The Origin and Early Evolution of Life Prebiotic Chemistry of Biomolecules Michele Fiore www.mdpi.com/journal/life Edited by Printed Edition of the Special Issue Published in Life The Origin and Early Evolution of Life The Origin and Early Evolution of Life: Prebiotic Chemistry of Biomolecules Special Issue Editor Michele Fiore MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editor Michele Fiore University of Lyon France Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Life (ISSN 2075-1729) from 2018 to 2019 (available at: https://www.mdpi.com/journal/life/special issues/ Prebiotic Chemistry) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year , Article Number , Page Range. 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Contents About the Special Issue Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Michele Fiore The Origin and Early Evolution of Life: Prebiotic Chemistry Reprinted from: Life 2019 , 9 , 73, doi:10.3390/life9030073 . . . . . . . . . . . . . . . . . . . . . . . . 1 Peter Strazewski The Beginning of Systems Chemistry Reprinted from: Life 2019 , 9 , 11, doi:10.3390/life9010011 . . . . . . . . . . . . . . . . . . . . . . . 3 Raffaele Saladino, Judit E. ˇ Sponer, Jiˇ r ́ ı ˇ Sponer, Giovanna Costanzo, Samanta Pino and Ernesto Di Mauro Chemomimesis and Molecular Darwinism in Action: From Abiotic Generation of Nucleobases to Nucleosides and RNA Reprinted from: Life 2018 , 8 , 24, doi:10.3390/life8020024 . . . . . . . . . . . . . . . . . . . . . . . . 10 Ibrahim Shalayel, Seydou Coulibaly, Kieu Dung Ly, Anne Milet and Yannick Vall ́ ee The Reaction of Aminonitriles with Aminothiols: A Way to Thiol-Containing Peptides and Nitrogen Heterocycles in the Primitive Earth Ocean Reprinted from: Life 2018 , 8 , 47, doi:10.3390/life8040047 . . . . . . . . . . . . . . . . . . . . . . . 25 Victor Sojo, Aya Ohno, Shawn E. McGlynn, Yoichi M.A. Yamada and Ryuhei Nakamura Microfluidic Reactors for Carbon Fixation under Ambient-Pressure Alkaline-Hydrothermal-Vent Conditions Reprinted from: Life 2019 , 9 , 16, doi:10.3390/life9010016 . . . . . . . . . . . . . . . . . . . . . . . . 39 Ziwei Liu, Jean-Christophe Rossi and Robert Pascal How Prebiotic Chemistry and Early Life Chose Phosphate Reprinted from: Life 2019 , 9 , 26, doi:10.3390/life9010026 . . . . . . . . . . . . . . . . . . . . . . . . 49 Tian Tian, Xin-Yi Chu, Yi Yang, Xuan Zhang, Ye-Mao Liu, Jun Gao, Bin-Guang Ma and Hong-Yu Zhang Phosphates as Energy Sources to Expand Metabolic Networks Reprinted from: Life 2019 , 9 , 43, doi:10.3390/life9020043 . . . . . . . . . . . . . . . . . . . . . . . . 65 Harold S Bernhardt Making Molecules with Clay: Layered Double Hydroxides, Pentopyranose Nucleic Acids and the Origin of Life Reprinted from: Life 2019 , 9 , 19, doi:10.3390/life9010019 . . . . . . . . . . . . . . . . . . . . . . . . 77 Michael S. Wang, Kenric J. Hoegler and Michael H. Hecht Unevolved De Novo Proteins Have Innate Tendencies to Bind Transition Metals Reprinted from: Life 2019 , 9 , 8, doi:10.3390/life9010008 . . . . . . . . . . . . . . . . . . . . . . . . 88 Zikri Altun, Erdi Bleda and Carl Trindle Production of Carbamic Acid Dimer from Ammonia-Carbon Dioxide Ices: Matching Observed and Computed IR Spectra Reprinted from: Life 2019 , 9 , 34, doi:10.3390/life9020034 . . . . . . . . . . . . . . . . . . . . . . . . 103 v Juan Francisco Carrascoza May ́ en, Jakub Rydzewski, Natalia Szostak, Jacek Blazewicz and Wieslaw Nowak Prebiotic Soup Components Trapped in Montmorillonite Nanoclay Form New Molecules: Car-Parrinello Ab Initio Simulations Reprinted from: Life 2019 , 9 , 46, doi:10.3390/life9020046 . . . . . . . . . . . . . . . . . . . . . . . . 114 Hyman Hartman and Temple F. Smith Origin of the Genetic Code Is Found at the Transition between a Thioester World of Peptides and the Phosphoester World of Polynucleotides Reprinted from: Life 2019 , 9 , 69, doi:10.3390/life9030069 . . . . . . . . . . . . . . . . . . . . . . . 132 Peter Strazewski Low-Digit and High-Digit Polymers in the Origin of Life Reprinted from: Life 2019 , 9 , 17, doi:10.3390/life9010017 . . . . . . . . . . . . . . . . . . . . . . . . 149 Annabelle Biscans Exploring the Emergence of RNA Nucleosides and Nucleotides on the Early Earth Reprinted from: Life 2018 , 8 , 57, doi:10.3390/life9030057 . . . . . . . . . . . . . . . . . . . . . . . . 162 Sankar Chatterjee and Surya Yadav The Origin of Prebiotic Information System in the Peptide/RNA World: A Simulation Model of the Evolution of Translation and the Genetic Code Reprinted from: Life 2019 , 9 , 25, doi:10.3390/life9010025 . . . . . . . . . . . . . . . . . . . . . . . . 