Prebiotic Evolution and Self-Assembly of Nucleic Acids - ACS Nano

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Prebiotic Evolution and Self-Assembly of Nucleic Acids Antonio Lazcano*

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El Colegio Nacional and Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico ABSTRACT: Prebiotic evolution is the stage that is assumed to have taken place prior to the emergence of the first living entities, during which time the abiotic synthesis of monomers, oligomers, and supramolecular systems that led to the hypothesized RNA world occurred. In this Perspective, the success of one-pot Miller−Urey type synthesis of organic compounds is compared with the multipot syntheses developed within the framework of systems chemistry, which attempts to demonstrate that RNA could have been formed directly in the primitive environment. The prebiotic significance of liquid-crystal ordering of nucleic acid oligomers and self-organizing assemblages of RNA and DNA that are formed in the absence of membranes or mineral matrices is also addressed.

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entities within the context of molecular biology, a relationship that would eventually lead to the prediction of the catalytic activities of RNA. The groundbreaking discovery of ribozymes in the early 1980s by the groups of Thomas Cech and Sidney Altman was a surprise and gave considerable credibility to the proposal that the first living entities were based on RNA, both as the genetic material and the catalyst, a hypothetical stage called the “RNA world.” Awareness of the manifold roles that RNA and ribonucleotides play in extant cells, together with the stunning widening of the catalytic repertoire of RNA under in vitro conditions, which enables new chemical abilities to evolve under selection pressures and to catalyze an increasingly large number of reactions, has lent support to the possibility of a RNA world.3,4

mid the social and political turmoil that followed the 1917 Russian revolution, Alexandr I. Oparin, a young biochemist with a strong background in evolutionary biology, became increasingly skeptical of the generally accepted idea of a spontaneous autotrophic origin of life. Based on the simplicity and ubiquity of fermentative metabolism, he proposed instead that the first organisms had been anaerobic heterotrophic bacteria that were the evolutionary outcome of a lengthy period of prebiotic syntheses and accumulation of organic molecules, whose feasibility, he argued, was demonstrated by the presence of organic compounds in meteorites and by the 19th century laboratory syntheses of urea, sugars, hydrocarbons, and alanine.1 Oparin proposed an inter- and multidisciplinary research program that separated spontaneous generation from the chemical origins of life, but it was not until the early 1950s that his ideas were tested by Stanley L. Miller, a graduate student of Harold Urey. Using electric discharges in a strongly reducing model atmosphere of CH4, NH3, H2O, and H2 based on Oparin’s hypothesis and Urey’s estimates, he reported the successful synthesis of racemic mixtures of amino acids as well as some hydroxy acids, short aliphatic acids, and urea. Miller’s paper appeared 10 days after the publication of Watson and Crick’s double-helix model of DNA and immediately drew the attention of both the media and academia. Although the Watson and Crick proposal had attracted few readers outside a relatively small circle of scholars, the birth of molecular biology changed life sciences forever, coercing subsequent attempts to discuss the origins of life within a framework defined by the details of DNA replication and protein biosynthesis. The abiotic synthesis of adenine achieved by Joan Oró by heating aqueous solutions of ammonium cyanide2 helped to place the emergence of living © XXXX American Chemical Society

Awareness of the manifold roles that RNA and ribonucleotides play in extant cells, together with the stunning widening of the catalytic repertoire of RNA under in vitro conditions, has lent support to the possibility of a RNA world. WHAT KIND OF PREBIOTIC CHEMISTRY? Miller−Urey type experiments are one-pot, high-energy chemical syntheses that typically produce one class of

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were formed simultaneously via the reductive homologation of HCN and some of its derivatives, supporting the contention that all the basic biochemical subsystems could have emerged simultaneously through common chemical processes. This is an encouraging teleological approach that supports the RNA world hypothesis, but it has been taken with a grain of salt by those who argue that, given adequate expertise and experimental conditions, it would be possible to synthesize abiotically almost any organic molecule in the laboratory. For instance, the cyanosulfidic protometabolism model yields alanine, threonine, leucine, isoleucine, valine, serine, asparagine, aspartic acid, glutamine, glutamic acid, and, interestingly, arginine, but it does not reflect the extraordinary diversity of amino acids present in carbonaceous chondrites, which, as noted above, are the best available models of primitive solar system chemical synthesis. According to its critics, the highly constrained processes of these stepwise strategies strongly limit their prebiotic significance because they require multipot steps involving several changes of pH, UV irradiation, and the sequential delivery of different reactants, such as hydrogen cyanide and hydrogen. This issue remains open.

