Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides.

The nature of the first genetic polymer is the subject of major debate1. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life2,3-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA4. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life5.

Photoinduced water-chromophore electron transfer causes formation of guanosine photodamage.

UV-induced photolysis of aqueous guanine nucleosides produces 8-oxo-guanine and Fapy-guanine, which can induce various types of cellular malfunction. The mechanistic rationale underlying photodestructive processes of guanine nucleosides is still largely obscure. Here, we employ accurate quantum chemical calculations and demonstrate that an excited-state non-bonding interaction of guanosine and a water molecule facilitates the electron-driven proton transfer process from water to the chromophore fragment. This subsequently allows for the formation of a crucial intermediate, namely guanosine photohydrate. Further (photo)chemical reactions of this intermediate lead to the known products of guanine photodamage.

Photochemistry of 2-thiooxazole: a plausible prebiotic precursor to RNA nucleotides.

Potentially prebiotic chemical reactions leading to RNA nucleotides involve periods of UV irradiation, which are necessary to promote selectivity and destroy biologially irrelevant side products. Nevertheless, UV light has only been applied to promote specific stages of prebiotic reactions and its effect on complete prebiotic reaction sequences has not been extensively studied. Here, we report on an experimental and computational investigation of the photostability of 2-thiooxazole (2-TO), a potential precursor of pyrimidine and 8-oxopurine nucleotides on early Earth. Our UV-irradiation experiments resulted in rapid decomposition of 2-TO into unidentified small molecule photoproducts. We further clarify the underlying photochemistry by means of accurate ab initio calculations and surface hopping molecular dynamics simulations. Overall, the computational results show efficient rupture of the aromatic ring upon the photoexcitation of 2-TO via breaking of the C-O bond. Consequently, the initial stage of the divergent prebiotic synthesis of pyrimidine and 8-oxopurine nucleotides would require periodic shielding from UV light either with sun screening chromophores or through a planetary scenario that would protect 2-TO until it is transformed into a more stable intermediate compound, e.g. oxazolidinone thione.

Total Synthesis and Prediction of Ulodione Natural Products Guided by DFT Calculations.

A biomimetic synthetic strategy has resulted in a two-step total synthesis of (±)-ulodione A and the prediction of two potential natural products, (±)-ulodiones C and D. This work was guided by computational investigations into the selectivity of a proposed biosynthetic Diels-Alder dimerization, which was then utilized in the chemical synthesis. This work highlights how biosynthetic considerations can both guide the design of efficient synthetic strategies and lead to the anticipation of new natural products.

Surprisingly broad applicability of the cc-pVnZ-F12 basis set for ground and excited states.

Excellent convergence properties for the (aug-)cc-pVnZ-F12 basis set family, purpose-made for explicitly correlated calculations, are demonstrated with conventional wave function methods and Kohn-Sham density functional theory for various ground and excited-state calculations. Among the ground-state properties studied are dipole moments, covalent bond lengths, and interaction and reaction energies. For excited states, we looked at vertical excitation energies, UV absorption, and excited-state absorption spectra. Convergence is compared against the basis sets cc-pVnZ, def2-nVD, aug-pcseg-n, and nZaPa-NR. It is established that the cc-pVnZ-F12 family consistently yields results of n + 1 quality and better. Especially, the cc-pVDZ-F12 basis set is found to be a basis set of good cost vs performance trade-off.

Photochromic reaction in 3H-naphthopyrans studied by vibrational spectroscopy and quantum chemical calculations.

Structural details on the species involved in the photochromic reaction of 3H-naphthopyrans in solution have been formerly determined using NMR spectroscopy. Herein we show that at room temperature time-resolved FT-IR spectroscopy is a simple and efficient tool for structural characterization of colored species generated upon continuous UV light irradiation of the model compound 3H-naphthopyran: 3,3-diphenyl-3H-naphtho[2,1-b]pyran. In solution and in the polymer matrix phase, a colored species transoid-cis is formed after a single-photon excitation process, while transoid-trans is a secondary long-lived photoproduct generated after two-step excitation involving two photons. Understanding the reaction mechanism leading to long-lived colored species can help with the design of new 3H-naphthopyran derivatives structurally optimized for making a photochromic reaction free from transoid-trans products, which is often important for applications. Ab initio calculations show that photoinduced ring-opening followed by isomerization occurs on a multidimensional potential-energy surface. The barriers separating the considered isomeric forms, both in the ground and in the excited state, help to interpret the step-by-step dynamics of the photoprocesses. The system is composed of a variety of ground state equilibrium forms. Each of them is characterized by fast excited-state deactivation pathways which may drive the system through different conical intersection regions.

Photodynamics of alternative DNA base isoguanine.