175 Stefano Piotto, Lucia Sessa, Andrea Piotto, Anna Maria Nardiello and Simona Concilio Plausible Emergence of Autocatalytic Cycles under Prebiotic Conditions Reprinted from: Life 2019 , 9 , 33, doi:10.3390/life9020033 . . . . . . . . . . . . . . . . . . . . . . . 246 Saskia Lamour, Sebastian Pallmann, Maren Haas and Oliver Trapp Prebiotic Sugar Formation Under Nonaqueous Conditions and Mechanochemical Acceleration Reprinted from: Life 2019 , 9 , 52, doi:10.3390/life9020052 . . . . . . . . . . . . . . . . . . . . . . . . 257 Chaitanya V. Mungi, Niraja V. Bapat, Yayoi Hongo and Sudha Rajamani Formation of Abasic Oligomers in Nonenzymatic Polymerization of Canonical Nucleotides Reprinted from: Life 2019 , 9 , 57, doi:10.3390/life9030057 . . . . . . . . . . . . . . . . . . . . . . . . 268 vi About the Special Issue Editor Michele Fiore , Associate Professor of organic chemistry at the University of Lyon, Claude Bernard, Lyon 1, conducts research in the field of systems chemistry, prebiotic chemistry, and on the preparation of synthetic protocells to identify abiotic models that enable understanding or a possible explanation for the origin of life. Michele Fiore is a Doctorate of the University of Naples “Federico II”, where he completed his thesis on the chemical and biological characterization of phytotoxins produced by phytopathogenic fungi under the direction of Prof. A. Evidente. Michele Fiore has worked at the USDA, ARS, NPURU (United States Department of Agriculture, Agricultural Research Service, Natural Product Utilization Research Unit) under the direction of Dr. S. O. Duke and Dr. A. M. Rimando. He was Senior Postdoc at the University of Ferrara (Prof. A. Dondoni) and Grenoble Rhone-Alpes (Prof. O. Renaudet) where he studies the synthesis of bioactive molecules against degenerative and proliferative diseases and the formulation of vaccine prototypes against cancer. In the last five years, he has collaborated with Prof. P. Strazewski of the SysChem laboratory at the Institut de Chimie et Biochimie Mol ́ eculaires et Supramol ́ eculaires of the University of Lyon on the formulation of evolutionary chemical systems. On the 4th of July 2019, he received the “Habilitation ` a Diriger des Recherches” from University of Lyon for his thesis entitled “Prebiotic Synthesis of Phospholipids and Membranogenic Compounds: Use and Application in Systems Chemistry. At present, Michele Fiore is Editor for the Royal Chemical Society. vii life Editorial The Origin and Early Evolution of Life: Prebiotic Chemistry Michele Fiore Universit é de Lyon, Claude Bernard Lyon 1, Institut de Chimie et Biochimie Mol é culaires et Supramol é culaires, Batiment Lederer, Bureau 11.002, 1 Rue Victor Grignard, F–69622 Villeurbanne CEDEX, France; michele.fiore@univ-lyon1.fr; Tel.: + 33-(0)472-448-080 Received: 4 September 2019; Accepted: 9 September 2019; Published: 12 September 2019 Microfossil evidence indicates that cellular life on Earth emerged during the Paleoarchean era be-tween 3.6 and 3.2 thousand million years ago (Gya) [ 1 ]. But what is really what we call life? How, where, and when did life arise on our planet? These questions have remained most-fascinating over the last hundred years. The German biologist Carl Richard Woese emphasized the urgency of conducting in-depth studies in search of what in the early days of the formation of the universe and then of our planet, gave rise to what is called Life and he wrote “ Biology today is no more fully understood in principle than physics was a century or so ago. In both cases the guiding vision has (or had) reached its end, and in both, a new, deeper, more invigorating representation of reality is (or was) called for .” [ 2 ] From the beginning of the last century, and in accord with what David Deamer highlighted “Life can emerge where physics and chemistry intersect” and for this reason the study of the origin of Life intersect not only the organic and inorganic chemistry but also biology, astrophysics, geochemistry, geophysics, planetology, earth science, bioinformatics, complexity theory, mathematics and philosophy from the equation. From an evolutionary chemical point of view, is possible to presume that life emerged from a mixture of inanimate matter: Organic and inorganic compounds. Such compounds reacted under favorable conditions, forming molecules that are commonly called “biotic” and that, thanks to a kind of self-organization, gave rise to the first biopolymers and to proto-metabolisms. The geology and the chemistry of Earth before the advent of