ECAL - General Track Autocatalysis Before Enzymes: The Emergence of Prebiotic Chain Reactions Nathaniel Virgo, Takashi Ikegami Ikegami Laboratory, University of Tokyo [email protected] Abstract these autocatalytic subnetworks means that a reaction in- volving one of the intermediates is likely to produce another How could complex, enzyme- or ribozyme-like molecules intermediate, thus overcoming the much-discussed problem first have arisen on planet Earth? Several authors have sug- of specificity in autocatalytic cycles. This suggests that com- gested autocatalytic cycles as a partial answer to this ques- tion, since such reactions exhibit the life-like property of ex- plex autocatalytic reaction networks formed from simple ponential growth while being composed of relatively simple molecules can be produced much more easily than simple molecules. However, a question remains as to the likelihood networks composed of complex “replicator” molecules. of an autocatalytic cycle forming spontaneously in the ab- Because the requirements for this phenomenon are so sence of highly specific catalysts. Here we show that such cy- cles form readily in a very simple model that includes no di- easy to meet, it should be possible to observe it experi- rect catalysis reactions. Catalytic effects nevertheless emerge mentally, in prebiotic chemistry experiments along the lines as properties of the reaction network. This suggests that the of the Miller-Urey experiment or HCN polymerisation. To conditions for the formation of such cycles are not difficult to achieve this one would need to change the conditions so that achieve. The resulting cycles solve the problem of specificity the breakdown of polymers via hydrolysis or oxidation oc- not by being small and simple but by being large and compli- cated, suggesting that early prebiotic metabolisms could have curs in the same system as their synthesis, at a comparable been extremely complex. We predict that this phenomenon rate. This simultaneous build-up and break-down of poly- can be reproduced in wet chemistry. We discuss the chal- mers is analogous to anabolism and catabolism in biology. lenges involved in this, as well as the implications for how We comment on the potential implications of such a result, we view the origins of life. and the challenges that would be involved in attaining it. It is worth pointing out a major difference between our Introduction model and one of the predominant existing approaches to ex- A necessary requirement for biological metabolism is auto- plaining the origin of biological autocatalysis. As discussed catalytic kinetics, i.e. the ability of a set of chemical species below, there are many studies that model the emergence of to increase its own rate of production. Without the ability to autocatalysis in networks of reactions between peptide or positively influence the production of its own chemical com- RNA-like molecules, via a mechanism known variously as ponents, the prebiotic equivalent of a living organism would reflexive autocatalysis, autocatalytic sets or RAF sets. This be able neither to reproduce nor to maintain its own compo- work has shown that autocatalysis is easy to achieve via sition over time. In this paper we investigate the possibility this mechanism even if the reaction networks are chosen that the earliest proto-metabolisms achieved this through a at random rather than having autocatalysis “designed” into mechanism known as an autocatalytic cycle. them (Kauffman, 1986); and that such autocatalytic sets are In this paper we present a highly simplified model of a capable of evolution by natural selection via an attractor- simple organic polymer chemistry operating away from ther- based heredity mechanism, even in the absence of specific modynamic equilibrium. This model is extremely simple, information-carrying molecules (Vasas et al., 2012). consisting only of basic synthesis and decomposition reac- However, this definition of autocatalysis presupposes the tions, with no catalytic kinetics assumed a priori. We find existence of single-step catalysis reactions, and therefore en- that autocatalytic cycles form readily in such a system, sug- tails an assumption that the molecules involved are complex gesting that the chemistry in which the first steps toward enough to behave as enzymes. Because our aim is to explain metabolism took place could have been much simpler than the emergence of such complex molecules from simpler re- generally supposed. The networks that emerge in our model actants, we focus instead on a different mechanism: the au- are complex, consisting of many interlinked catalytic and tocatalytic cycle or branching chain reaction (King, 1978). autocatalytic cycles. The highly interconnected nature of For our purposes, a branching chain reaction may be de- ECAL 2013 240 ECAL - General Track (a) (b) (a) (b) Figure 1: (a) Schematic of the reductive citric acid cycle, re- Figure 2: Some other known examples of autocatalysis via drawn from Morowitz et al. (2000). The branching step is chain reactions. (a) A few of the