Formamide-Based Prebiotic Synthesis of Nucleobases: A Kinetically Accessible Reaction Route

Synthesis of nucleobases in nonaqueous environments is an alternative way for the emergence of terrestrial life, which could solve the fundamental problem connected to the hydrolytic instability of nucleic acid components in an aqueous environment. In this contribution, we present a plausible reaction route for the prebiotic synthesis of nucleobases in formamide, which does not require participation of the formamide trimer and aminoimidazole-carbonitrile intermediates. The computed activation energy of the proposed pathway is noticeably higher than that of the HCN-based synthetic route, but it is still feasible under the experimental conditions of the Saladino synthesis. We show that, albeit both the pyrimidine and purine ring formation utilizes the undissociated form of formamide, the dehydration product of formamide, HCN, may also play a key role in the mechanism. The rate determining step of the entire reaction path is the cyclization of the diaza-pentanimine precursor. The subsequent formation of the imidazole ring proceeds with a moderate activation energy. Our calculations thus demonstrate that the experimentally suggested reaction path without the involvement of aminoimidazole-carbonitrile intermediates is also a viable alternative for the nonaqueous synthesis of nucleobases

Energies and 2′-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations

Sugar–phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2′-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2′-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD­(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD­(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2′-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2′-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2′-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2′-hydroxyl group orientations can be attributed to clashes between occupied orbitals

Energies and 2′-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations

Sugar–phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2′-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2′-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD­(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD­(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2′-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2′-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2′-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2′-hydroxyl group orientations can be attributed to clashes between occupied orbitals

Conceptions of the good, rivalry, and liberal neutrality

Liberal neutrality is assumed to pertain to rival conceptions of the good. The nature of the rivalry between conceptions of the good is pivotal to the coherence, scope and realisation of liberal neutrality. Yet, liberal theorists have said very little about rivalry. This paper attempts to fill this gap by reviewing three conceptions of rivalry: incompatibility rivalry, intra-domain rivalry and state power rivalry. I argue that state power rivalry is the morally relevant conception of rivalry, and that it has significant implications for the scope and realisation of liberal neutrality. I conclude that in the light of state power rivalry, the only feasible liberal neutral state is a very minimal one

On the Geometry and Electronic Structure of the As-DNA Backbone

High-level quantum chemical calculations have been applied to investigate the geometry and electronic properties of the arsenate analogue of the DNA backbone. The optimized geometries as well as hyperconjugation effects along the C3′O3′XO5′C5′ linkage (X = P,As) exhibit a remarkable similarity for both arsenates and phosphates. This suggests that arsenates, if present, might serve as a potential substitute for phosphates in the DNA backbone

On the Road from Formamide Ices to Nucleobases: IR-Spectroscopic Observation of a Direct Reaction between Cyano Radicals and Formamide in a High-Energy Impact Event

The formamide-based synthesis of nucleic acids is considered as a nonaqueous scenario for the emergence of biomolecules from inorganic matter. In the current study, we scrutinized the chemical composition of formamide ices mixed with an FeNi meteorite material treated with laser-induced dielectric breakdown plasma created in nitrogen buffer gas. These experiments aimed to capture the first steps of those chemical transformations that may lead to the formation of nucleobases during the impact of an extraterrestrial icy body containing formamide on an early Earth atmosphere. High-resolution FT-IR spectroscopy combined with quantum chemical calculations was used to analyze the volatile fraction of the products formed during such an event. We have found that the spectrum of the evaporated formamide ices is dominated by the spectral signatures of the dimeric form of formamide. Upon exposure to laser sparks, new well-defined bands appear in the spectrum centered at ∼820, ∼995, and ∼1650 cm^–1. On the basis of quantum chemical calculations, these bands can be assigned to the absorptions of 2-amino-2-hydroxy-acetonitrile and to 2-amino-2-hydroxy-malononitrile, which are formed in a direct reaction between formamide and CN^• radicals upon the high-energy impact event. We also show that there is an exergonic reaction route via these intermediates leading to diaminomaleonitrile, which is generally considered to play a key role in the synthesis of nucleobases

Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles

We report a reparameterization of the glycosidic torsion χ of the Cornell et al. AMBER force field for RNA, χ_OL. The parameters remove destabilization of the anti region found in the ff99 force field and thus prevent formation of spurious ladder-like structural distortions in RNA simulations. They also improve the description of the syn region and the syn–anti balance as well as enhance MD simulations of various RNA structures. Although χ_OL can be combined with both ff99 and ff99bsc0, we recommend the latter. We do not recommend using χ_OL for B-DNA because it does not improve upon ff99bsc0 for canonical structures. However, it might be useful in simulations of DNA molecules containing syn nucleotides. Our parametrization is based on high-level QM calculations and differs from conventional parametrization approaches in that it incorporates some previously neglected solvation-related effects (which appear to be essential for obtaining correct anti/high-anti balance). Our χ_OL force field is compared with several previous glycosidic torsion parametrizations

Understanding the Sequence Preference of Recurrent RNA Building Blocks Using Quantum Chemistry: The Intrastrand RNA Dinucleotide Platform

