Prebiotic Synthesis of 3',5'-Cyclic Adenosine and Guanosine Monophosphates through Carbodiimide-Assisted Cyclization.

3',5'-Cyclic nucleotides play a fundamental role in modern biochemical processes and have been suggested to have played a central role at the origin of terrestrial life. In this work, we suggest that a formamide-based systems chemistry might account for their availability on the early Earth. In particular, we demonstrate that in a liquid formamide environment at elevated temperatures 3',5'-cyclic nucleotides are obtained in good yield and selectivity upon intramolecular cyclization of 5'-phosphorylated nucleosides in the presence of carbodiimides.

A Computational Quantum-Based Perspective on the Molecular Origins of Life's Building Blocks.

The search for the chemical origins of life represents a long-standing and continuously debated enigma. Despite its exceptional complexity, in the last decades the field has experienced a revival, also owing to the exponential growth of the computing power allowing for efficiently simulating the behavior of matter-including its quantum nature-under disparate conditions found, e.g., on the primordial Earth and on Earth-like planetary systems (i.e., exoplanets). In this minireview, we focus on some advanced computational methods capable of efficiently solving the Schro¨dinger equation at different levels of approximation (i.e., density functional theory)-such as ab initio molecular dynamics-and which are capable to realistically simulate the behavior of matter under the action of energy sources available in prebiotic contexts. In addition, recently developed metadynamics methods coupled with first-principles simulations are here reviewed and exploited to answer to old enigmas and to propose novel scenarios in the exponentially growing research field embedding the study of the chemical origins of life.

Acid-Catalyzed RNA-Oligomerization from 3',5'-cGMP.

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.

Stereocontrolled Synthesis of (-)-Bactobolin A.

A stereoselective synthesis of the ribosome-binding antitumor antibiotic (-)-bactobolin A is reported. The presented approach makes effective use of (-)-quinic acid as a chiral pool starting material and substrate stereocontrol to establish the five contiguous stereocenters of (-)-bactobolin A. The key steps of the synthesis include a stereoselective vinylogous aldol reaction to introduce the unusual dichloromethyl substituent, a completely diastereoselective rhodium(II)-catalyzed C-H amination reaction to set the configuration of the axial amine, and an intramolecular alkoxycarbonylation to build the bicyclic lactone framework. The developed synthetic route was used to prepare 90 mg of (-)-bactobolin A trifluoroacetate in 10% overall yield.

High-Energy Proton-Beam-Induced Polymerization/Oxygenation of Hydroxynaphthalenes on Meteorites and Nitrogen Transfer from Urea: Modeling Insoluble Organic Matter?

Formation and structural modification of oxygenated polycyclic aromatic hydrocarbons (oxyPAHs) by UV irradiation on minerals have recently been proposed as a possible channel of PAH transformation in astrochemical and prebiotic scenarios of possible relevance for the origin of life. Herein, it is demonstrated that high-energy proton-beam irradiation in the presence of various meteorites, including stony iron, achondrite, and chondrite types, promotes the conversion of two representative oxyPAH compounds, 1-naphthol and 1,8-dihydroxynaphthalene, to complex mixtures of oxygenated and oligomeric derivatives. The main identified products include polyhydroxy derivatives, isomeric dimers encompassing benzofuran and benzopyran scaffolds, and, notably, a range of quinones and perylene derivatives. Addition of urea, a prebiotically relevant chemical precursor, expanded the range of identified species to include, among others, quinone diimines. Proton-beam irradiation of oxyPAH modulated by nitrogen-containing compounds such as urea is proposed as a possible contributory mechanism for the formation and processing of insoluble organic matter in meteorites and in prebiotic processes.

Formic Acid, a Ubiquitous but Overlooked Component of the Early Earth Atmosphere.

Terrestrial volcanism has been one of the dominant geological forces shaping our planet since its earliest existence. Its associated phenomena, like atmospheric lightning and hydrothermal activity, provide a rich energy reservoir for chemical syntheses. Based on our laboratory simulations, we propose that on the early Earth volcanic activity inevitably led to a remarkable production of formic acid through various independent reaction channels. Large-scale availability of atmospheric formic acid supports the idea of the high-temperature accumulation of formamide in this primordial environment.