Isoguanine is an alternative nucleobase that has been proposed as a component of expanded genetic codes. It has also been considered as a molecule with potential relevance to primordial informational polymers. Here, we scrutinize the photodynamics of isoguanine, because photostability has been proposed as a critical criterion for the prebiotic selection of biomolecular building blocks on an early Earth. We discuss resonance-enhanced multiphoton ionization, IR-UV double resonance spectroscopy and pump-probe measurements performed for this molecule to track the excited-state behaviour of its different tautomeric forms in the gas phase. These experiments, when confronted with highly accurate quantum chemical calculations and nonadiabatic dynamics simulations provide a complete mechanistic picture of the tautomer-specific photodynamics of isoguanine. Our results indicate that UV-excited enol tautomers of isoguanine are relatively short lived and therefore photostable. In contrast, the biologically more relevant keto forms are trapped in dark nπ* states which are sufficiently long lived to participate in destructive photochemistry. The resulting lower photostability compared to canonical nucleobases may have been one of the reasons why isoguanine was not incorporated into DNA and RNA.

Electron-driven proton transfer enables nonradiative photodeactivation in microhydrated 2-aminoimidazole.

2-Aminoimidazole (2-AIM) was proposed as a plausible nucleotide activating group in a nonenzymatic copying and polymerization of short RNA sequences under prebiotically plausible conditions. One of the key selection factors controlling the lifespan and importance of organic molecules on early Earth was ultraviolet radiation from the young Sun. Therefore, to assess the suitability of 2-AIM for prebiotic chemistry, we performed non-adiabatic molecular dynamics simulations and static explorations of potential energy surfaces of the photoexcited 2-AIM-(H2O)5 model system by means of the algebraic diagrammatic construction method to the second order [ADC(2)]. Our quantum mechanical simulations demonstrate that 1πσ* excited states play a crucial role in the radiationless deactivation of the UV-excited 2-AIM-(H2O)5 system. More precisely, electron-driven proton transfer (EDPT) along water wires is the only photorelaxation pathway leading to the formation of 1πσ*/S0 conical intersections. The availability of this mechanism and the lack of destructive photochemistry indicate that microhydrated 2-AIM is characterized by substantial photostability and resistance to prolonged UV irradiation.

Water-chromophore electron transfer determines the photochemistry of cytosine and cytidine.

Many of the UV-induced phenomena observed experimentally for aqueous cytidine were lacking the mechanistic interpretation for decades. These processes include the substantial population of the puzzling long-lived dark state, photohydration, cytidine to uridine conversion and oxazolidinone formation. Here, we present quantum-chemical simulations of excited-state spectra and potential energy surfaces of N1-methylcytosine clustered with two water molecules using the second-order approximate coupled cluster (CC2), complete active space with second-order perturbation theory (CASPT2), and multireference configuration interaction with single and double excitation (MR-CISD) methods. We argue that the assignment of the long-lived dark state to a singlet nπ* excitation involving water-chromophore electron transfer might serve as an explanation for the numerous experimental observations. While our simulated spectra for the state are in excellent agreement with experimentally acquired data, the electron-driven proton transfer process occurring on the surface may initiate the subsequent damage in the vibrationally hot ground state of the chromophore.

Photorelaxation of imidazole and adenine via electron-driven proton transfer along H2O wires.

Photochemically created πσ* states were classified among the most prominent factors determining the ultrafast radiationless deactivation and photostability of many biomolecular building blocks. In the past two decades, the gas phase photochemistry of πσ* excitations was extensively investigated and was attributed to N-H and O-H bond fission processes. However, complete understanding of the complex photorelaxation pathways of πσ* states in the aqueous environment was very challenging, owing to the direct participation of solvent molecules in the excited-state deactivation. Here, we present non-adiabatic molecular dynamics simulations and potential energy surface calculations of the photoexcited imidazole-(H2O)5 cluster using the algebraic diagrammatic construction method to the second-order [ADC(2)]. We show that electron driven proton transfer (EDPT) along a wire of at least two water molecules may lead to the formation of a πσ*/S0 state crossing, similarly to what we suggested for 2-aminooxazole. We expand on our previous findings by direct comparison of the imidazole-(H2O)5 cluster to non-adiabatic molecular dynamics simulations of imidazole in the gas phase, which reveal that the presence of water molecules extends the overall excited-state lifetime of the chromophore. To embed the results in a biological context, we provide calculations of potential energy surface cuts for the analogous photorelaxation mechanism present in adenine, which contains an imidazole ring in its structure.

Ultrafast excited-state dynamics of isocytosine.