molecules together with low yields of some additional compounds and an intractable mixture of organic polymers. These experiments are models of plausible prebiotic routes for a number of monomers of biochemical significance including amino acids, purines, pyrimidines, and sugars as well as urea, carboxylic acids, alcohols, a wide variety of aliphatic and aromatic hydrocarbons, and branched and straight fatty acids, including some that are membrane-forming compounds. The remarkable coincidence between the molecules synthesized in prebiotic experiments and their occurrence in the 4.5 × 109 years old Murchison meteorite suggests that a rather complex array of nonbiological amino acids and many other compounds were present in the prebiotic environment. Analysis of the Murchison and other carbon-rich meteorites shows that, in addition to significant amounts of an insoluble organic component, there are over 90 different amino acids present as well as a rich repertoire of molecules that includes a wide assortment of nucleobases, carboxylic and hydroxyl acids, aliphatic and aromatic hydrocarbons, and polyols and amines (cf. ref 5). The different compounds formed in Miller−Urey type simulations are generally synthesized under independent, separate experimental conditions that are not always truly compatible. For instance, cyanide and ammonia react under ambient conditions and form some of the nucleobases found in nucleic acids, but also form many other compounds including cyanide polymeric material. Condensation of H2CO at basic conditions yields a complex mixture of sugars that includes small amounts of a racemic mixture of D,L-ribose, but the reaction is rapidly inhibited by cyanamide, an HCN derivative that was probably a ubiquitous molecule in the primitive environment. Left on its own, the array of carbohydrates produced from formaldehyde is transformed into a complex tar-like mixture that does not partake in the formation of nucleosides. Attempts to overcome these issues have led to alternative low-energy strategies that are seen by many as supporting the likelihood that RNA was a direct outcome of prebiotic chemistry.6 This possibility is backed by the system chemistry strategy developed by Powner et al. for the abiotic formation of pyrimidine ribonucleotides.7 The traditional approach for the synthesis of these key compounds has been based on the separate formation of ribose and pyrimidines, which are subsequently mixed and phosphorylated. However, ribose is prone to decomposition, and no plausible mechanism has been found for the nucleoside formation. Powner et al. found that the addition of inorganic phosphate to a mix of prebiotic reactants that included glycolaldehyde and cyanamide catalyzed the formation of the highly volatile 2-aminooxazole, which, in a series of well-understood steps, forms ribocytidine. When the mixture is irradiated by ultraviolet light, a number of side products are decomposed, and the oxidative deamination of the activated cytidine rapidly forms ribouridine. Subsequent work by Sutherland and co-workers on a cyanosulfidic chemistry experimental model has shown that glycolaldehyde and glyceraldehyde will react with HCN and H2S forming α-aminonitriles, which can be hydrolyzed and form α-amino acids.8 Ultraviolet irradiation of a mixture that included cyanamide, acetylene, dihydroxyacetone, and several transition metals lead to the simultaneous formation of precursors of ribonucleotides and phosphorylated glycerols, which are the starting material for phospholipid synthesis. In other words, precursors of proteins, RNA, and membranes