Rewarming the Primordial Soup: Revisitations and Rediscoveries in Prebiotic Chemistry.

A short history of Campbell's primordial soup: In this essay we try to disclose some of the historical connections between the studies that have contributed to our current understanding of the emergence of catalytic RNA molecules and their components from an inanimate matter.

High-energy chemistry of formamide: a unified mechanism of nucleobase formation.

The coincidence of the Late Heavy Bombardment (LHB) period and the emergence of terrestrial life about 4 billion years ago suggest that extraterrestrial impacts could contribute to the synthesis of the building blocks of the first life-giving molecules. We simulated the high-energy synthesis of nucleobases from formamide during the impact of an extraterrestrial body. A high-power laser has been used to induce the dielectric breakdown of the plasma produced by the impact. The results demonstrate that the initial dissociation of the formamide molecule could produce a large amount of highly reactive CN and NH radicals, which could further react with formamide to produce adenine, guanine, cytosine, and uracil. Based on GC-MS, high-resolution FTIR spectroscopic results, as well as theoretical calculations, we present a comprehensive mechanistic model, which accounts for all steps taking place in the studied impact chemistry. Our findings thus demonstrate that extraterrestrial impacts, which were one order of magnitude more abundant during the LHB period than before and after, could not only destroy the existing ancient life forms, but could also contribute to the creation of biogenic molecules.

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

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.

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.

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 a 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 the 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.

Four Ways to Oligonucleotides Without Phosphoimidazolides.

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.

Emergence of the First Catalytic Oligonucleotides in a Formamide-Based Origin Scenario.

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.

Prebiotic synthesis of nucleic acids and their building blocks at the atomic level - merging models and mechanisms from advanced computations and experiments.

The origin of life on Earth is one of the most fascinating questions of contemporary science. Extensive research in the past decades furnished diverse experimental proposals for the emergence of first informational polymers that could form the basis of the early terrestrial life. Side by side with the experiments, the fast development of modern computational chemistry methods during the last 20 years facilitated the use of in silico modelling tools to complement the experiments. Modern computations can provide unique atomic-level insights into the structural and electronic aspects as well as the energetics of key prebiotic chemical reactions. Many of these insights are not directly obtainable from the experimental techniques and the computations are thus becoming indispensable for proper interpretation of many experiments and for qualified predictions. This review illustrates the synergy between experiment and theory in the origin of life research focusing on the prebiotic synthesis of various nucleic acid building blocks and on the self-assembly of nucleotides leading to the first functional oligonucleotides.

Tetraloop-like geometries could form the basis of the catalytic activity of the most ancient ribooligonucleotides.

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.

Molecular mechanism of diaminomaleonitrile to diaminofumaronitrile photoisomerization: an intermediate step in the prebiotic formation of purine nucleobases.

The photoinduced isomerization of diaminomaleonitrile (DAMN) to diaminofumaronitrile (DAFN) was suggested to play a key role in the prebiotically plausible formation of purine nucleobases and nucleotides. In this work we analyze two competitive photoisomerization mechanisms on the basis of state-of-the-art quantum-chemical calculations. Even though it was suggested that this process might occur on the triplet potential-energy surface, our results indicate that the singlet reaction channel should not be disregarded either. In fact, the peaked topography of the S1 /S0 conical intersection suggests that the deexcitation should most likely occur on a sub-picosecond timescale and the singlet photoisomerization mechanism might effectively compete even with a very efficient intersystem crossing. Such a scenario is further supported by the relatively small spin-orbit coupling of the S1 and T2 states in the Franck-Condon region, which does not indicate a very effective triplet bypass for this photoreaction. Therefore, we conclude that the triplet reaction channel in DAMN might not be as prominent as was previously thought.

How to understand quantum chemical computations on DNA and RNA systems? A practical guide for non-specialists.

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.