life was completely different from what we know today. At that time, sunlight, volcanic heat, and hydrothermal sites were the main energy sources that could drive the synthesis of many molecules, including nucleosides, peptides, sugars and amphiphilic compounds. The atmosphere was mostly nitrogen (N 2 ), as today, with a substantial amount of carbon dioxide (CO 2 ) and much smaller amounts of carbon monoxide, ammonia, and methane (CO, NH 3 , CH 4 ). It is also likely that water, present in locally limited amounts, contained hydrogen cyanide (HCN), formaldehyde (HCHO) and formamide (HCONH 2 ). Intriguingly, those molecules are found in the interstellar space together with many other that can be considered as building blocks for the assembling of biomolecules such as water (H 2 O), formic acid (HCOOH), methanol (CH 3 OH) cyanamide (NH 2 CN), acetic acid (CH 3 COOH), acetamide (CH 3 CONH 2 ), ethylene glycol (HOCH 2 CH 2 OH) and glycine [ 3 , 4 ]. Prebiotic chemistry experiences showed that the chemical combinations of different building blocks can give rise to the formations of different classes of biotic molecules such as 2’,3’-cyclic pyrimidine nucleotides, various–amino acids and glycerol phosphate [ 5 – 11 ]. The plausible scenarios for the assembling of these building blocks thus of such complex biomolecules are depicted as two: Hydrothermal vents and hydrothermal pools. Hydrothermal vents are systems whose heat source is the underlying magma or hot water generated by convection currents due to high thermal gradients [ 12 ]. The alternatives to hydrothermal vents are hydrothermal fields known also as hydrothermal pools. Recently, Damer and Deamer pointed out that fluctuating hydrothermal pools (FHPs) could be considered as plausibly prebiotic reactors for the synthesis of several key molecules for the development of life, including lipids, nucleic acids and peptides [ 13 ]. This short r é sum é is to say that the seventeen papers published in this special issue perfectly matches with the aim of the study of the origin of Life from a system chemistry and prebiotic chemistry perspective. We expect Life 2019 , 9 , 73; doi:10.3390 / life9030073 www.mdpi.com / journal / life 1 Life 2019 , 9 , 73 that this collection of original articles and reviews will provide the reader with an updated view of some important aspects of prebiotic chemistry thought. We hope that in the further investigations on the origin of Life will bring scientist to combine prebiotic chemistry and system chemistry in order to develop new strategies for the best understanding of how life emerged on planet based on the use of protocells models that can encapsulate sort of primitive metabolisms [14,15]. Acknowledgments: Michele Fiore wish to warmly thank all the contributors of the special issue of LIFE (ISSN 2075-1729): “The Origin and Early Evolution of Life: Prebiotic Chemistry”. My daily work is dedicated to the memory of my beloved daughter Oc é ane (2015–2017). Conflicts of Interest: The author declares no conflict of interest. References 1. Wacey, D.; Kilburn, M.R.; Saunders, M.; Cli ff , J.; Brasier, M.D. Microfossils of sulphur-metabolizing cells in 3.4-billion-year-old rocks of Western Australia. Nat. Geosci. 2011 , 4 , 698–702. 2. Woese, C.R. A new biology for a new century. Microbiol. Mol. Biol. Rev. 2004 , 68 , 173–186. [CrossRef] [PubMed] 3. Cleaves, H.J., II. Prebiotic Chemistry: Geochemical Context and Reaction Screening. Life 2013 , 3 , 331–345. [CrossRef] [PubMed] 4. Zahne, K.; Schaefer, L.; Fegley, B. Earth’s Earliest Atmospheres. Cold Spring Harbor Perps Biol. 2010 , 2 , a004895. 5. Patel, B.H.; Percivalle, C.; Ritson, D.J.; Du ff y, C.D.; Sutherland, J.D. Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nat. Chem. 2015 , 7 , 301–307. [CrossRef] [PubMed] 6. Saladino, R.; Crestini, C.; Pino, S.; Costanzo, G.; Di Mauro, E. Formamide and the origin of life. Phys. Life Rev. 2012 , 9 , 84–104. [CrossRef] [PubMed] 7. Fiore, M.; Strazewski, P. Bringing Prebiotic Nucleosides and Nucleotides Down to Earth. Angew. Chem. Int. Ed. 2016 , 55 , 13930–13933. [CrossRef] [PubMed] 8. Fiore, M.; Strazewski, P. Prebiotic Lipidic Amphiphiles and Condensing Agents on the Early Earth. Life 2016 , 6 , 17. [CrossRef] [PubMed] 9. Fiore, M. The synthesis of mono-alkyl phosphates and their derivatives: An overview of their nature, preparation and use, including synthesis under plausible prebiotic conditions. Org. Biomol. Chem. 2018 , 16 , 3068–3086. [CrossRef] [PubMed] 10. Fayolle, D.; Altamura, E.; D’Onofrio, A.; Madanamothoo, W.J.; Fenet, B.; Mavelli, F.; Buchet, R.; Stano, P.; Fiore, M.; Strazewski, P. Crude