CONDENSATION REACTIONS AND PREBIOTIC POLYMERIZATION Glycylglycine and 2,5-diketopiperazines have been reported in samples of the Yamato-791198 and Murchison meteorites. However, it is unlikely that the processes could have taken place directly in the dilute aqueous bodies of water that could have accumulated on the primitive earth. Determining how simple organic compounds were assembled into polymers and then into the first living entities remains a major scientific challenge. There are several types of environments in which the formation of abiotic polymers could have taken place in the primitive earth. The list includes oceanic sediments, intertidal zones, shallow ponds, cation-rich salty brines, membranebound systems, freshwater lakes, lagoons undergoing wet and dry cycles, and glacial ponds where evaporation, eutectic separations, or other physicochemical mechanisms such as the adherence of biochemical monomers to active surfaces could have raised local concentrations and promoted polymerization. Low-temperature environments such as glacial ponds or winter freezing of small ponds may have favored the formation of oligopeptides and other polymers, including polyribonucleotides, which are synthesized in the eutectic phase between ice crystals where ribonucleotide concentrate.9,10 There are several condensing agents that may have catalyzed prebiotic polymerization reactions. Perhaps the most significant is cyanamide, which is found in the interstellar medium, is easily formed under possible prebiotic conditions, and may have had catalyzed peptide-bond formation simultaneously with Strecker-type synthesis of amino acids.10 Under mild conditions, diamidophosphate has been shown to phosphorylate aqueous solutions or paste mixtures of nucleosides, amino acids and fatty acids, and glycerol, in one-pot reactions that yield oligonucleotides and peptides, together with vesicleforming lipids.11 The first to underline the role of clays and other mineral matrices in the polymerization of monomers under primordial conditions was Bernal.12 Condensation of acidic amino acids by positively charged mineral surfaces such as montmorillonite is well established.13 Most condensation reactions use glycine or other α-amino acids, but the formation of the peptide-bondB

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important role in enriching the primitive broth in molecules not readily synthesized by other abiotic reactions, but they are not ancestral to extant proteins, whose origin can only be understood within the framework of the catalytic abilities of RNA molecules. Like montmorillonite and other catalytic mineral surfaces, prebiotic oligopeptides may have been transitory scaffolds for the formation of other molecules and may have favored the formation of chemically active microenvironments, but the evidence that protein synthesis first evolved in the RNA world indicates that experiments on the abiotic formation of oligopeptides have little, if any, relevance to our understanding of the ultimate emergence of enzymes (cf. ref 19).

rich oligo-depsipeptide formed in an iterative dehydration− rehydratation process from a mixture of α-hydroxy acids and αamino acids shows the importance of more realistic models of the chemistry of the primitive environment (cf. ref 14). The role of abundant minerals like silica in the formation of polypeptides via α-hydroxy acid-mediated amide-bond formation has been recently described,15 supporting Bernal’s prediction on the catalytic properties of quartz under possible primitive conditions. The role of montmorillonite in the condensation of activated ribonucleotides that form oligoribonucleotides that remain attached to the clay matrix is well-known.13 Polynucleotide binding to hydroxyapatite is known to increase with the length of the polymer and its secondary structure, without apparently affecting its template properties.16,17 As described by Todisco et al. in this issue of ACS Nano, formation of supramolecular nucleic acid assemblages may have provided the environment for their own elongation in the absence of clays or other external factors.18 In an aqueous environment at physiological pH and moderate temperatures, RNA oligomers self-assemble and phase separate into highly concentrated liquid-crystal microdomains in which nonenzymatic end-to-end formation of interchain phosphodiester bonds takes place.

COMPARTMENTS AND SELF-ORGANIZATION There is no known fossil evidence of the systems that preceded cellular life, nor is there a consensus on the attributes of the first living entities. Despite these seemingly insurmountable obstacles, there has been no shortage of discussion on the nature of the precellular systems that may have preceded the first cells. How the transition from abiotically synthesized organic matter into the first living entities took place is pure conjecture, but several different experimental models have been proposed, including liposomes, porous rocks, particulate mineral surfaces, noncovalent assemblies of oligonucleotides, emulsion droplets, and phase-separated droplets, including coacervates.3 Joyce and Szostak’s inventory includes noncovalent nucleic acid assemblages such as DNA and RNA self-replicative origami systems.3 As shown by the work of Bellini and Clark and their co-workers,18,23−25 the list can also include complexes that result from the liquid-crystal ordering of nucleic acid oligomers; in addition, self-organizing assemblages of RNA and DNA are easily formed under moderate conditions in the absence of membranes or mineral matrices and could provide insight into prebiotic supramolecular structures. Due to their amphiphilic character and ability to form hydrogen bonds, highly concentrated mixtures of short oligonucleotides and mononucleoside triphosphates selfaggregate and exhibit phase transitions that result in stacked aggregates in the absence of templates.24 Short DNA and RNA oligomers form nematic liquid-crystal environments in which ligation reactions take place at moderate conditions of 25 °C at pH 7.5 and self-assemble in liquid-crystal structures that not only raise their local concentrations but also protect against degradation. Liquid crystallization of short six-base RNA oligomers is a self-organizing supramolecular system that acts as a template in the formation of linear chains, where the most efficient step is the enzyme-free formation of interstrand phosphodiester bonds.18 RNA oligomers self-assemble and undergo phase separation into highly concentrated ordered fluid liquid-crystal microdomains under a wide range of moderate conditions. Their formation provides a template that facilitates their ligation into hundred base-long chains, i.e., nucleic acid liquid crystals boost the rate of end-to-end ligation and suppress the formation of the otherwise dominant cyclic oligomers. Given the proper supply of chemical precursors, these self-synthesizing systems form supramolecular structures that enhance the formation of new molecules that partake in the process and represent a phenomenon of self-organization that leads to nanoscale microenvironments favoring replication and protection against environmental insults. These results show that liquid

