Prebiological and the Andrew J. Pratt* Metabolic Origins of University of Canterbury

Keywords , origin of life, , hydrothermal, Abstract The model of cells posits three subsystems: metabolism, compartmentalization, and . A specific model for the prebiological evolution of a reproducing system with rudimentary versions of these three interdependent subsystems is presented. This is based on the initial and reproduction of autocatalytic networks in hydrothermal microcompartments containing iron . The driving force for life was of the dissipation of the intrinsic gradient of the planet. The codependence of life on iron and provides chemical constraints on the ordering of prebiological evolution. The initial protometabolism was based on loops associated with in situ fixation in which the initial protometabolites modified the catalytic capacity and mobility of -based catalysts, especially iron- centers. A number of selection mechanisms, including catalytic efficiency and specificity, hydrolytic stability, and selective solubilization, are proposed as key determinants for autocatalytic reproduction exploited in protometabolic evolution. This evolutionary process led from autocatalytic networks within preexisting compartments to discrete, reproducing, mobile vesicular with the capacity to use soluble and hence the opportunity to develop nucleic . Fidelity of information transfer in the reproduction of these increasingly complex autocatalytic networks is a key selection pressure in prebiological evolution that eventually to the selection of nucleic acids as a digital information subsystem and hence the emergence of fully functional chemotons capable of Darwinian evolution.

1 Introduction: Chemoton Subsystems and Evolutionary Pathways

Living cells are autocatalytic entities that harness redox via the selective catalysis of biochemical transformations. The complexity of cells requires that they emerged from evolutionary processes that predate life: a form of prebiological evolution [71]. Understanding this prebiological evolution, and the selection processes that gave rise to the complexity of cells, is a key to unraveling the origin of life. The simplest model for cells is the chemoton model, which regards them as fluid automata [28]. Chemoton theory proposes that living cells are composed of three essential interconnected subsystems associated with metabolism, compartmentalization, and information. A metabolic subsystem is required to provide the building blocks and chemical energy for life. Compartmentalization is required for evolution to act

* Department of , University of Canterbury, Christchurch, PB4800, New Zealand. E-mail: [email protected]

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on discrete competing entities. Finally, an information subsystem allows the evolution of levels of complexity that are a distinctive feature of life. A theory of the origin of life based on the chemoton, or a related model, must explain a clear pathway to the coexistence of these three interdependent subsystems [71]. Simultaneous creation of an entity with all three subsystems in place is exceedingly improbable [19]; it is more likely that cells arose via a pathway involving accretion of one or two subsystem(s) by a simpler system. There are competing perspectives based on the assumed timing of events. What comes first: compartments, information, and/or metabolism? The two main competing hypotheses both assume compartmentalization as an early feature, either via the self-assembly of membranes [17] or via surface [77]. They differ in the initially associated subsystem: information first or metabolism first. The closest synthetic models we have of partial chemotons are protocells based on - encapsulated RNA [31, 47]. These build on the demonstration of within in vitro RNA systems [42] and the success of the RNA world hypothesis in exploring the dual ability of RNA molecules to act as both catalysts and stores of hereditary information [1]. However, an RNA world depends on the continued availability of complex raw materials, including sources of chemically activated for , and of turnover of these materials to allow selection of func- tional macromolecular structures. A significant challenge for this model is to understand the energy that created and sustained an RNA world—in particular the underpinning functional metabolism that harnessed redox energy for the evolution of the system and that provided the basis for con- temporary . In this model it is often assumed that metabolism emerges to replace spent preexisting metabolites. This model for the of metabolic pathways backward to alternative starting materials, originally due to Horowitz [35], is out of step with recent insights into the evolution of biochemical metabolism [83] and unlikely to be the complete story. The competing viewpoint is that the first steps to life were based on compartmentalized proto- metabolism that subsequently developed an information subsystem. Wächtershäuser, Russell, de Duve, Morowitz, and others have developed models of this type in which protometabolic reactions are catalyzed and organized on iron sulfide surfaces [15, 62, 74, 77]. One major challenge for models based on networks of catalysts as initiators of life, such as those envisaged in the GARD model [66], is the limited evolvability of such systems [75]. This article presents a model for the origin of life that links iron-sulfur and RNA world models. It is proposed here that these two perspectives can be reconciled if there is a particular ordering of pre- biological events. The chemical constraints posed by two of the essential elements of life fundamental to these models, iron and phosphate, underpin this ordering. Iron catalysis is a key feature required for the development of protometabolic processes. Phosphate is a required building of a sugar phosphate metabolism and of RNA itself. A fundamental problem is that phosphates precipitate in the presence of some free multivalent metal , notably iron and . Precipitation of phosphates provides a concentration mechanism for this otherwise scarce resource that was likely to be a limiting for life at its inception [7]. However, precipitation compromises the development of a soluble metabolism that incorporates phosphate species [54]. Cells avoid this precipitation problem via a com- bination of encapsulation and exclusion of multivalent metal ions [27]. Essentially all iron within living cells is encapsulated within either as iron clusters or as complexes. Both oligopeptides and [24] are derivable from amino building blocks that are, in principle, accessible from plausible prebiotic catalysis. This is a key insight in developing a model for the ordering of events leading to life. It is proposed that self-organizing autocatalytic cycles based on iron predate the utilization of phosphate-containing protometabolites. The initial autocatalytic chem- istry gave rise to that could encapsulate iron. Once the free metal iron levels were controlled in this way, it became possible for phosphates to be solubilized and hence integrated with an emerging protometabolism. As protometabolic systems became more complex, the reproduction of this informa- tion became a key selection mechanism for the emergence of protocells utilizing RNA. It is proposed that the RNA world, with vesicle-based compartmentalization, emerged in response to this demand for enhanced fidelity of information reproduction. An evolutionary account is presented that provides a series of specific chemical and physical selection mechanisms for the early stage development of a

