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Dynamic foldamers are synthetic folded molecules which can change their conformation in response to an external stimulus and are currently at the forefront of foldamer chemistry. However, constitutionally dynamic foldamers, which can change not only their conformation but also their molecular constitution in response to their environment, are without precedent. We now report a size- and shape-switching small dynamic covalent foldamer network which responds to changes in pH. Specifically, acidic conditions direct the oligomerization of a dipeptide-based building block into a 16-subunit macrocycle with well-defined conformation and with high selectivity. At higher pH the same building block yields another cyclic foldamer with a smaller ring size (9mer). The two foldamers readily and repeatedly interconvert upon adjustment of the pH of the solution. We have previously shown that addition of a template can direct oligomerization of the same building block to yet other rings sizes (including a 12mer and a 13mer, accompanied by a minor amount of 14mer). This brings the total number of discrete foldamers that can be accessed from a single building block to five. For a single building block system to exhibit such highly diverse structure space is unique and sets this system of foldamers apart from proteins. Furthermore, the emergence of constitutional dynamicity opens up new avenues to foldamers with adaptive behavior.

Self-replicating molecules provide a simple approach for investigating fundamental processes in scenarios of the emergence of life. Although homochirality is an important aspect of life and of how it emerged, the effects of chirality on self-replicators have received only little attention so far. Here we report several self-assembled self-replicators with chiral selectivity, that emerge spontaneously and grow only from enantiopure material. These require a relatively small number of chiral units in the replicators (down to 8) and in the precursors (down to a single chiral unit), compared to the only other chiral selective replicator reported previously. One replicator was found to incorporate material of its own handedness with high fidelity when provided with a racemic mixture of precursors, thus sorting (L)- and (D)-precursors into (L)- and (D)-replicators. Systematic studies reveal that the presence or absence of chiral selectivity depends on structural features (ring size of the replicator) that appear to impose constraints on its supramolecular organization. This work reveals new aspects of the little researched interplay between chirality and self-replication and represents another step towards the de novo synthesis of life.

Dynamic covalent chemistry (DCC) has proven to be a valuable tool in creating fascinating molecules, structures, and emergent properties in fully synthetic systems. Here we report a system that uses two dynamic covalent bonds in tandem, namely disulfides and hydrazones, for the formation of hydrogels containing biologically relevant ligands. The reversibility of disulfide bonds allows fiber formation upon oxidation of dithiol-peptide building block, while the reaction between NH-NH2 functionalized C-terminus and aldehyde cross-linkers results in a gel. The same bond-forming reaction was exploited for the "decoration" of the supramolecular assemblies by cell-adhesion-promoting sequences (RGD and LDV). Fast triggered gelation, cytocompatibility and ability to "on-demand" chemically customize fibrillar scaffold offer potential for applying these systems as a bioactive platform for cell culture and tissue engineering.

The complex interplay between systems and their environment plays an important role in processes ranging from self-assembly to evolution. Polymorphism, where, from the same ingredients different products can be formed, is likely to be an important enabler for evolutionary adaptation. Environmental pressures may induce polymorphic behaviour, where different pressures result in different structural organisation. Here we show that by combining covalent and non-covalent bond formation three distinct polymorphs can emerge from the same small dynamic molecular network: vesicular aggregates, self-replicating fibres and nanoribbons, depending on the nature of the solvent environment. Additionally, a particular set of conditions allows the transient co-existence of both vesicles and fibres.

Fueled chemical systems have considerable functional potential that is still largely unexplored. Here, we report a new approach to transient amide bond formation and use it to harness chemical energy and convert it to mechanical motion by integrating dissipative self-assembly and the Marangoni effect in a source-sink system. Droplets are formed through dissipative self-assembly following the reaction of octylamine with 2,3-dimethylmaleic anhydride. The resulting amides are hydrolytically labile making the droplets transient, which allows them to act as a source of octylamine. A sink for octylamine was created by placing a drop of oleic acid on the air-water interface. This source – sink system sets up a gradient in surface tension, which gives rise to a macroscopic Marangoni flow that can transport the droplets in solution with tunable speed. Carbodiimides can fuel this motion by converting diacid waste back to anhydride. This study shows how fueling at the molecular level can, via assembly at the supramolecular level, lead to liquid flow at the macroscopic level.

Nature segregates fundamental tasks such as information storage/transmission and catalysis between two different compound classes (e.g. polynucleotides for replication and folded polyamides for catalysis). This division of labor is likely a product of evolution, raising the question of how simpler systems in which replicators and folded macromolecules co‐exist may emerge in the transition from chemistry to biology. In synthetic systems, achieving co‐existence of replicators and foldamers in a single molecular network remains an unsolved problem. Previous work on dynamic molecular networks has given rise to either self‐replicating fibers or well‐defined foldamer structures (or completely un‐sorted complex systems). We report a system in which two cross‐reactive dithiol (nucleobase‐ and peptide‐based) building blocks self‐sort into a replicator fiber and foldamer that both emerge spontaneously and co‐exist. The self‐sorting behavior remains prevalent across different building block ratios as two phases of emergence occur: replicator growth followed by foldamer formation. This is attributed to the autocatalytic formation of the replicator fiber, followed by enrichment of the system in the remaining building block, which is subsequently incorporated into a foldamer., Two different dithiol building blocks interconvert through reversible covalent bonds to initially form a dynamic combinatorial library of macrocycles of various size. The self‐sorting process starts by the amplification of a single library member to form self‐replicating fibers. This step is followed by enrichment of the system in the remaining building block, which forms a large macrocyclic foldamer.