Solvent effects on the photochemistry of 4-aminoimidazole-5-carbonitrile, a prebiotically plausible precursor of purines.

4-Aminoimidazole-5-carbonitrile (AICN) was suggested as a prebiotically plausible precursor of purine nucleobases and nucleotides. Although it can be formed in a sequence of photoreactions, AICN is immune to further irradiation with UV-light. We present state-of-the-art multi-reference quantum-chemical calculations of potential energy surface cuts and conical intersection optimizations to explain the molecular mechanisms underlying the photostability of this compound. We have identified the N-H bond stretching and ring-puckering mechanisms that should be responsible for the photochemistry of AICN in the gas phase. We have further considered the photochemistry of AICN-water clusters, while including up to six explicit water molecules. The calculations reveal charge transfer to solvent followed by formation of an H3O(+) cation, both of which occur on the (1)πσ* hypersurface. Interestingly, a second proton transfer to an adjacent water molecule leads to a (1)πσ*/S0 conical intersection. We suggest that this electron-driven proton relay might be characteristic of low-lying (1)πσ* states in chromophore-water clusters. Owing to its nature, this mechanism might also be responsible for the photostability of analogous organic molecules in bulk water.

High-energy chemistry of formamide: a simpler way for nucleobase formation.

The formation of nucleobases from formamide during a high-energy density event, i.e., the impact of an extraterrestrial body into the planetary atmosphere, was studied by irradiation of formamide ice and liquid samples with a high-power laser in the presence of potential catalysts. FTIR spectroscopy, time-resolved emission spectroscopy, and GC-MS were subsequently used to monitor the dissociation of this molecule into stable molecular fragments (HCN, H2O, HNCO, H2, CO, and NH3) and unstable species (HNC, •CN, and •NH). The kinetic and thermodynamic models of the high-energy density event molecular dynamics have been suggested together with the reaction routes leading from the dissociation products to the nucleobases. In addition, using theoretical calculations, we propose a simple new reaction pathway for the formation of both pyrimidine and purine nucleobases involving •CN radical chemistry.

How does hydroxyl introduction influence the double helical structure: the stabilization of an altritol nucleic acid:ribonucleic acid duplex.

Altritol nucleic acids (ANAs) are a promising new tool in the development of artificial small interfering ribonucleic acids (siRNAs) for therapeutical applications. To mimic the siRNA:messenger RNA (mRNA) interactions, the crystal structure of the ANA:RNA construct a(CCGUAAUGCC-P):r(GGCAUUACGG) was determined to 1.96 Å resolution which revealed the hybrid to form an A-type helix. As this A-form is a major requirement in the RNAi process, this crystal structure confirms the potential of altritol-modified siRNAs. Moreover, in the ANA strands, a new type of intrastrand interactions was found between the O2' hydroxyl group of one residue and the sugar ring O4' atom of the next residue. These interactions were further investigated by quantum chemical methods. Besides hydration effects, these intrastrand hydrogen bonds may also contribute to the stability of ANA:RNA duplexes.

Nature and magnitude of aromatic base stacking in DNA and RNA: Quantum chemistry, molecular mechanics, and experiment.

Base stacking is a major interaction shaping up and stabilizing nucleic acids. During the last decades, base stacking has been extensively studied by experimental and theoretical methods. Advanced quantum-chemical calculations clarified that base stacking is a common interaction, which in the first approximation can be described as combination of the three most basic contributions to molecular interactions, namely, electrostatic interaction, London dispersion attraction and short-range repulsion. There is not any specific π-π energy term associated with the delocalized π electrons of the aromatic rings that cannot be described by the mentioned contributions. The base stacking can be rather reasonably approximated by simple molecular simulation methods based on well-calibrated common force fields although the force fields do not include nonadditivity of stacking, anisotropy of dispersion interactions, and some other effects. However, description of stacking association in condensed phase and understanding of the stacking role in biomolecules remain a difficult problem, as the net base stacking forces always act in a complex and context-specific environment. Moreover, the stacking forces are balanced with many other energy contributions. Differences in definition of stacking in experimental and theoretical studies are explained.