Folded RNA molecules are shaped by an astonishing variety of highly conserved noncanonical molecular interactions and backbone topologies. The dinucleotide platform is a widespread recurrent RNA modular building submotif formed by the side-by-side pairing of bases from two consecutive nucleotides within a single strand, with highly specific sequence preferences. This unique arrangement of bases is cemented by an intricate network of noncanonical hydrogen bonds and facilitated by a distinctive backbone topology. The present study investigates the gas-phase intrinsic stabilities of the three most common RNA dinucleotide platforms5′-GpU-3′, ApA, and UpCvia state-of-the-art quantum-chemical (QM) techniques. The mean stability of base–base interactions decreases with sequence in the order GpU > ApA > UpC. Bader’s atoms-in-molecules analysis reveals that the N2(G)···O4(U) hydrogen bond of the GpU platform is stronger than the corresponding hydrogen bonds in the other two platforms. The mixed-pucker sugar–phosphate backbone conformation found in most GpU platforms, in which the 5′-ribose sugar (G) is in the C2′-endo form and the 3′-sugar (U) in the C3′-endo form, is intrinsically more stable than the standard A-RNA backbone arrangement, partially as a result of a favorable O2′···O2P intraplatform interaction. Our results thus validate the hypothesis of Lu et al. (Lu, X.-J.; et al. <i>Nucleic Acids Res</i>. <b>2010</b>, <i>38</i>, 4868–4876) that the superior stability of GpU platforms is partially mediated by the strong O2′···O2P hydrogen bond. In contrast, ApA and especially UpC platform-compatible backbone conformations are rather diverse and do not display any characteristic structural features. The average stabilities of ApA and UpC derived backbone conformers are also lower than those of GpU platforms. Thus, the observed structural and evolutionary patterns of the dinucleotide platforms can be accounted for, to a large extent, by their intrinsic properties, as described by modern QM calculations. In contrast, we show that the dinucleotide platform is not properly described in the course of atomistic explicit-solvent simulations. Our work also gives methodological insights into QM calculations of experimental RNA backbone geometries. Such calculations are inherently complicated by rather large data and refinement uncertainties in the available RNA experimental structures, which often preclude reliable energy computations

Can We Accurately Describe the Structure of Adenine Tracts in B-DNA? Reference Quantum-Chemical Computations Reveal Overstabilization of Stacking by Molecular Mechanics

Sequence-dependent local variations of helical parameters, structure, and flexibility are crucial for molecular recognition processes involving B-DNA. A-tracts, i.e., stretches of several consecutive adenines in one strand that are in phase with the DNA helical repeat, mediate significant DNA bending. During the past few decades, there have been intense efforts to understand the sequence dependence of helical parameters in DNA. Molecular dynamics (MD) simulations can provide valuable insights into the molecular mechanism behind the relationship between sequence and structure. However, although recent improvements in empirical force fields have helped to capture many sequence-dependent B-DNA properties, several problems remain, such as underestimation of the helical twist and suspected underestimation of the propeller twist in A-tracts. Here, we employ reference quantum mechanical (QM) calculations, explicit solvent MD, and bioinformatics to analyze the underestimation of propeller twisting of A-tracts in simulations. Although we did not identify a straightforward explanation, we discovered two imbalances in the empirical force fields. The first was overestimation of stacking interactions accompanied by underestimation of base-pairing energy, which we attribute to anisotropic polarizabilities that are not reflected by the isotropic force fields. This may lead to overstacking with potentially important consequences for MD simulations of nucleic acids. The second observed imbalance was steric clash between A­(N1) and T­(N3) nitrogens of AT base pairs in force-field descriptions, resulting in overestimation of the AT pair stretch in MD simulations. We also substantially extend the available set of benchmark estimated CCSD­(T)/CBS data for B-DNA base stacking and provide a code that allows the generation of diverse base-stacking geometries suitable for QM computations with predefined intra- and interbase pair parameters

Can We Accurately Describe the Structure of Adenine Tracts in B-DNA? Reference Quantum-Chemical Computations Reveal Overstabilization of Stacking by Molecular Mechanics

Sequence-dependent local variations of helical parameters, structure, and flexibility are crucial for molecular recognition processes involving B-DNA. A-tracts, i.e., stretches of several consecutive adenines in one strand that are in phase with the DNA helical repeat, mediate significant DNA bending. During the past few decades, there have been intense efforts to understand the sequence dependence of helical parameters in DNA. Molecular dynamics (MD) simulations can provide valuable insights into the molecular mechanism behind the relationship between sequence and structure. However, although recent improvements in empirical force fields have helped to capture many sequence-dependent B-DNA properties, several problems remain, such as underestimation of the helical twist and suspected underestimation of the propeller twist in A-tracts. Here, we employ reference quantum mechanical (QM) calculations, explicit solvent MD, and bioinformatics to analyze the underestimation of propeller twisting of A-tracts in simulations. Although we did not identify a straightforward explanation, we discovered two imbalances in the empirical force fields. The first was overestimation of stacking interactions accompanied by underestimation of base-pairing energy, which we attribute to anisotropic polarizabilities that are not reflected by the isotropic force fields. This may lead to overstacking with potentially important consequences for MD simulations of nucleic acids. The second observed imbalance was steric clash between A­(N1) and T­(N3) nitrogens of AT base pairs in force-field descriptions, resulting in overestimation of the AT pair stretch in MD simulations. We also substantially extend the available set of benchmark estimated CCSD­(T)/CBS data for B-DNA base stacking and provide a code that allows the generation of diverse base-stacking geometries suitable for QM computations with predefined intra- and interbase pair parameters