phosphorylation mixitures containing racemic lipid amphiphiles self-assemble to give stable primitive compartments. Sci. Rep. 2017 , 7 , 18106. [CrossRef] [PubMed] 11. Fiore, M.; Madanamoothoo, W.; Berlioz-Barbier, A.; Manniti, O.; Girard-Egrot, A.; Buchet, R.; Strazewski, P. Giant vesicles from rehydrated crude phosphorylation mixtures containing mono-alkyl phosphoethanolamine and its analogues. Org. Biomol. Chem. 2017 , 15 , 4231–4238. [CrossRef] [PubMed] 12. Miller, S.L.; Bada, J.L. Submarine hot springs and the origin of life. Nature 1988 , 334 , 609–611. [CrossRef] [PubMed] 13. Damer, B.; Deamer, D. Coupled Phases and Combinatorial Selection in Fluctuating Hydrothermal Pools: A Scenario to Guide Experimental Approaches to the Origin of Cellular Life. Life 2015 , 5 , 872–887. [CrossRef] [PubMed] 14. Fiore, M.O.; Maniti, O.; Girard-Egrot, A.; Monnard, P.-A.; Strazewski, P. Glass Microsphere-Supported Giant Vesicles as Tools for Observation of Self-reproduction of Lipid Boundaries. Angew. Chem. Int. Ed. 2018 , 57 , 282–286. [CrossRef] [PubMed] 15. Lopez, A.; Fiore, M. Investigating prebiotic protocells for a comprehensive understanding of the origins of life: A prebiotic systems chemistry perspective. Life 2019 , 9 , 49. [CrossRef] [PubMed] © 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http: // creativecommons.org / licenses / by / 4.0 / ). 2 life Review The Beginning of Systems Chemistry Peter Strazewski Institut de Chimie et Biochimie Mol é culaires et Supramol é culaires (Unit é Mixte de Recherche 5246), Universit é de Lyon, Claude Bernard Lyon 1, 43 bvd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France; strazewski@univ-lyon1.fr; Tel.: +33-472-448-234 Received: 2 January 2019; Accepted: 17 January 2019; Published: 24 January 2019 Abstract: Systems Chemistry has its roots in the research on the autocatalytic self-replication of biological macromolecules, first of all of synthetic deoxyribonucleic acids. A personal tour through the early works of the founder of Systems Chemistry, and of his first followers, recalls what’s most important in this new era of chemistry: the growth and evolution of compartmented macromolecular populations, when provided with “food” and “fuel” and disposed of “waste”. Keywords: population growth; replication; growth order; Darwinian evolution; selection Dedicated to Günter von Kiedrowski, the Founder of Systems Chemistry, on the Occasion of His Retirement Leslie Eleazer Orgel (1927–2007) was the prophet of Systems Chemistry, his pupil Günter von Kiedrowski is the founder and name inventor of Systems Chemistry, and Eörs Szathm á ry is the mastermind of the first theoretical concepts in Systems Chemistry. I am an active witness of Günter’s and Eörs’ first steps in laying the grounds for Systems Chemistry one year before the first workshop on Systems Chemistry took place in Venice, 2005 [ 1 ]. So let me give a very short, very personal and subjective view on how Systems Chemistry started. Ever since, the field has evolved in wide steps, but the first questions still remain generally unanswered. Orgel’s immense work in prebiotic chemistry and on enzyme-free template-directed nucleic acid chain elongation had a profound influence on the founder of Systems Chemistry (Figure 1). Figure 1. Template-directed enzyme-free RNA chain elongation versus untemplated polymerization and ligation. Parts (a,b,c) taken from [ 2 ] and reproduced with permission from Taylor & Francis © 2004. Life 2019 , 9 , 11; doi:10.3390/life9010011 www.mdpi.com/journal/life 3 Life 2019 , 9 , 11 The first success in understanding autocatalytic molecular replicators was pioneered by Günter’s experiments on the enzyme-free autocatalytic chemical fuel-driven ligation of synthetically end-capped DNA fragments A* + B, in particular, the discovery by minute HPLC analysis of the growth rate of these ligated templates T (Figure 2). Figure 2. Abiotic templated ligation of oligonucleotides. Structure formula taken from [ 3 ] and reproduced with permission from Wiley-VCH Verlag GmbH & Co. KGaA © 1986. The formulation of an experimentally derived “square-root law” from the fitting of the obtained peak intensities has proven to be a robust concept and general molecular property of self-replicating and cross-replicating macromolecules [ 4 , 5 ] that are in principle able to carry over sequence information through multiple rounds of ligation (Figure 3). Figure 3. Autocatalytic production of ligation product T from oligodeoxynucleotides A* and B follows a square-root law. Reaction scheme taken from [ 3 ] and reproduced with permission from Wiley-VCH Verlag GmbH & Co. KGaA © 1986. 