As described by Todisco et al. in this issue of ACS Nano, formation of supramolecular nucleic acid assemblages may have provided the environment for their own elongation in the absence of clays or other external factors. As reviewed elsewhere,19 the interaction of relatively simple peptides in solution or with salts and lipids can lead to stable α-helices, β sheets, and complexes of small peptides,20,21 raising the possibility of catalytic interactions between prebiotic biochemical monomers and oligomers.22 These interactions may be particularly relevant for simple dipeptides with histidine moieties, which are known to catalyze polymerization reactions of amino acids as well as ribonucleotide dephosphorylation and polymerization. However, no catalysis of templated RNA polymerization by small catalytic peptides has been shown to date. It is doubtful that these observations provide any direct information on the origin of protein biosynthesis and enzymes. Bernal’s book was published in 1951, well before the mechanism of ribosome-mediated protein synthesis was elucidated. Regardless of their possible catalytic activity and structural complexity, noncoded peptides of abiotic origin would have an ephemeral character. Even if an extremely rich prebiotic supply of chemically active oligo- or polypeptides is assumed, sooner or later they would be exhausted. Continuous geochemical mechanisms replenishing the supply of noncoded oligopeptides can be postulated, but in the absence of hereditary mechanisms ensuring the stability and diversification of encoded proteins, catalytic peptides would have come and gone without leaving any direct descendants able to resurrect the process. It is possible that some metallic cofactors required for biological catalysis by enzymes and ribozymes are the evolutionary vestiges of primitive interactions with minerals. Prebiotic oligo- and polypeptides could have played an C

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the surprising ability of RNA oligomers to self-assemble and to phase-separate into highly concentrated ordered fluid liquidcrystal microdomains,18 are consistent with the proposal that they played a key role in early evolution and, perhaps, in the origin of life itself.4 The RNA world hypothesis has stood the test of time extraordinarily well. The surprising widening of the catalytic repertoire of ribozymes thanks to the systematic evolution of ligands by exponential enrichment (SELEX) experiments, which enable an increasingly large number of catalytic abilities to appear under selection pressure, has greatly simplified our understanding of the origins of protein biosynthesis and of the genetic code. Until a few years ago, the origins of the genetic code and of protein synthesis were considered synonymous with the appearance of life itself. This is no longer the case. The demonstration that ribosomal peptide synthesis is a ribozyme-catalyzed reaction makes it almost certain that there was once an RNA world and that protein biosynthesis is one of its evolutionary outcomes. Nevertheless, our current evolutionary narratives are not without difficulties, and there are of course massive blind spots. The search for the nature and origin of life is not a modest scientific undertaking, and those involved in this field know that we have plenty to be modest about, as we should be.

