effects. The reference computations are compared with DFT-D and DFT-D3 approaches, the SAPT method, and the molecular mechanics force field. The computations, besides providing the basic benchmark for the BPh interactions, allow some refinements of the original classification, including identification of some potential doubly bonded BPh patterns. The reference computations are followed by analysis of some larger RNA fragments that consider the context of the BPh interactions. The computations demonstrate the complexity of interaction patterns utilizing the BPh interactions in real RNA structures. The BPh interactions are often involved in intricate interaction networks. We studied BPh interactions of protonated adenine that can contribute to catalysis of hairpin ribozyme, the key BPh interaction in the S-turn motif of the sarcin--ricin loop, which may predetermine the S-turn topology and complex BPh patterns from the glmS riboswitch. Finally, the structural stability of BPh interactions in explicit solvent molecular dynamics simulations is assessed. The simulations well preserve key BPh interactions and allow dissection of structurally/functionally important water-meditated BPh bridges, which could not be considered in earlier bioinformatics classification of BPh interactions. [ABSTRACT FROM AUTHOR]