The fundamental roles that peptides and proteins play in today's biology makes it almost indisputable that peptides were key players in the origin of life. Insofar as it is appropriate to extrapolate back from extant biology to the prebiotic world, one must acknowledge the critical importance that interconnected molecular networks, likely with peptides as key components, would have played in life's origin. In this review, we summarize chemical processes involving peptides that could have contributed to early chemical evolution, with an emphasis on molecular interactions between peptides and other classes of organic molecules. We first summarize mechanisms by which amino acids and similar building blocks could have been produced and elaborated into proto-peptides. Next, non-covalent interactions of peptides with other peptides as well as with nucleic acids, lipids, carbohydrates, metal ions, and aromatic molecules are discussed in relation to the possible roles of such interactions in chemical evolution of structure and function. Finally, we describe research involving structural alternatives to peptides and covalent adducts between amino acids/peptides and other classes of molecules. We propose that ample future breakthroughs in origin-of-life chemistry will stem from investigations of interconnected chemical systems in which synergistic interactions between different classes of molecules emerge.

Prebiotic Peptides: Molecular Hubs in the Origin of Life.

The ability to evolve is a key characteristic that distinguishes living things from non-living chemical compounds. The construction of an evolvable cell-like system entirely from non-living molecules has been a major challenge. Here we construct an evolvable artificial cell model from an assembly of biochemical molecules. The artificial cell model contains artificial genomic RNA that replicates through the translation of its encoded RNA replicase. We perform a long-term (600-generation) replication experiment using this system, in which mutations are spontaneously introduced into the RNA by replication error, and highly replicable mutants dominate the population according to Darwinian principles. During evolution, the genomic RNA gradually reinforces its interaction with the translated replicase, thereby acquiring competitiveness against selfish (parasitic) RNAs. This study provides the first experimental evidence that replicating systems can be developed through Darwinian evolution in a cell-like compartment, even in the presence of parasitic replicators.

Darwinian Evolution in a Translation-Coupled RNA Replication System Within a Cell-Like Compartment

This Review aims to critically analyse the emerging field of chemical reactivity at aqueous interfaces. The subject has evolved rapidly since the discovery of the so-called ‘on-water catalysis’, alluding to the dramatic acceleration of reactions at the surface of water or at its interface with hydrophobic media. We review critical experimental studies in the fields of atmospheric and synthetic organic chemistry, as well as related research exploring the origins of life, to showcase the importance of this phenomenon. The physico-chemical aspects of these processes, such as the structure, dynamics and thermodynamics of adsorption and solvation processes at aqueous interfaces, are also discussed. We also present the basic theories intended to explain interface catalysis, followed by the results of advanced ab initio molecular-dynamics simulations. Although some topics addressed here have already been the focus of previous reviews, we aim at highlighting their interconnection across diverse disciplines, providing a common perspective that would help us to identify the most fundamental issues still incompletely understood in this fast-moving field. Enhanced chemical reactivity on-water has major implications in many fields, ranging from atmospheric to prebiotic chemistry. This Review analyses recent experimental and theoretical studies in this fast-moving research area and brings together some key findings across diverse fields.

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Molecular reactions at aqueous interfaces

Progress in development of biophysical analytic approaches has recently crossed paths with macromolecule condensates in cells. These cell condensates, typically termed liquid-like droplets, are formed by liquid-liquid phase separation (LLPS). More and more cell biologists now recognize that many of the membrane-less organelles observed in cells are formed by LLPS caused by interactions between proteins and nucleic acids. However, the detailed biophysical processes within the cell that lead to these assemblies remain largely unexplored. In this review, we evaluate recent discoveries related to biological phase separation including stress granule formation, chromatin regulation, and processes in the origin and evolution of life. We also discuss the potential issues and technical advancements required to properly study biological phase separation.

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Biological phase separation: cell biology meets biophysics

Prebiotic Systems Chemistry: Complexity Overcoming Clutter

In search of a connection between prebiotic peptide chemistry and lipid compartments, the reaction of a 5(4H)-oxazolone with leucinamide was extensively explored under buffered aqueous conditions, where diverse amphiphiles and surfactants could form supramolecular assemblies. Significant increases in yield and changes in stereoselectivity were observed when fatty acids exceeded their critical aggregation concentration, self-assembling into vesicles in particular. This effect does not take place below the fatty acid solubility limit, or when other anionic amphiphiles/surfactants are used. Data from fluorimetric and Langmuir trough assays, complementary to the main HPLC results reported here, demonstrate that the dipeptide product co-localizes with fatty acid bilayers and monolayers. Additional experiments in organic solvents suggest that acid-base catalysis operates at the water-aggregate interface, linked to the continuous proton exchange dynamics that fatty acids undergo at pH values around their effective pKa. These simple amphiphiles could therefore play a dual role as enhancers of peptide chemistry under prebiotic conditions, providing soft and hydrophobic organic domains through self-assembly and actively inducing catalysis at their interface with the aqueous environment. Our results support a systems chemistry approach to life's origin.

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Fatty acids' double role in the prebiotic formation of a hydrophobic dipeptide

Correction for ‘Fatty acids' double role in the prebiotic formation of a hydrophobic dipeptide’ by Sara Murillo-Sanchez et al., Chem. Sci., 2016, DOI: 10.1039/c5sc04796j.

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Correction: Fatty acids' double role in the prebiotic formation of a hydrophobic dipeptide

Conceiving the process of biogenesis as the evolutionary development of highly dynamic and integrated protocell populations provides the most appropriate framework to address the difficult problem of how prebiotic chemistry bridged the gap to full-fledged living organisms on the early Earth. In this contribution we briefly discuss the implications of taking dynamic, functionally integrated protocell systems (rather than complex reaction networks in bulk solution, sets of artificially evolvable replicating molecules, or even these same replicating molecules encapsulated in passive compartments) as the proper units of prebiotic evolution. We highlight, in particular, how the organisational features of those chemically active and reactive protocells, at different stages of the process, would strongly influence their corresponding evolutionary capacities. As a result of our analysis, we suggest three experimental challenges aimed at constructing protocell systems made of a diversity of functionally coupled components and, thereby, at characterizing more precisely the type of prebiotic evolutionary dynamics that such protocells could engage in.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-13-135.pdf

Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research.

We here offer an alternative view of synthetic biology, quite distant from the engineering approaches that currently set the main research agenda of the field. Our analysis centres on those lines of work, both theoretical and experimental, whose primary objective is understanding the living phenomenon per se. A detailed review of several cases of artificial in vitro implementation of ‘self-productive’ chemical systems will help us reflect on the enormous challenge of transforming a descriptive scientific discipline, like biology, into an enterprise that comprises and fosters investigations articulated around the notion of synthesis or fabrication. The challenge is huge because of the intrinsic metabolic nature of biological systems, what makes our efforts to control or build them de novomuch harder, forcing us to develop intervention/implementation platforms at the molecular level that do not threaten that inherent autonomous dimension of the living.

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Sara Murillo-Sánchez

Papers

Fatty acids' double role in the prebiotic formation of a hydrophobic dipeptide

Correction: Fatty acids' double role in the prebiotic formation of a hydrophobic dipeptide

Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research.

La biología sintética como desafío para comprender la autonomía de lo vivo