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three-subsystem RNA world chemoton in which the RNA world emerges as a logical consequence of a prebiological (non-Darwinian) evolutionary process.

2 Protometabolism in Preexisting Compartments

2.1 Why and How Did Life Emerge? Life depends on a continuous input of energy that can redox chemistry. This proposal follows the hypothesis of Russell and Kanik [64] that life emerged to exploit the intrinsic redox gradient of the that has existed since its origin. Reactive acceptors, such as , were scavenged when the earth formed. The residual components separated out into physically segregated domains. The electron- rich core of the earth was locked away beneath the crust, separated from a weakly oxidizing containing , , and other moderate electron acceptors. The large store of potential energy in this physical segregation of the planet could be harnessed if and when there was mixing of chemicals from the electron-rich interior with exterior electron acceptors. For this reason, life emerged in pores [63] within hydrothermal mineral deposits where there is a mixing of these otherwise segregated zones of the planet. The driving force for the emergence of life was the so-called fourth law of thermo- dynamics, which proposes that systems with sufficient degrees of freedom self-organize to maximize the rate of production [43, 70]. Life provided a mechanism to channel ever more efficiently from the interior to the exterior of the earth, thereby allowing increasing rates of entropy generation. This feature of life continues to this day (now augmenting geochemical electron flux with solar-powered variants), with evidence pointing to the fact that act in an analogous fashion to maximize the rate of entropy production [34]. It was not only the physical barrier to electron flow that was important for the fourth law to act and life to emerge. If reactions were facile in hydrothermal mixing zones, then simple chemical processes would serve to dissipate the redox gradient directly, leaving no opportunity for complex autocatalytic networks to develop. Only if autocatalytic networks were more efficient at me- diating electron transfer than direct chemical processes could there be selection of complex systems. On this basis, it is proposed that the critical features of the earthʼs environment for the emergence of life were: (i) a continuous input of redox energy; (ii) a kinetic barrier to the dissipation of the intrinsic redox gradient; (iii) the availability of catalysts in a mixing zone that could speed dissipation of the gradient, but where initial catalysts were inefficient and capable of increased efficiency by diversification to networks of more specific catalysts; and (iv) protection against significant external shocks (irradiation, variations in pH and , etc.) to facilitate evolution by allowing the reproduction of catalytic networks as discrete entities. This environment provided an evolutionary opportunity for the emergence of networks of catalysts of increasing complexity and was necessary, but not sufficient, for life. There is a limit to the complexity of simple catalytic cycles, associated with limits to fidelity of reproduction [75]. It is proposed that life, as we know it, emerged when a digital information subsystem evolved that transcended the information limits of simple chemical networks and allowed open-ended Darwinian evolution with .

