RESUMO
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.
Assuntos
Adenosina , Guanosina Monofosfato , Ciclização , Nucleosídeos/química , Nucleotídeos Cíclicos , Formamidas/química , GuanosinaRESUMO
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.
RESUMO
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 15-20â 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 pHâ 9.
Assuntos
GMP Cíclico , RNA , Catálise , Oligonucleotídeos , PolimerizaçãoRESUMO
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.
Assuntos
Benzopiranos/síntese química , Catálise , EstereoisomerismoRESUMO
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.
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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.
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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.
Assuntos
Prebióticos , Nucleosídeos/química , Nucleotídeos/química , RNA/metabolismo , RNA Catalítico/metabolismo , Ribossomos/metabolismoRESUMO
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.
RESUMO
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.
Assuntos
CMP Cíclico/química , CMP Cíclico/efeitos da radiação , Oligorribonucleotídeos/síntese química , RNA/síntese química , Dicroísmo Circular , Evolução Química , Modelos Químicos , Polimerização , Prótons , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Raios UltravioletaRESUMO
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.
Assuntos
Formamidas/química , Simulação de Dinâmica Molecular , Nucleotídeos Cíclicos/química , Estabilidade de RNA , Água/química , Isomerismo , Estrutura Molecular , Prebióticos , RNA/química , Soluções/química , Temperatura , TermodinâmicaRESUMO
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.
Assuntos
Evolução Molecular , Nucleotídeos/metabolismo , Oligonucleotídeos/biossíntese , Origem da Vida , RNARESUMO
50â 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 15â 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.
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Formamidas/química , Oligonucleotídeos/química , RNA/química , Catálise , Oligonucleotídeos/metabolismo , Origem da VidaRESUMO
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.
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Simulação de Dinâmica Molecular , Origem da Vida , Prebióticos , Evolução Química , Ácidos NucleicosRESUMO
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.
Assuntos
Oligonucleotídeos/química , Oligonucleotídeos/síntese química , RNA Catalítico/química , Sequência de Bases , Catálise , Cinética , Simulação de Dinâmica MolecularRESUMO
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.
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Fumaratos/química , Nitrilas/química , Nucleotídeos/química , Purinas/química , Modelos Moleculares , Fotoquímica , Prebióticos , Teoria QuânticaRESUMO
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.
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DNA/química , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , RNA/química , Simulação por Computador , Modelos MolecularesRESUMO
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.
Assuntos
Imidazóis/química , Modelos Químicos , Modelos Moleculares , Nitrilas/química , Prebióticos , Purinas/química , Solventes/química , Simulação por Computador , Imidazóis/efeitos da radiação , Luz , Teste de Materiais , Nitrilas/efeitos da radiação , Fotoquímica/métodos , Purinas/efeitos da radiação , Solventes/efeitos da radiaçãoRESUMO
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, â¢CN, and â¢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 â¢CN radical chemistry.
Assuntos
Formamidas/química , Nucleotídeos/química , Modelos Moleculares , Conformação Molecular , Nitrilas/química , Temperatura , TermodinâmicaRESUMO
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.
Assuntos
RNA de Cadeia Dupla/química , RNA Interferente Pequeno/química , Álcoois Açúcares/química , Ligação de Hidrogênio , Modelos Moleculares , Conformação de Ácido Nucleico , Água/químicaRESUMO
Because of their unique proton-conductivity, chains of phosphoric acid molecules are excellent proton-transfer catalysts. Here we demonstrate that this property could have been exploited for the prebiotic synthesis of the first oligopeptide sequences on our planet. Our results suggest that drying highly diluted solutions containing amino acids (like glycine, histidine and arginine) and phosphates in comparable concentrations at elevated temperatures (ca. 80 °C) in an acidic environment could lead to the accumulation of amino acid:phosphoric acid crystalline salts. Subsequent heating of these materials at 100 °C for 1-3 days results in the formation of oligoglycines consisting of up to 24 monomeric units, while arginine and histidine form shorter oligomers (up to trimers) only. Overall, our results suggest that combining the catalytic effect of phosphate chains with the crystalline order present in amino acid:phosphoric acid salts represents a viable solution that could be utilized to generate the first oligopeptide sequences in a mild acidic hydrothermal field scenario. Further, we propose that crystallization could help overcoming cyclic oligomer formation that is a generally known bottleneck of prebiotic polymerization processes preventing further chain growth.