4 Life 2019 , 9 , 11 Ten years after, Reza Ghadiri and coworkers showed that the square-root law also applies to the kinetics of autocatalytic ligation of synthetically activated peptide fragments, one being electrophilic at its C-terminus (thioester), the other nucleophilic at its N-terminus (Cys thiol) through template-directed native chemical ligation (Figure 4). Figure 4. Autocatalytic production of ligation product T from oligopeptides E and N follows the square-root law. Figures and text taken from [ 6 ] and reproduced with permission from https://www. nature.com/ © 1996. The concentration or density of autocatalytic or cross-catalytic molecular—as opposed to supramolecular—replicators in well mixed homogeneous milieus thus grows sub-exponentially with time t (Figure 5). For any doubling template population {[T:T] + [T]} = x , at any apparent growth rate constant k , the resulting parabolic growth order 0 < p < 1 describes a growth dynamics where each generation produces on the average fewer descendants per parent than the previous generation (see also right graph in Figure 3). This contrasts exponential and hyperbolic growth orders ( p ≥ 1) where in each generation, on average, the same number or even more descendants are produced per parent than in the previous generation. Figure 5. Parabolic (inhibited), exponential (forceless, simple) and hyperbolic (accelerated) growth orders (regimes). Exemplary integrations apply to 1 → 2 stoichiometric growth (doublings) only. 5 Life 2019 , 9 , 11 The corresponding growth regimes are termed “inhibited”, “forceless” (“simple”) and “accelerated”, respectively; they apply to all stoichiometries (doubling, tripling and so forth), and explicitly include any selection of the fittest fertile individuals from changes in the environment and the degradation or death rates over time. For example, the human population, domesticated animals and plants—like pigs, cows, chicken, wheat, rice, maize, potatoes, tomatoes, grapes and oranges—globally spread in the accelerated growth regime, owing to increasingly optimised life qualities such as food, fertiliser, health, genetic manipulation, safe transportation and peace. Persisting populations of wild animals and plants, also cloned bacteria and in vitro selected macromolecules (cf. PCR), spread in the forceless growth regime, unless the animals or plants belong to endangered species, the resources are diminishing or the waste is undisposed of for some reason. The inhibited growth regime for the doubling of well-mixed and resourceful autocatalytic and cross-catalytic macromolecules has its roots in a general self-capturing phenomenon termed “strand inhibition”. Without external “help”, usually from enzymes, the unfolding of T:T double-strands (T:T:T triple-strands and so forth, if applicable) is difficult for intrinsic molecular reasons, which is hardly the case for bacterial populations, plants and animals. It is as if grown-up children could not become fully reproductive because, during much of their fertile time, the siblings would prefer to stay together on the playground rather than to go out and mate. Hence, in spite of plentiful resources, fully suppressed side reactions—no degradation or chain elongation instead of replication—and negligible waste product concentrations, viz. under ideal initial conditions, the growth order of the vast majority of macromolecular replicators remains parabolic. The second phenomenal coup out of Günter’s kitchen was to show SPREAD, that is, that the exponential regime can be achieved enzyme-free through the surface-promoted replication and exponential amplification of DNA analogues [ 7 ]. The immobilisation of the template strand allows for sequential enzyme-free ligation. The copy is released, and reimmobilised at another part of the solid support to become a template for the next cycle of steps. Irreversible immobilisation of template molecules is thus a means to overcome strand inhibition. In other words, once the grown-up children happen to be out of the playground, don’t let them go back. Before that demonstration, and soon after Günter’s first pioneering discovery, Eörs’ and colleagues’ early insight was to realise that this general strand inhibition was a problem for competing parabolic replicators, and how generally it could be solved [ 8 , 9 ]. In the absence of efficient T:T double-strand unfolders, different macromolecular replicators, bearing markedly different sequences and lengths for example, that are