most important reaction the splitting up of citrate into oxaloacetate and acetyl CoA, steps in the early stages of the combustion of H2, demon- which is then transformed into a second oxaloacetate, so that strating autocatalysis via a more complex network than a its concentration doubles on every turn of the cycle. (b) The single cycle. H2 and O2 can be mixed without reacting, but mechanism of the formose reaction, as proposed by Breslow due to this mechanism they will react very rapidly after an (1959). The branching step is the decomposition of an al- initial spark produces small quantities of H and O. (b) Tem- dotetrose into two molecules of glycoaldehyde. The formose plate replication is a special case of chain reaction autocatal- reaction has been observed experimentally, without the use ysis. Here, an AB dimer catalyses the formation of another of biological catalysts. AB dimer through complementary base pairing. Figure 2b is taken from Virgo et al. (2012), in which a physical in- stantiation of template replication was demonstrated using fined as a net chemical reaction, at least one of whose prod- macroscopic “monomers” floating above an air table. ucts is also an intermediate. This allows the concentration of intermediates to build up over time, which under the right conditions can lead to exponential growth. Such reac- These ideas have been criticised on the grounds that it tions are not uncommon and are often the mechanism behind would be difficult to find mineral catalysts that would catal- combustion and explosive reactions. A more formal defini- yse every step in this relatively complex cycle (Orgel, 2000) tion of this type of autocatalysis is given by Andersen et al. without also catalysing side-reactions that would reduce (2012). In the classification of Plesson et al. (2011), this the replicator’s specificity to a non-viable level (Szathmary,´ definition includes direct, indirect and autoinductive forms 2000). This latter problem must be solved by any approach of autocatalysis. to the origins of life. In any autocatalytic chemical sys- Some known examples of autocatalysis via branching tem there will be reactions that contribute to the autocat- chain reactions are shown in Fig. 1 and 2. This definition alytic network (branching reactions and propagating reac- is similar in spirit to that of an autocatalytic set, but in our tions) and reactions that deplete its constituents (terminating case the catalysis mechanism emerges from the system’s dy- reactions). If the latter dominate then growth will not occur. namics, rather than being a property of individual molecules. In this paper we offer solutions to these problems. King Autocatalytic cycles have been hypothesised as playing an (1982) gave a heuristic argument that the formation of au- important role in the origins of life. Wachtersh¨ auser¨ (1988), tocatalytic cycles is very likely in systems that are driven and later Morowitz et al. (2000) proposed the reductive cit- by a flow of energy across their boundary but closed to ric acid cycle (Figure 1a) as a possible means by which matter flow. This is because the products of any reaction molecules such as sugars, lipids and amino acids could have will eventually be recycled, and this recycling process has been generated on the early Earth. The citric acid cycle is a high probability of forming part of an autocatalytic cycle. important in modern biology but its intermediate steps are Our model confirms that this phenomenon can occur in very catalysed by enzymes. Wachtersh¨ auser’s¨ argument was that simple driven systems, even if the system is not completely inorganic surface catalysts might have been able to play the closed to matter flow. This suggests that there may be a great same role on the early Earth. Morowitz et al. argued that number of simpler autocatalytic systems that could have the reductive citric acid cycle might be unique, in the sense preceded the reductive citric acid cycle, perhaps ultimately of being the only autocatalytic cycle that could lead to the leading to the production of complex organic molecules that complexity of modern life on an Earth-like planet. could play the role of enzymes. 241 ECAL 2013 ECAL - General Track In the same paper, King argued that autocatalytic cycles work has spawned a multitude of successors. with many intermediate species are statistically unlikely to However, it must be stressed that, due to its origins in a be viable, in the sense of being able to grow exponentially. theory of protein interactions, this body of work assumes a This is because every step in an autocatalytic cycle is vulner- particular mechanism for autocatalysis, which can only oc- able to side reactions. Every reaction step may be assigned cur in relatively complex chemistries. This mechanism re- a number between 0 and 1 representing its specificity, and lies on the idea that the molecules involved are each able to it can be shown that the cycle is only viable if the product behave like enzymes, selectively catalysing some reactions of the specificities passes a threshold.