The alternative nucleobase isocytosine has long been considered as a plausible component of hypothetical primordial informational polymers. To examine this hypothesis we investigated the excited-state dynamics of the two most abundant forms of isocytosine in the gas phase (keto and enol). Our surface-hopping nonadiabatic molecular dynamics simulations employing the algebraic diagrammatic construction to the second order [ADC(2)] method for the electronic structure calculations suggest that both tautomers undergo efficient radiationless deactivation to the electronic ground state with time constants which amount to τketo = 182 fs and τenol = 533 fs. The dominant photorelaxation pathways correspond to ring-puckering (ππ* surface) and C[double bond, length as m-dash]O stretching/N-H tilting (nπ* surface) for the enol and keto forms respectively. Based on these findings, we infer that isocytosine is a relatively photostable compound in the gas phase and in these terms resembles biologically relevant nucleobases. The estimated S1 [radiolysis arrow - arrow with voltage kink] T1 intersystem crossing rate constant of 8.02 × 10(10) s(-1) suggests that triplet states might also play an important role in the overall excited-state dynamics of the keto tautomer. The reliability of ADC(2)-based surface-hopping molecular dynamics simulations was tested against multireference quantum-chemical calculations and the potential limitations of the employed ADC(2) approach are briefly discussed.

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.

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.

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.

Prebiotic synthesis of dihydrouridine by photoreduction of uridine in formamide.

In this report, we show that a very common modification (especially in tRNA), dihydrouridine, was efficiently produced by photoreduction of the canonical pyrimidine ribonucleoside, uridine in formamide. Formamide not only acts as a solvent in this reaction, but also as the reductant. The other three components of the canonical alphabet (C, A, G) remained intact under the same conditions, suggesting that dihydrouridine might have coexisted with all four canonical RNA nucleosides (C, U, A, G) at the dawn of life.

The tautomer-specific excited state dynamics of 2,6-diaminopurine using resonance-enhanced multiphoton ionization and quantum chemical calculations.

2,6-Diaminopurine (2,6-dAP) is an alternative nucleobase that potentially played a role in prebiotic chemistry. We studied its excited state dynamics in the gas phase by REMPI, IR-UV hole burning, and ps pump-probe spectroscopy and performed quantum chemical calculations at the SCS-ADC(2) level of theory to interpret the experimental results. We found the 9H tautomer to have a small barrier to ultrafast relaxation via puckering of its 6-membered ring. The 7H tautomer has a larger barrier to reach a conical intersection and also has a sizable triplet yield. These results are discussed relative to other purines, for which 9H tautomerization appears to be more photostable than 7H and homosubstituted purines appear to be less photostable than heterosubstituted or singly substituted purines.

Photoinduced charge separation and DNA self-repair depend on sequence directionality and stacking pattern.

Charge separation is one of the most common consequences of the absorption of UV light by DNA. Recently, it has been shown that this process can enable efficient self-repair of cyclobutane pyrimidine dimers (CPDs) in specific short DNA oligomers such as the GAT[double bond, length as m-dash]T sequence. The mechanism was characterized as sequential electron transfer through the nucleobase stack which is controlled by the redox potentials of nucleobases and their sequence. Here, we demonstrate that the inverse sequence T[double bond, length as m-dash]TAG promotes self-repair with higher quantum yields (0.58 ± 0.23%) than GAT[double bond, length as m-dash]T (0.44 ± 0.18%) in a comparative study involving UV-irradiation experiments. After extended exposure to UV irradiation, a photostationary equilibrium between self-repair and damage formation is reached at 33 ± 13% for GAT[double bond, length as m-dash]T and at 40 ± 16% for T[double bond, length as m-dash]TAG, which corresponds to the maximum total yield of self-repair. Molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) simulations allowed us to assign this disparity to better stacking overlap between the G and A bases, which lowers the energies of the key A-˙G+˙ charge transfer state in the dominant conformers of the T[double bond, length as m-dash]TAG tetramer. These conformational differences also hinder alternative photorelaxation pathways of the T[double bond, length as m-dash]TAG tetranucleotide, which otherwise compete with the sequential electron transfer mechanism responsible for CPD self-repair. Overall, we demonstrate that photoinduced electron transfer is strongly dependent on conformation and the availability of alternative photodeactivation mechanisms. This knowledge can be used in the identification and prediction of canonical and modified DNA sequences exhibiting efficient electron transfer. It also further contributes to our understanding of DNA self-repair and its potential role in the photochemical selection of the most photostable sequences on the early Earth.

Theoretical studies of the mechanism of 2-aminooxazole formation under prebiotically plausible conditions.

2-Aminooxazole is generally considered to play a central role in the origin of informational polymers. In the current contribution we use density functional calculations to investigate the detailed mechanism of 2-aminooxazole formation from the prebiotic soup according to the scenario suggested by M. W. Powner, B. Gerland and J. D. Sutherland, Nature, 2009, 459, 239-242. Parallel to the phosphate-catalyzed reaction pathway we also describe its water-assisted variant. Our calculations show that phosphate-catalysis is indispensable not only in the cyclization and the subsequent water-elimination steps, as previously suggested, but also in the very first reaction step leading to the formation of the carbinolamine intermediate. In addition, we suggest concurrent reaction channels for the cyclization and water-elimination reaction steps, both involving catalytic phosphate ions.