competing for the same resources, can all slowly thrive in the parabolic growth regime, but will virtually never outcompete one another in a well-mixed milieu where food is plentiful and their waste is properly disposed of (Figure 6). In such a situation, Darwinian evolution, being defined as evolution through natural selection, as opposed to evolution through genetic drift, migration, mutations, etc., cannot commence. All abiotically produced parabolic replicators will coexist and spread at different rates. In other words, no speciation at the well-mixed macromolecular level is possible. The idea how to solve the problem originates from the notion of group selection. Rather than being well-mixed, compartmented parabolic replicators are in a different population dynamic situation, since selective forces do not affect them directly but address the fitness of whole systems (Figure 7). Eörs calls it the “stochastic (error) corrector” model [ 10 ]. This is the most fundamental reason for why life needs to be cellular—other important reasons being confinement, protection, concentration, import-export control, and so forth. My naïve human equivalent: as long as the grown-up children insist on playing instead of mating, those clans that furnish the best housing conditions can maintain their collective fertility potential longer than other clans, who may be at risk of dying without progeny. 6 Life 2019 , 9 , 11 Figure 6. Survival of everyone. Competing but different parabolic replicators (different k but same p , cf. Figure 5) cannot outcompete one another in a well-mixed milieu. Figure 7. Survival of the fittest whole systems. Once different parabolic replicators are randomly distributed over periodically growing and randomly dividing compartments, the fittest compartments can outcompete less fit compartments, thus, whole populations specify despite the absence of efficient T:T double-strand unfolders. Of course, once exponential replicators self-evolve inside selected compartments, the hosting populations are predisposed for their spreading rates to “shoot off exponentially”, if sufficiently fed and disposed of waste products. Such populations can outcompete without hesitation the throng of selected parabolic compartments, now compete with one another in the exponential regime, and spread by Darwinian evolution as we know it from biological cells, organisms and populations. Just how exactly can the integrity of parabolic replicators be maintained long enough throughout their spreading? How can parabolic replicators self-evolve at all? These questions did escort Systems Chemistry right from the start; Eörs exposed yet another fundamental problem that needs to be solved 7 Life 2019 , 9 , 11 (Figure 8). Manfred Eigen realised long before the founding works of Systems Chemistry that any error propagation sets limits to the amount of information that can be soundly and recurrently inherited through many generations [ 11 ]. Solutions to the problem of the self-evolution of the replication fidelity of parabolic, exponential and hyperbolic replicators have been proposed ever since, and are manifold [12], still under vivid debate, and out of the scope of this article. Figure 8. Minimal mutability needed for the robust spreading of useful information. Taken from [ 12 ]. What can we learn from the pioneering works? The pudels kern of Systems Chemistry always was, and still is, the growth and evolution of molecular populations, when provided with “food” and “fuel”, and when disposed of “waste”. Formidable work has been published in the decades that followed this pioneering phase, but there remains much chemistry to be discovered where chemical systems are developed that can “inherit”, i.e., transmit through replication a large amount of highly diverse information (open-ended evolution), that remain robust and dynamically stable over many rounds of replication in the presence of competing replicators and parasites, and that are also sufficiently diverse to be useful for the whole system—therefore, most likely localised in, and carried over from covalent macromolecules—but nevertheless subtly mutable, evolvable, and self-evolvable. This is the essence of Systems Chemistry (to be continued elsewhere). Acknowledgments: This work summarises results of a collaborative effort undertaken within the COST Actions D27 “Prebiotic Chemistry and Early Evolution”, CM0703 “Systems Chemistry”, and CM1304 “Emergence and Evolution of Complex Chemical Systems”. This article is based on parts of the author’s presentation “Population growth and encoding principles in self-evolving chemical systems” held on 2 August 2018 at the Gordon Research Conference on Systems Chemistry: From Concepts to Conception in Newry, ME, USA. The financial support from the Volkswagen Foundation for the project “Molecular Life” (Az 92850) is gratefully acknowledged. Conflicts of Interest: The authors declare no conflict of interest. References 1. Stankiewicz, J.; Eckhardt, L.H. Meeting Reviews: Chembiogenesis 2005 and Systems Chemistry Workshop. Angew. Chem. Int. Ed. 2006 , 45 , 342–344. [CrossRef] 2. Orgel, L.E. Prebiotic Chemistry an the Origin of the RNA World. Crit. Rev. Biochem. Mol. Biol. 2004 , 39 , 99–123. 