Mapping primordial reaction networks

Chemists seeking to understand the origins of life have published a wide range of reactions that may have yielded the building blocks of proteins, nucleic acids, and lipids from simple precursors. Woos et al. scoured the literature to document each such reaction class and then wrote software that applied the reactions first to the simplest compounds such as cyanide, water, and ammonia, and then iteratively to each successive generation of products. The resulting network predicted a variety of previously unappreciated routes to biochemically relevant compounds, several of which the authors validated experimentally.

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Although hundreds of organic reactions have been validated under consensus prebiotic conditions, we still have only a fragmentary understanding of how these individual steps combined into complete synthetic pathways to generate lifes building blocks, which other abiotic molecules might have also formed, how independent reactions gave rise to chemical systems, and how membranes encapsulating these systems came into being. Answering such questions requires consideration of very large numbers of possible synthetic pathways. Starting with even a few primordial substratese.g., H2O, N2, HCN, NH3, CH4, and H2Sthe number of prebiotically synthesizable molecules grows rapidly into the tens of thousands. Detailed analysis of this space and its synthetic connectivity may be beyond the cognition of individual chemists but can be performed by smart computer algorithms.

We harnessed the power of computer-assisted organic synthesis to map the network of molecules that are synthesizable from basic prebiotic feedstocks. This was done by encoding currently known prebiotic reactions in a machine-readable format, augmenting these reaction transforms with information about incompatible groups and reaction conditions, and then applying them iteratively to a set of basic prebiotic substrates. The reaction network thus created was queried by algorithms to identify complete synthetic routes as well as those tracing reaction systemsnotably, reaction cycles. All calculations were supported by a software application that is freely available to the scientific community.

We demonstrate that this network comprises more abiotic molecules than biotic molecules. The biotic compounds differ from the abiotic compounds in several ways: They are more hydrophilic, more thermodynamically stable, and more balanced in terms of the hydrogen bond donors and acceptors they contain and are synthesizable along routes with fewer changes of conditions. The network contains not only all known syntheses of biotic compounds but also previously unidentified routes, several of which (e.g., prebiotic syntheses of acetaldehyde and diglycine, as well as malic, fumaric, citric, and uric acids) we validated by experiment. We also demonstrate three notable forms of chemical emergence: (i) that the molecules created within the network can themselves enable new types of prebiotic reactions; (ii) that within just a few synthetic generations, simple chemical systems (including self-regenerating cycles) begin to emerge; and (iii) that the network contains prebiotic routes to surfactant species, thus outlining a path to biological compartmentalization. We support these conclusions with experimental results, establishing previously undescribed prebiotic reactions and entire reaction systemsnotably, a self-regenerating cycle of iminodiacetic acid.

Computer-generated reaction networks are useful in identifying synthetic routes to prebiotically relevant targets and are indispensable for the discovery of prebiotic chemical systems that are otherwise challenging to discern. As our network continues to grow by means of crowd-sourcing of newly validated prebiotic reactions, it will allow continued simulation of chemical genesis, beginning with molecules as simple as water, ammonia, and methane and leading to increasingly complex targets, including those of current interest in the chemical and pharmaceutical industries.

Computer simulation of plausible prebiotic reactions creates a network of molecules that are synthesizable from prebiotic feedstocks and establishes multiple unreportedbut now experimentally validatedsyntheses of prebiotic targets as well as self-regenerating cycles. In this schematic illustration, light blue nodes represent abiotic molecules, dark blue nodes represent molecules along newly discovered prebiotic syntheses of uric and citric acids, and red nodes represent other biotic molecules.

The challenge of prebiotic chemistry is to trace the syntheses of lifes key building blocks from a handful of primordial substrates. Here we report a forward-synthesis algorithm that generates a full network of prebiotic chemical reactions accessible from these substrates under generally accepted conditions. This network contains both reported and previously unidentified routes to biotic targets, as well as plausible syntheses of abiotic molecules. It also exhibits three forms of nontrivial chemical emergence, as the molecules within the network can act as catalysts of downstream reaction types; form functional chemical systems, including self-regenerating cycles; and produce surfactants relevant to primitive forms of biological compartmentalization. To support these claims, computer-predicted, prebiotic syntheses of several biotic molecules as well as a multistep, self-regenerative cycle of iminodiacetic acid were validated by experiment.

Read more:
Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry - Science Magazine