crystallization of RNA oligomers leads to molecular scaffolds for higher order supramolecular ordering that can promote replication, polymerization, and protection against degradation, which may have played a role in the origin and maintenance of the RNA world.18 Regardless of their extraordinary set of genetic properties, catalytic versatility, structural flexibility, and self-assembly properties, it is difficult to picture RNA-based systems in blissful isolation from the other components of the prebiotic environment. If liquid-crystal assemblies of RNA molecules in which self-elongation is observed in the absence of external components, as described by Todisco et al.,18 were formed in the primitive earth, they could have interacted with a wide range of chemical species, including amino acids, oligopeptides, metallic cations, and mineral matrices, among others. The phase separation of liquid-crystal domains forms membrane-less compartmentalized systems, but company would have been kept by many other compounds, including a wide variety of aliphatic and aromatic hydrocarbons, alcohols, and membrane-forming branched and straight fatty acids. Different types of lipids may have been present in the primitive earth due to the deposition of meteoritic material or endogenous abiotic syntheses, but precellular systems could not thrive forever on the prebiotic fat of the land. Even if an extremely rich prebiotic supply of membrane-forming compounds is assumed, the issue of the evolutionary development of lipid biosynthesis has to be considered. It is tempting to assume that fatty acid anabolism first appeared during an evolutionary period in which ribozymes played a more conspicuous role in biosynthetic processes. This possibility is supported, albeit weakly, by the key roles that ribonucleotide coenzymes play in fatty acid biosynthesis, as shown by (a) the elongation of the growing fatty acid chain by the sequential addition of two-carbon units derived from acetyl CoA; (b) malonyl CoA being the activated donor of two-carbon units during elongation; (c) NADPH being the reductant in fatty acid synthesis; and (d) the intermediates being linked to an acyl carrier protein, which can be regarded as a “macro CoA”.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The author declares no competing financial interest.

ACKNOWLEDGMENTS I am indebted to Drs. Tommaso Bellini and Tommaso Fraccia for introducing me to the possible prebiotic significance of nucleic acid liquid crystallization and to Professor Ana Barahona for pointing out the adequacy of the term “scaffold” to describe some of the phenomena discussed here. I thank José Alberto Campillo Balderas and Ricardo Hernandez Morales for help with the manuscript.

CONCLUSIONS AND PROSPECTS Recent theoretical and experimental developments in the reconstruction of primitive terrestrial environments, laboratory models of prebiotic evolution, and the recognition of the manifold roles of RNA in extant cells have provoked a dramatic shift in the questions that we ask today from those raised only a few decades ago. Quite significantly, RNA is no longer seen as a mere molecular handyman but as an essential component of the processes that led to extant life forms.3,4

REFERENCES (1) Lazcano, A. Alexandr I. Oparin and the Origin of Life: A Historical Reassessment of the Heterotrophic Theory. J. Mol. Evol. 2016, 83, 214−222. (2) Oró, J. Synthesis of Adenine from Ammonium Cyanide. Biochem. Biophys. Res. Commun. 1960, 2, 407−412. (3) Joyce, G. F.; Szostak, J. W. Protocells and RNA Self-Replication. Cold Spring Harbor Perspect. Biol. 2018, 10, a034801. (4) Vázquez-Salazar, A.; Lazcano, A. Early Life: Embracing the RNA World. Curr. Biol. 2018, 28, R220−R222. (5) Glavin, D. P.; Alexander, C. M. O’D.; Aponte, J. C.; Dworkin, J. P.; Elsila, J. E.; Yabuta, H. The Origin and Evolution of Organic Matter in Carbonaceous Chondrites and Links to their Parent Bodies. In Primitive Meteorites and Asteroids; Abreu, N., Ed.; Elsevier: Amsterdam, The Netherlands, 2018: pp 205−271. (6) Sutherland, J. D. The Origin of Life − Out of the Blue. Angew. Chem., Int. Ed. 2016, 55, 104−121. (7) Powner, M. W.; Gerland, B.; Sutherland, J. D. Synthesis of Activated Pyrimidine Ribonucleotides in Prebiotically Plausible Conditions. Nature 2009, 459, 239−242. (8) Patel, B. H.; Percivalle, C.; Ritson, J.; Duffy, C. D.; Sutherland, J. D. Common Origins of RNA, Protein and Lipid Precursors in a Cyanosulfidic Protometabolism. Nat. Chem. 2015, 7, 301−307.

RNA is no longer seen as a mere molecular handyman but as an essential component of the processes that led to extant life forms. However, the RNA world should not be thought of as depicting a simplistic image of a worldwide ocean rich in selfreplicating RNA molecules and accompanied by all sorts of biochemical monomers. Although the ultimate origin of ribozymes remains an open issue, the catalytic, regulatory, and structural properties of RNA molecules and ribonucleotides, combined with their ubiquity in cellular processes and D