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Sub-Exponential Growth and Coexistence of Non-Enzymatically Replicating Templates. J. Theor. Biol. 1989 , 138 , 55–58. [CrossRef] 10. Szathm á ry, E.; Maynard-Smith, J. From Replicators to Reproducers: The First Major Transitions Leading to Life. J. Theor. Biol. 1997 , 187 , 555–571. [CrossRef] [PubMed] 11. Eigen, M. Selforganization of Matter and the Evolution of Biological Macromolecules. Naturwissenschaften 1971 , 58 , 465–523. [CrossRef] [PubMed] 12. Szil á gyi, A.; Zachar, I.; Scheuring, I.; Kun, Á .; Könny ̋ u, B.; Cz á r á n, T. Ecology and Evolution in the RNA World Dynamics and Stability of Prebiotic Replicator Systems. Life 2017 , 7 , 48. [CrossRef] [PubMed] © 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 9 life Review Chemomimesis and Molecular Darwinism in Action: From Abiotic Generation of Nucleobases to Nucleosides and RNA Raffaele Saladino 1 , Judit E. Šponer 2, *, Jiˇ r í Šponer 2 , Giovanna Costanzo 3 , Samanta Pino 1 and Ernesto Di Mauro 1, * 1 Biological and Ecological Department, University of Tuscia, 01100 Viterbo, Italy; saladino@unitus.it (R.S.); samantapino78@libero.it (S.P.) 2 Institute of Biophysics of the Czech Academy of Sciences, Kr á lovopolsk á 135, 61265 Brno, Czech Republic; sponer@ncbr.muni.cz 3 Institute of Molecular Biology and Pathology, CNR, 00185 Rome, Italy; giovanna.costanzo@uniroma1.it * Correspondence: judit@ncbr.muni.cz (J.E.Š.); ernesto.dimauro@uniroma1.it (E.D.M.) Received: 23 May 2018; Accepted: 19 June 2018; Published: 20 June 2018 Abstract: Molecular Darwinian evolution is an intrinsic property of reacting pools of molecules resulting in the adaptation of the system to changing conditions. It has no a priori aim. From the point of view of the origin of life, Darwinian selection behavior, when spontaneously emerging in the ensembles of molecules composing prebiotic pools, initiates subsequent evolution of increasingly complex and innovative chemical information. On the conservation side, it is a posteriori observed that numerous biological processes are based on prebiotically promptly made compounds, as proposed by the concept of Chemomimesis. Molecular Darwinian evolution and Chemomimesis are principles acting in balanced cooperation in the frame of Systems Chemistry. The one-pot synthesis of nucleosides in radical chemistry conditions is possibly a telling example of the operation of these principles. Other indications of similar cases of molecular evolution can be found among biogenic processes. Keywords: origin of life; systems chemistry; Chemomimesis; Molecular Darwinism 1. Introduction In the absence of life, the components of biogenic processes were necessarily generated in abiotic reactions [ 1 – 5 ]. The conditions under which these syntheses occurred and may still occur are multiform and, as such, are widespread in the Universe. Hence the observations in different interstellar spaces and in different lifeless celestial bodies of molecules which, on our Planet, are starting points and/or are part of biological systems [6–10]. The chemical composition and complexity of the pools of potentially biogenic compounds differ, necessarily depending on a large number of parameters. Many of these parameters are still poorly characterized or are possibly unknown. Nevertheless, it is increasingly clear that prebiotic syntheses occur under a variety of energy sources, of different mixtures of simple starting compounds, of catalysts, and of physico-chemical conditions. Is it possible to identify some of the principles guiding their evolution towards Life? 2. The Principles Underlying Progress towards Further Complexity Darwinian selection has no aims; it does not work for a purpose. It only has consequences, the major of which being the adaptive variation, otherwise called “evolution”, of the system following the modification of the conditions in which the system has existed thus far. The process