2.2 Iron-Sulfur Species and the Early Evolution of Catalytic Centers Following the patchwork model of evolution of biochemical catalysts [40], the best starting point for evolution is the availability of generic, but inefficient catalysts that are capable of evolving increased specificity and efficiency [71]. One key issue for self-organizing autocatalytic networks, highlighted by Orgel [52], is the need for a series of catalysts that mediate all the processes of the network. Iron-sulfur-based species [5] are well placed to fill this role, since they are capable of catalyzing a diverse range of both redox and acid- chemistry. Much of this chemistry is utilized in contemporary core metabolism via iron-sulfur clusters that resemble iron sulfide mineral structures (Figure 1) [60]. Iron- sulfur clusters occur naturally in aqueous systems [61]. Biochemical clusters of this kind mediate the following processes: (i) bioenergetic electron-transfer processes (e.g., [11, 82]); (ii) other metabolic redox chemistry (e.g., [57], [23], reversible formation [51],

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Figure 1. Iron-sulfur and catalytic biochemical clusters. 1: mackinawite substructure; 2: [2Fe,2S] electron transfer cluster; 3: greigite substructure; 4: [4Fe,4S] electron transfer cluster; 5: acid-base catalyst ( with citrate bound); 6: generating cluster (with S-adenosylmethionine bound, R = adenosyl); 7: model for Ni-substituted greigite; 8: carbon fixing cluster of ACS.

and organic radical chemistry [6, 50]); and (iii) a diverse range of acid-base chemistry, including hydration- dehydration chemistry (e.g., aconitase, dehydratase, and related [26]). The specific catalytic properties of iron-sulfur-dependent enzymes are controlled by the composition of the metal-sulfur cluster and the details of the coordinating ligands (Figure 1). For example, iron-sulfur clusters completely coordinated by sulfur ligands (2 and 4) act as specific electron transfer proteins in which the redox potential is moderated by cluster size and details [58]. Clusters, such as the [4Fe,4S] cluster in aconitase (5), with one nonsulfur coordination site, can undergo active metal and exchange chemistry. Ligands, such as , transiently bound to such clusters can undergo re- actions involving acid-base catalysis [26]. When bound to an iron-sulfur cluster, the deriva- tive S-adenosylmethionine is a source of organic radicals (6). Iron sulfide minerals contain other metal ions (7) [63]. The presence of adjacent metal ions (e.g., , , and ) provides new distinctive catalytic chemistry that can exploit the electron transfer chemistry of iron . For example, nickel-iron-sulfur clusters are utilized in a number of enzymes, including both key en- zymes of the Wood-Ljungdahl carbon fixation pathway, CO dehydrogenase and acetyl-CoA synthase (8) [76]; likewise, molybdenum-iron-sulfur clusters are utilized in [23]. The ability to modify and control specific catalytic activities via coordination chemistry provides the potential for the evolution of catalysts of diversified specificity and activity in an emerging division of (protometabolic) labor. There is an opportunity for positive feedback loops in the interactions between metal-sulfur clusters and that underpins the development of an expanding web of protometabolic reactions. New protometabolites provide new catalytic opportunities for metal-sulfur clusters that, in turn, catalyze the formation and interconversion of new protometabolites.

2.3 Prebiotic Wood-Ljungdahl Carbon Fixation: The First Step The shortest and simplest known route to biological carbon fixation is the Wood-Ljungdahl pathway (Figure 2), in which carbon dioxide is reduced to at an iron-nickel-sulfur center of CO dehydrogenase (CODH). The carbon monoxide is then transferred internally to acetyl CoA synthase (ACS), another iron-, nickel-, and sulfur-dependent , where it carbonylates a methyl-nickel species. The resulting acetyl nickel intermediate is intercepted by the coenzyme A to produce acetyl CoA [29, 33, 65]. The methyl is sourced from methyl tetrahydrofolate (CH3-THF) and is de- livered to this system by a cobalt corrinoid iron-sulfur (CFeSP) [69]. In this carbon fixation pathway the key manipulations of carbon species are mediated by nickel and cobalt centers with adjacent iron-sulfur clusters supplying electrons. In geochemical systems the initially deposited iron monosulfide is nanoparticulate mackinawite, which adsorbs divalent metal ions [81] such as nickel and cobalt. Huber and Wächtershäuser [37] have shown that inorganic iron-nickel sulfide catalyzes a simple analogue of acetyl CoA synthase chemistry in , converting to methyl thioacetate (Figure 2). The

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product is hydrolyzed under the reaction conditions to , providing a strong overall thermodynamic driving force for the process [67]. This simple immediately provides a positive feedback mechanism that can underpin the generation of more complex catalytic networks as introduced above. Carbon fixation involves the reductive formation of organic compounds, notably carboxylates [48], which provide the first of a family of ligands that can coordinate to, and modify, the of the metal ions present. Re- duction of carbon-containing species results in the concomitant oxidation of the iron sulfide:

! þ ð Þþ - ð Þ 4FeS ▾ Fe3S4 Fe II 2e 1 (mackinawite) (greigite)

Mackinawite is a two-dimensional with a layered structure [60]. Surface oxidation pro- cesses (e.g., at a catalytically active nickel center) will draw electrons from the iron sulfide. Oxidation of mackinawite produces greigite and other pyrrhotite iron sulfide minerals [46]. Mackinawite oxidation is inefficient in the absence of suitable additives, and it is known that redox-active organic compounds can facilitate such transformations [59]. Once carbon fixation is established, additional organic and mineral chemistry can proliferate. Mackinawite and greigite are both based on a close-packed sulfide lattice [60]. In mackinawite the iron is in a tetragonal environment. In the transition to greigite some of the iron centers become octahedral. It is expected that this change will diversify the chemistry and catalytic properties of the iron sulfide local to the site of oxidation. In support of this view, Russell and Hall have pointed out that mackinawite bears some resemblance to [2Fe,2S] clusters found in some simple electron transfer proteins, whereas greigite contains a subunit analogous to the [4Fe,4S] clusters found in many iron-sulfur-dependent enzymes, including the key Wood-Ljungdahl enzymes (Figure 1) [63]. Furthermore, interconversion of the two minerals involves a relocation of iron ions (Equation 1); these will presumably migrate to the surface. Organic compounds produced by the carbon fixation chemistry that are ligands will bind to the surface metal ions, including the newly exposed iron cen- ters, modifying their chemistry. The generation of new catalytic centers that increase the overall activity with respect to carbon fixation will act as a positive feedback loop where the flux of oxidized carbon and reducing power (e.g., geochemically generated hydrogen) will be differentially turned over by catalytically active microporous domains within the hydrothermal rocks, which contain both ligands and diverse catalytic metal centers. Subsequent known iron-sulfur-mediated transformations can produce a suite of core proto- metabolites, thereby expanding the family of ligands that can bind to, and modify, the catalytic chemistry of iron-sulfur centers (Figure 3). Reductive carboxylation of from carbon fixation can produce a-keto acids, such as pyruvate [12]. These chelating ligands can undergo further chemistry

Figure 2. Overview of (i) Wood-Ljungdahl carbon fixation pathway and (ii) biomimetic geochemical analogue.

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Figure 3. Generation of core protometabolites within an iron-sulfide system. Binding of representative protometabolites to iron-sulfur centers is illustrated in the box.

once bound. Reductive amination of bound a-keto acids, using from the reductive fixation of nitrogen [18] and/or [9], can then give rise to a-amino acids via reductive amination [39]. Utilization of related substrates would produce a core of simple protometabolites that are selected on the basis of their being ligands for iron that modify the catalytic chemistry of exposed iron sites and hence the catalytic turnover of the emerging family of protometabolites. A family of diversified catalytic centers, with complementary activity, provides the basis for networks that are more produc- tive than individual catalysts. In a porous hydrothermal mound, a diverse variety of potential micro- environments would be evaluated as potential sources of autocatalytic networks. In essence, such a geochemical setting provides a massively parallel set of chemical flow reactors that will sample a range of related possible protometabolic networks. Individual pores with distinctive mineral chemistry can develop distinctive chemical variants in an early form of compartmentalized protometabolism, and the most successful of these can be selected.

2.4 The First Oligomers and Molecular Evolution Complex are a key feature of biochemistry. All biological macromolecules are con- densation , created by the dehydration of monomeric building blocks. In water, polymers are unstable with respect to . These condensation polymers require biochemical energy, usually equated with ATP or related , for their synthesis. ATP is the arche- typal water compatible dehydrating agent [79]. The discovery of pathways to condensation polymers in an aqueous system is one of the key foundational features underpinning the origin of life, since it opened the doors for prebiological evolutionary processes that facilitated the emergence of func- tional macromolecules. A critical feature of the prebiotic Wood-Ljungdahl chemistry is that it generates thioesters as obli- gate intermediates. Thioesters are the other major class of water compatible biochemical dehydrating agents, and their intermediacy in carbon fixation chemistry provides dehydrating power that makes condensation polymers accessible. Since this chemistry was quickly associated with a growing pool of a-amino acids, oligopeptides were among the early oligomeric compounds to arise (Figure 3). It has been shown that can be formed from amino acids in water using the intrinsic dehydrating power of prebiotic Wood-Ljungdahl catalysis [38]. Such oligopeptides are also ligands that are able to bind to iron-sulfur and other metal species and thereby modify the catalytic activity of the system by controlling coordination spheres. The production of condensation oligomers provides an explicit molecular selection mechanism. Since condensation oligomers are unstable with respect to hydrolysis in water, such condensation polymers only accumulate if they are generated faster than the rate at which they “die” via hydrolysis. Oligopeptides that facilitate the overall catalytic potential of the system will facilitate the production of further oligopeptides; condensation oligomers that participate in this feed- back loop will be selected. Likewise, oligopeptides with greater hydrolytic stability will persist for longer

