An Approach to the De Novo Synthesis of Life

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: As the remit of chemistry expands beyond molecules to systems, new synthetic targets appear on the horizon. Among these, life represents perhaps the ultimate synthetic challenge. Building on an increasingly detailed understanding of the inner workings of living systems and advances in organic synthesis and supramolecular chemistry, the de novo synthesis of life (i.e., the construction of a new form of life based on completely synthetic components) is coming within reach. This Account presents our first steps in the journey toward this long-term goal.The synthesis of life requires the functional integration of different subsystems that harbor the different characteristics that are deemed essential to life. The most important of these are self-replication, metabolism, and compartmentalization. Integrating these features into a single system, maintaining this system out of equilibrium, and allowing it to undergo Darwinian evolution should ideally result in the emergence of life. Our journey toward de novo life started with the serendipitous discovery of a new mechanism of self-replication. We found that self-assembly in a mixture of interconverting oligomers is a general way of achieving self-replication, where the assembly process drives the synthesis of the very molecules that assemble. Mechanically induced breakage of the growing replicating assemblies resulted in their exponential growth, which is an important enabler for achieving Darwinian evolution. Through this mechanism, the self-replication of compounds containing peptides, nucleobases, and fully synthetic molecules was achieved. Several examples of evolutionary dynamics have been observed in these systems, including the spontaneous diversification of replicators allowing them to specialize on different food sets, history dependence of replicator composition, and the spontaneous emergence of parasitic behavior. Peptide-based replicator assemblies were found to organize their peptide units in space in a manner that, inadvertently, gives rise to microenvironments that are capable of catalysis of chemical reactions or bindinginduced activation of cofactors. Among the reactions that can be catalyzed by the replicators are ones that produce the precursors from which these replicators grow, amounting to the first examples of the assimilation of a proto-metabolism. Operating these replicators in a chemically fueled out-of-equilibrium replication-destruction regime was found to promote an increase in their molecular complexity. Fueling counteracts the inherent tendency of replicators to evolve toward lower complexity (caused by the fact that smaller replicators tend to replicate faster). Among the remaining steps on the road to de novo life are now to assimilate compartmentalization and achieve open-ended evolution of the resulting system. Success in the synthesis of de novo life, once obtained, will have far-reaching implications for our understanding of what life is, for the search for extraterrestrial life, for ...

The Systems Chemistry of Nucleic‐acid‐Peptide Networks

“…As several examples in the review illustrate, current efforts in systems chemistry focus on developing a plausible connection between the dynamic formation (or destruction) of molecular assemblies and information transfer towards function, such as catalysis, replication, and translation. Moreover, such synthetic systems are now being designed to perform more elaborate systems level functions that integrate all three (or in simpler cases, only two) of the distinct characteristics of life; compartmentalization, replication, and metabolism [6c] . While both the peptide and nucleic acid precursors appear capable of forming in prebiotic environments from simpler building blocks, it is their cooperative assembly, synergistic activity, and mutualistic functions that must emerge on the way to cellular life [15d,53] .…”

“…In successful cases, strong interactions lead to irreversible phase separation and aggregation while with weaker interactions the favorable folds remain sufficiently dynamic to promote the emergence of supramolecular stability, adaptivity, and flexibility. These assemblies lead naturally into the acquisition of function that mimic a living systems ability to replicate, metabolize, and spatiotemporally isolate reaction networks from their environment [6c,15] . Indeed, synthetic networks consisting NA‐pep components have been shown to both replicate and translate the NA information into peptide scaffolds.…”

A Ribonucleotide ↔ Phosphoramidate Reaction Network Optimized by Computer-Aided Design

“…Furthermore, carbodiimides recently fueled the ratcheted and directional motion of molecular machines. , Mimicking nature’s dissipative systems can be crucial to understanding the origins of life, which requires out-of-equilibrium systems featuring self-replication, metabolism, and compartmentalization. ,, Recently, phosphoramidates have been identified as a compound class with prebiotic relevance. For example, efficient non-enzymatic primer extension of 3′-NP DNA , and template-directed synthesis of 3N′-5P′-RNA have been reported (self-replication).…”

Heat triggered molecular restructuring results in triple gel–gel–gel transformations in a Li+-integrated metallogel

“…In these processes, a pristine molecule gets dynamically sacrificed in an out-of-equilibrium fashion to generate a new hierarchical self-assembly. 1–3 However, the synthetic self-assembled structures are often devoid of such complex self-regulatory properties and hence are rarely reported. Thus, to decode the complexity of self-adjusting and/or dissipative natural assemblies, a growing research interest in the area of supramolecular stimuli-responsive gels has been witnessed.…”