of Life 2018 , 8 , 24; doi:10.3390/life8020024 www.mdpi.com/journal/life 10 Life 2018 , 8 , 24 “adaptive variation” implies “adaptation” to the new conditions. The word “adaptation” describes the qualitative/quantitative modification of the components of the system as a consequence of the process started by the variation of the initial conditions. When dealing with a population of molecules generated in a synthetic system endowed with biogenic potential, the variation of the conditions of the system depends upon external and internal factors. Internal factors essentially consist of the singly independent and/or of the multiple interacting reactivity of the molecules present. In the absence of special quenching factors, all the molecular populations produced in prebiotic synthetic pools are bound to evolve up to a given point, adapting themselves to the environment that their synthesis has contributed to establish, till exhaustion of the intrinsic reactivity of the system. As discussed below, energy aspects are paramount. What could be hinted at by recent findings on prebiotic synthetic pools about prebiotic evolutionary processes? 3. Principles for Systems Chemistry One way of considering the progress of first-generation prebiotic pools towards biogenic processes is to consider them at the light of Systems Chemistry. In Systems Chemistry [ 11 – 14 ] the focus does not a priori lie on individual chemical components, but rather on the overall ensemble of interacting molecules and on their emergent properties. Systems Chemistry would benefit from the definition of working principles. We propose to use the expression “Systems Chemistry” for the ensemble of considerations dictated by Molecular Darwinism and Chemomimesis. Molecular Darwinism is a term first introduced, to the best of our knowledge, by J. S. Wicken [ 15 ], who critically considered it as a primordial selective process based on unwarranted assumptions. The term was later progressively used as a means to refer to genetic phenomena at the molecular level, like the principle underlying spontaneously occurring genetic variants as driving force of biological evolution by W. Arber [ 16 ]. The complexity level considered was high: local sequence changes, intragenomic reshuffling of DNA segments, acquisition of a segment of a foreign DNA, and the like. This complexity defines the purport of the term at a mature biological level. In what follows, we use this term in the meaning originally suggested by the Göttingen school of Molecular Darwinism, which extends the operation of Darwinian principles of random mutations and selection to chemical processes occurring at the abiotic level of complexity [ 17 ]. Molecular Darwinism is Chemical Evolution in Higgs’ purport [ 18 ], with the additional attributes of intrinsic selection and competition processes which is the core essence of Darwinism. Chemomimesis is a term introduced by A. Eschenmoser and E. Loewenthal [ 19 ] to indicate that chemical compounds and processes characterizing biological phenomena often have purely abiotic precedents: something is copied and used that already existed. In trying to understand the mechanisms characterizing the passages from the abiotic through the prebiotic to the biotic, Chemomimesis is a powerful concept [ 20 , 21 ] which, however, can only be applied according to a posteriori logics: a natural process becomes chemomimetic after the organisms which use it have come into being. The combination of Molecular Darwinism and Chemomimesis may be instrumental for a fact-based understanding of the abiotic-to-prebiotic-to-biotic paths. 4. One-Pot Initial Events under a Variety of Energy Sources: An Example Pools of potentially prebiotic compounds are obtained in early-Earth conditions [ 22 , 23 ], in hydrothermal environments [ 24 , 25 ], and in irradiated and/or impacted Earth atmosphere [ 26 , 27 ]. The HCN and formamide (NH 2 COH) chemistries are interrelated [ 28 , 29 ] and are the natural chemical frames into which a rich panel of prebiotic compounds have been obtained. The ubiquitous [ 30 – 33 ] compound formamide has in particular shown its worth [ 34 – 37 ], due to its peculiar physico-chemical properties [ 34 , 35 ], allowing its liquid state to have a 200 ◦ C-wide interval, as well as its facile accumulation [ 38 , 39 ]. In Ref. [ 40 ], we suggested a prebiotic scenario, which assumed that liquid formamide could accumulate on some hot surface on the early Earth at temperatures around 180 ◦ C as a thermal dissociation product of ammonium formate. This paper responds to the critical notes of 11