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and can accumulate better. Families of related oligopeptide-metal centers will emerge that can harness the chemistry of metal-sulfide clusters found in aqueous systems [61] and mediate distinct classes of chemical transformation with rudimentary specificity (e.g., acid-base chemistry versus redox chemistry). There will be some structural and metal-binding selectivity in these ligands, but they will lack the order- ing and hence specificity available from contemporary enzymes. The birth of functional oligopeptides by this route provides an explanation for the ultimate emer- gence of functional proteins. Contemporary proteins are large macromolecules whose structural com- plexity is based on the hydrophobic effect. By joining sufficient amino acids with polar and nonpolar side chains in a specified order, the protein chain spontaneously folds in such a way as to bury nonpolar side chains away from water. The chemical and structural diversity of these macromolecules is the basis for their varied biological function. In general, the emergence of large macromolecules requires selec- tion mechanisms for simpler, truncated variants. There are also a number of specific challenges to be surmounted in the creation of functional proteins in particular. These are associated with the require- ment for hydrophobic cores to nucleate structural integrity. Firstly, amino acids with nonpolar side chains are produced by specialized biosynthetic routes, corresponding to the complex chemistry needed for their preparation; they are unlikely to have been readily available to simple protometabolic systems. Secondly, short oligopeptides (with or without nonpolar side chains) are conformationally flexible, and their low structural integrity undermines both function and hydrolytic stability. By templating short oligopeptides around metal-based clusters, the need for a hydrophobic core is obviated; the oligomers adopt well-defined structures that offer greater opportunities for function and stability to be selected. Of course, it would take the later invention of ribosomal synthesis to elevate the precision of oligopeptide synthesis to a point where larger proteins could be produced accurately. At this point the oligomers could be weaned from the need for metal templates, via the controlled production of non- polar amino acids and their recruitment to generate hydrophobic cores.

3 Mobile Autocatalytic Networks and Fully Functional Chemotons

3.1 and Prebiological Evolution At this point, families of protometabolic networks had arisen in hydrothermal mounds with their own characteristic microenvironments. These networks were founded on metal cluster catalysis of element fixation and organic transformations. The organic ligands present were involved in diver- sifying and enhancing the catalytic capabilities of the system. As proposed by Russell and Hall [63], if the emerging autocatalytic networks developed in pores within hydrothermally deposited minerals, these discrete cavities provided an initial rudimentary compartmentalization mechanism. They prevented the free loss of soluble protometabolites, allowing metabolism to emerge. Furthermore, protometabolites could accumulate in these pores by a hydrothermal concentration mechanism [2, 10]. However, all of this protometabolic information was inherently finite because of the limited lifetime of hydrothermal mounds in general and individual pores in particular. There is a strong selection for the reproduction of this protometabolic information, since only mobile systems would endure. The solubility of chemicals associated with catalytically active hydrothermal pores would play a critical role in the chemistry that evolves and in the reproduction of that chemistry. This is another of the major prebiological selection mechanisms. minerals and bound ligands are retained within a finite location of a hydrothermal environment. Such a location has a finite lifetime for active chemistry until the supplies of raw materials are exhausted. A permanently localized autocatalytic network will eventually “die” from starvation, generating a selection pressure for mobility. Chemical products of autocatalytic networks will be leached from the system by solubilization. This is both a purifying mechanism and a seeding or reproduction mechanism. Chemicals, individually or en masse, that are lost but not replaced are removed from the system as waste. However, mobile com- ponents that seed neighboring sites with autocatalytic chemistry are potentially a selectable means of reproduction.