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(9) Kanavarioti, A.; Monnard, P. A.; Deamer, D. W. Eutectic Phases in Ice Facilitate Nonenzymatic Nucleic Acid Synthesis. Astrobiology 2001, 1, 271−281. (10) Parker, E.; Cleaves, H. J.; Callahan, M. P.; Dworkin, J. P.; Glavin, D. P.; Lazcano, A.; Bada, J. L. Prebiotic Synthesis of Methionine and Other Sulfur-Bearing Organic Compounds on the Primitive Earth: A Contemporary Reassessment Based on an Unpublished 1958 Stanley Miller Experiment. Origins Life Evol. Biospheres 2011, 41, 201−212. (11) Gibard, C.; Bhowmik, S.; Karki, M.; Kim, E. K.; Krishnamurthy, R. Phosphorylation, Oligomerization and Self-Assembly in Water Under Potential Prebiotic Conditions. Nat. Chem. 2018, 10, 212− 217. (12) Bernal, J. D. The Physical Basis of Life; Routledge and Paul, London, 1951. (13) Ferris, J. P.; Hill, A. R.; Liu, R.; Orgel, L. E. Synthesis of Long Prebiotic Oligomers on Mineral Surfaces. Nature 1996, 381, 59−61. (14) Krishnamurthy, R. Life’s Biological Chemistry: A Destiny or Destination Starting from Prebiotic Chemistry? Chem. - Eur. J. 2018, DOI: 10.1002/chem.201801847. (15) McKee, A. D.; Solano, M.; Saydjari, A.; Bennett, C. J.; Hud, N. V.; Orlando, T. M. A Possible Path to Prebiotic Peptides Involving Silica and Hydroxyl Acid-Mediated Amide Bond Formation. ChemBioChem 2018, 19, 1913. (16) Gibbs, D.; Lohrmann, R.; Orgel, L. E. Template-Directed Synthesis and Selective Adsorption of Oligoadenylates on Hydroxyapatite. J. Mol. Evol. 1980, 15, 347−354. (17) Schwartz, A. W.; Orgel, L. E. Template-Directed Polynucleotide Synthesis on Mineral Surfaces. J. Mol. Evol. 1985, 21, 299−300. (18) Todisco, M.; Fraccia, T.; Smith, G.; Corno, A.; Bethge, L.; Klussmann, S.; Paraboschi, E.; Asselta, R.; Colombo, D.; Zanchetta, G.; Clark, N.; Bellini, T. Nonenzymatic Polymerization into Long Linear RA Template by Liquid Crystal Self-Assembly. ACS Nano 2018, DOI: 10.1021/acsnano.8b05821. (19) Raggi, L.; Bada, J. L.; Lazcano, A. On the Lack of Evolutionary Continuity Between Prebiotic Peptides and Extant Enzymes. Phys. Chem. Chem. Phys. 2016, 18, 20028−20032. (20) Hammes, G. G.; Schullery, S. E. Structure of Molecular Aggregates. II. Construction of Model Membranes from Phospholipids and Polypeptides. Biochemistry 1970, 9, 2555−2558. (21) Bertrand, M.; Brack, A. Conformational Variety of Polyanionic Peptides at Low Salt Concentrations. Origins Life Evol. Biospheres 1997, 27, 585−595. (22) Plankensteiner, K.; Reiner, H.; Rode, B. M. From Earth’s Primitive Atmosphere to Chiral Peptides − The Origin of Precursors of Life. Chem. Biodiversity 2004, 1, 1308−1315. (23) Fraccia, T. P.; Smith, G. P.; Zanchetta, G.; Paraboschi, E.; Yi, Y.; Walba, D. M.; Dieci, G.; Clark, N. A.; Bellini, T. Abiotic Ligation of DNA Oligomers Templated by their Liquid Crystal Ordering. Nat. Commun. 2015, 6, 6424. (24) Fraccia, T. P.; Smith, G. P.; Bethge, L.; Zanchetta, G.; Nava, G.; Klussmann, S.; Clark, N. A.; Bellini, T. Liquid Crystal Ordering and Isotropic Gelation in Solutions of Four-Base-Long DNA Oligomers. ACS Nano 2016, 10, 8508−8516. (25) Smith, G. P.; Fraccia, T. P.; Todisco, M.; Zanchetta, G.; Zhu, C.; Hayden, E.; Bellini, T.; Clark, N. A. Backbone-Free DuplexStacked Monomer Nucleic Acids Exhibiting Watson−Crick Selectivity. Proc. Natl. Acad. Sci. U. S. A. 2018, 115, E7658−E7664.

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