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3.2 Iron Encapsulation, Phosphates, and A significant challenge for the development of complex soluble chemistry within a specific pore of a hydrothermal deposit is the presence of high levels of free multivalent metal ions, including iron. As indicated earlier, highly charged cations encourage precipitation of counter anions, notably phosphates, which cells avoid by a combination of encapsulation and exclusion of multivalent metal ions. Iron is a critical resource and is encapsulated within proteins, often in the form of iron clusters or porphyrin complexes. Calcium ions cannot be readily encapsulated because of their dynamic coordination chemistry, and so they are actively pumped out of cells, whereupon they form extracellular precipitates, such as calcium exoskeletons and . These extracellular deposits provide a homeostatic backdrop to the chemistry of cells (e.g., bone acts as a reservoir of calcium and phosphate) [27]. Both encapsulation and external precipitation were utilized in prebiological evolution. The combination of chelating ligands from carbon fixation (e.g., a-substituted carboxylates) and templated synthesis [14] of oligomeric ligands (e.g., porphyrins and oligopeptides on iron centers) provided selective routes to ligands that could sequester ions of free iron within the system by com- petitive coordination chemistry. Oligomeric ligands would tailor the catalytic chemistry of iron-sulfur catalytic centers by controlling the of the ligand coordination sphere (Figure 1). They would also control free metal levels and thereby allow partial solubilization of polyanionic species from pore surfaces. In the presence of significant concentrations of free iron ions, any inorganic phosphates pre- cipitate, providing a concentration mechanism for this otherwise scarce resource on the surfaces of hydrothermal pores. Surface-catalyzed phosphoryl transfer from acetyl phosphate, available from acetyl thioesters [78], generates , which accumulates under these conditions [16] and becomes a second source of dehydrating power in water [3] once it can be solubilized. Iron(II) phosphates are sparingly soluble [54]; organic phosphates have significantly higher solubility than inorganic phosphates, and, when the quantities of iron present are limiting, these are selectively desorbed into solution. For example, under conditions where there is for iron, phos- phate and pyrophosphate are selectively precipitated in the presence of phosphates, leaving the latter free in solution [56]. Thus a selection mechanism for the utilization of soluble organophos- phates (e.g., ) arises. As surface-bound inorganic phosphates react with organic species generated by protometabolism, they selectively desorb into solution and become integrated with the thioester and amino-acid-based catalytic networks. Once available, phosphates brought important opportunities to biochemical systems [79]. The combination of thermodynamic lability and kinetic stability of anionic phosphate anhydrides and in water facilitated molecular evolution: Polyphosphates could be adopted as an alternative biochemical energy source to thioesters; phosphate esters could be formed and turned over by hydrolysis, and increase the opportunity for prebiological evolutionary processes [55]. Precipitated sparingly, soluble iron phosphate, iron pyrophosphate, and iron sulfide provided a homeostatic back- drop to the emerging protometabolic networks, with concentrations adjusting as catalysis consumes protometabolites. This backdrop became an essential feature in the subsequent development of an RNA world.

3.3 Reproduction, Mobility, and Selection The emerging protometabolic networks now had access to sugar phosphate metabolites that could be incorporated within an expanding autocatalytic web. These networks exploited solubility equilibria to provide the foundation of a soluble metabolism. This set the scene for the final two major innovations required to establish an RNA world: vesicle-based compartmentalization and the emergence of RNA itself. There is no fundamental constraint on the ordering of these two innovations. The selection pressures operating are valid irrespective of the order. For simplicity, the following account discusses the innovations in turn, with vesicles considered prior to RNA. As individual pores evolved soluble protometabolic networks, some of the materials was washed to neighboring pores, where they could seed new autocatalytic networks: Ligands could carry metal

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ions and influence the coordination chemistry, and hence catalytic activity, of metal sites; phosphates and other key protometabolites could be relocated. Productive autocatalytic networks would be more successful in seeding neighboring pores. For simple catalytic networks this provided a select- able form of reproduction based on catalytic efficiency. However, the amount of protometabolic information that could be relocated in this piecemeal fashion would be very limited in scope, and so only simple autocatalytic networks could reproduce by this mechanism. Autocatalytic networks that developed the capability of relocating populations of catalytically active chemicals to neighbor- ing pores could reproduce more effectively and evolve to more complex systems. There will be a range of among the components of the emerging autocatalytic networks: both the protometabolites and the oligopeptide-encapsulated metal catalysts. Amphipathic molecules that arise, such as some of the oligopeptide complexes and any fatty acids present, would aggregate to form higher-order structures, including micelles and vesicles [17]. Hydrothermal concentration mechanisms would facilitate the generation of such structures [10]. The resulting micelles and vesicles would be heterogeneous aggregates of chemicals that would be relocated to neighboring pores en masse. This acted as a selection mechanism for reproducing more complex networks (either with or without RNA). More sophisticated and productive networks would be relocated to new environments in which they would have access to renewed chemical feedstocks.

3.4 A Stochastic Corrector Model of Metabolic Reproduction Lipopeptide encapsulation allowed relocation of multiple catalysts and protometabolites as envisaged by autocatalytic network theories, for example, the GARD model [66]. Individual components would be distributed between lipopeptide vesicles in a stochastic manner. As long as a representative sample of the constituents of the autocatalytic network were present, then the catalytic cycles in the vesicle would be fully active. Such vesicles could relocate, grow, and divide [73] in the buffered environment of the hydrothermal pores. Omission of any critical species would to compromised networks that would reproduce more slowly, if at all, and fail to compete with fully functional networks. This situation is analogous to the stochastic corrector model developed by Szathmáry to describe the group selection of populations of replicators in an RNA world scenario [30, 72]. An analogous stochastic corrector model for catalysts (Figure 4) leads to the selection of functional reproducing networks of metabolic information [66] with or without the presence of RNA. Early vesicular structures would be loose dynamic associations. These allow exchange of material with the environment so new feedstocks can be taken up. Furthermore, discrete vesicles could fuse on contact, allowing deficient vesicles to regenerate fully functioning autocatalytic networks, and growing vesicles to generate new combinations of metabolic processes via symbiotic events. Two significant features limit the complexity of such systems: The statistical distribution of - cules provides a limit to the number of discrete components that can be reliably distributed during growth-and-division cycles; in addition, the accuracy of metabolic turnover is limited by the lack of precision in the ordering of in -based catalysts where specificity arises from sim- ple chemical selectivity, in contrast with the degree of control that can be exerted by macromolecular catalysts (enzymes and ) of well-defined sequences. Such autocatalytic systems can develop general classes of protometabolic function involving the presence or absence of particular processes; however, as Szathmáry and colleagues have shown [75], purely metabolic systems are not capable of open-ended Darwinian evolution where incremental variants can be selected and maintained in popula- tions of competing entities. Nevertheless, the protometabolic history is likely to vary from one set of hydrothermal pores to another, with the resulting autocatalytic networks being a function of the par- ticular local geochemistry.

3.5 Reproduction Fidelity and the Analogue-to-Digital Information Transition Fidelity of the reproduction of biochemical information is a critical selection pressure for the develop- ment of complex . Eigenʼs work has highlighted the critical role of error threshold limits in the reproduction of biochemical information in simple replicator systems [20–22]. The fundamental

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Figure 4. A stochastic corrector model of metabolic reproduction. Only vesicles containing representative populations of catalysts can grow and divide efficiently.

discovery needed for the generation of digital information, in the form of well-defined macro- molecular sequence information, was the generation of oligomers capable of carrying informa- tion but whose physical properties are approximately independent of composition. Benner [4] has noted the importance of linear polyionic oligomers, built from monomeric units of similar size and structure and identical charge, in providing the requisite properties for genetic molecules. The ability of phosphate to link two units and retain a negative charge is critical to the structure and function of nucleic acids [79]. A subset of protometabolic systems provided a range of features that facilitated the development of RNA-based coding systems. They provided access to metallo-oligopeptide catalysts that generated both organic molecules and dehydrating power in water. They also manipulated phosphate precipitation equilibria, by encapsulating free divalent metal ions and thereby allowing release of solubilized organo- phosphate species from precipitated stores. The ability of phosphate to channel sugar chemistry to useful metabolites [25, 49] could then be exploited, opening the way to derivatives [53]. Once phosphate precipitation equilibria were made freely reversible by cation binding, pyrophosphate from autocatalytic iron-sulfur networks became a more general source of activated phosphate species [3]. It was also possible to exploit reversible surface binding of oligomeric sugar phosphate species, including oligonucleotides [32], to allow templated oligomer synthesis [41]. Once sugar phosphate derivatives, including rudimentary nucleotide analogues, became available to protometabolism, their oligomerization was subject to the same molecular selection processes that re- fined the properties of simple oligopeptides. Oligomeric derivatives that provided useful catalytic ac- tivity enhanced the productivity of the protocells and were produced faster than they hydrolyzed. They were initially selected on this basis. In this way mixed protometabolic networks arose in which catalysis was carried out by both oligopeptide complexes and nucleotide derivatives [80]. The oligopeptide and oligonucleotide systems interfaced via simple aminoacylated nucleotide derivatives. Amino acids linked as esters to nucleotides could undergo a version of templated formation, facilitated by base stack- ing of the nucleotide component. This provided a rudimentary precursor to .

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Once catalytically useful oligomeric nucleotide derivatives emerged, a second property was selected: namely, the replication mechanisms associated with access to precise ordering of units in- herent in structures [68]. This provided the basis for RNA replication. The coevolution of translation occurred via increasingly precise versions of templated oligopeptide synthesis [36]. This was the final technology needed for the creation of replicators with a protometabolism built on an interdependent combination of iron-sulfur catalysis, oligopeptides, and oligonucleotides. The move to RNA replication and to rudimentary translation was associated with homochiral var- iants of autocatalytic systems because of the enhanced efficiency they provided for reproduction. As Cornforth [13] pointed out, “there [is] no such thing as a racemic .… Each molecular event produces a chiral product, not a racemic product, so if by chance a molecule arises which can direct its own replication, that molecule will be chiral if it contains chiral centres.” Selection at the level of individual molecules for replicative processes, either direct or indirect, will give rise to homochiral systems. This will arise via the amplification of stochastic variations in levels that are a feature of autocatalytic systems [8]. One facilitating mechanism for the emergence of homochiral systems is the interconversion of molecules having a single chiral center via a planar analogue. For a-amino acids, a-keto acids and related compounds provide an appropriate starting point. In the case of sugar phosphates, including nucleic acids, the most likely analogous source of would be a forerunner of the enolase reaction that interconverts achiral phosphoenol pyruvate (PEP) and chiral 2-phosphoglycerate, establishing the foundational D-chiral center of sugar phosphates. Once the stereo- chemistry of L-amino acids and D- phosphates was established, all further stereochemical dis- crimination would be carried out relative to that configuration. The continuing action of evolution, with replication fidelity as a key selection pressure [20–22], set the stage for the emergence of a modified version of the RNA world [1, 44] in which oligopeptide- and oligonucleotide-derived catalysts coexisted within reproducing vesicles. In these systems the oligo- nucleotides developed a unique function as a repository for precise replicable sequence information: Open-ended Darwinian evolution had emerged. This was harnessed as the basis for coding oligo- of reproducible sequence via the refinement of translation. The resulting enhancement in the catalytic specificity of oligopeptides provided ever more efficient variants on metabolism. The same opportunities and evolutionary driving forces led to protocell membranes becoming more rigid barriers to the outside world, once precise transport mechanisms became available via protein evolu- tion. The resulting entities were the first true chemotons, having the irreducible complexity associated with living cells.

4 Concluding Remarks

The model presented here provides a plausible account of a combination of specific prebiological processes that explain the early steps by which a functional chemoton, with three interdependent sub- systems, can emerge. By this account life is not inevitable, but requires an ordered sequence of proto- metabolic innovations in a microenvironment that supplies an appropriate array of , such as iron, carbon, nitrogen, sulfur, and phosphate. Porous hydrothermal mineral mounds provided an exceedingly large number of discrete geochemical environments that allowed parallel testing of vast numbers of chemical systems. Complex chemotons arose as a result of a series of molecular selection processes occurring within at least one of these environments. This model is potentially testable, for example, via combinatorial microfluidic technology [45] with screening of diverse chemical systems for proposed protometabolic innovations. The ordering of events also carries implications for these and more conventional experiments. In general, RNA world experiments eschew iron because of the in- compatibilities with phosphate. This account suggests that investigations involving encapsulated iron species alongside RNA systems would be an important step in building an experimental connection between the RNA and iron-sulfur worlds. It is proposed that the creation and selection of metabolic diversity occurred via simple chemical and physical steps. Initially selection was based on catalytic efficiencies of networks that emerged in

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specific preexisting mineral micropore compartments. Encapsulation of metal species by organic ligands provided more active and specific catalysts and also allowed the development of a soluble protometabolism incorporating sugar phosphates. Systems that evolved the capacity to relocate en masse in lipopeptide vesicles, before their access to chemical feedstocks ends, selectively propagated. Protocells emerged with autocatalytic networks that included catalysts based on both oligopeptides and oligonucleotides, which could then evolve complex oligonucleotide structures via molecular evolution. These first chemotons were the forerunners of an RNA world that evolved by open- ended Darwinian evolution.

Acknowledgments I am deeply grateful to Mark Dörr, Vladimir Golovko, Janos Hajdu, Pierre-Alain Monnard, Ant Poole, and Mike Russell for insightful discussions.

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