Natural selection is the cornerstone of Darwinian evolution and acts on reproducing entities exhibiting variations that can be inherited and selected for based on, among others, interactions with the environment. Conversely, the replicating entities can also affect their environment generating a two-way feedback on evolutionary dynamics. The onset of such ecological-evolutionary dynamics marks a stepping stone in the transition from chemistry to biology. Yet the bottom-up creation of a molecular system that exhibits ecological-evolutionary dynamics has remained elusive. Here, we describe the onset of such dynamics in a minimal system containing two synthetic self-replicators. The replicators are capable of binding and activating a cofactor, enabling them to change the oxidation state of their environment through photoredox catalysis. The replicator distribution adapts to this change and, depending on light intensity, one or the other replicator prevails. In both cases the replicator distribution evolves towards higher dynamic kinetic stability, rooted in a faster replication rate under the specific environmental conditions. This study opens the world of chemistry to evolutionary dynamics that has until now been restricted to biology.

Unravelling how the complexity of living systems can (have) emerge(d) from simple chemical reactions is one of the grand challenges in contemporary science. Evolving systems of self‐replicating molecules may hold the key to this question. Here we show that, when a system of replicators is subjected to a regime where replication competes with replicator destruction, simple and fast replicators can give way to more complex and slower ones. The structurally more complex replicator was found to be functionally more proficient in the catalysis of a model reaction. These results show that chemical fueling can maintain systems of replicators out of equilibrium, populating more complex replicators that are otherwise not readily accessible. Such complexification represents an important requirement for achieving open‐ended evolution as it should allow improved and ultimately also new functions to emerge., Chemical fueling enables complex self‐replicating molecules to outcompete structurally simpler and faster replicators, revealing an important mechanism behind complexification that is required to transform chemistry into biology.

Dynamic combinatorial chemistry is a method widely used for generating responsive libraries of compounds, with applications ranging from chemical biology to materials science. It relies on dynamic covalent bonds that are able to form in a reversible manner in mild conditions, and therefore requires the discovery of new types of these bonds in order to progress. Amides, due to their high stability, have been scarcely used in this field and typically require an external catalyst or harsh conditions for exchange. Compounds able to undergo uncatalysed transamidation at room temperature are still rare exceptions. In this work, we describe reversible amide formation and transamidation in a class of compounds known as maleamic acids. Due to the presence of a carboxylic acid in β-position, these compounds are in equilibrium with their anhydride and amine precursors in organic solvents at room temperature. First, we show that this equilibrium is responsive to external stimuli: by alternating the additions of a Brønsted acid and a base, we can switch between amide and anhydride several times without side-reactions. Next, we prove that this equilibrium provides a pathway for reversible transamidation without any added catalyst, leading to thermodynamic distributions of amides at room temperature. Lastly, we use different preparation conditions and concentrations of Brønsted acid to access different library distributions, easily controlling the transition between kinetic and thermodynamic regimes. Our results show that maleamic acids can undergo transamidation in mild conditions in a reversible and tunable way, establishing them as a new addition to the toolbox of dynamic combinatorial chemistry.

Unraveling how chemistry can give rise to biology is one of the greatest challenges of contemporary science. Achieving life-like properties in chemical systems is therefore a popular topic of research. Synthetic chemical systems are usually deterministic: the outcome is determined by the experimental conditions. In contrast, many phenomena that occur in nature are not deterministic but caused by random fluctuations (stochastic). Here, we report on how, from a mixture of two synthetic molecules, two different self-replicators emerge in a stochastic fashion. Under the same experimental conditions, the two self-replicators are formed in various ratios over several repeats of the experiment. We show that this variation is caused by a stochastic nucleation process and that this stochasticity is more pronounced close to a phase boundary. While stochastic nucleation processes are common in crystal growth and chiral symmetry breaking, it is unprecedented for systems of synthetic self-replicators.

Among the key characteristics of living systems are their ability to self-replicate and the fact that they exist in an open system away from equilibrium. Herein, we show how the outcome of the competition between two self-replicators, differing in size and building block composition, is different depending on whether the experiments are conducted in a closed vial or in an open and out-of-equilibrium replication-destruction regime. In the closed system, the slower replicator eventually prevails over the faster competitor. In a replication-destruction regime, implemented through a flow system, the outcome of the competition is reversed and the faster replicator dominates. The interpretation of the experimental observations is supported by a mass-action-kinetics model. These results represent one of the few experimental manifestations of selection among competing self-replicators based on dynamic kinetic stability and pave the way towards Darwinian evolution of abiotic systems.

Self-assembly features prominently in fields ranging from materials science to biophysical chemistry. Assembly pathways, often passing through transient intermediates, can control the outcome of assembly processes. Yet, the mechanisms of self-assembly remain largely obscure due to a lack of experimental tools for probing these pathways at the molecular level. Here, the self-assembly of self-replicators into fibers is visualized in real-time by high-speed atomic force microscopy (HS-AFM). Fiber growth requires the conversion of precursor molecules into six-membered macrocycles, which constitute the fibers. HS-AFM experiments, supported by molecular dynamics simulations, revealed that aggregates of precursor molecules accumulate at the sides of the fibers, which then diffuse to the fiber ends where growth takes place. This mechanism of precursor reservoir formation, followed by one-dimensional diffusion, which guides the precursor molecules to the sites of growth, reduces the entropic penalty associated with colocalizing precursors and growth sites and constitutes a new mechanism for supramolecular polymerization.

The process by which chemistry can give rise to biology remains one of the biggest mysteries in contemporary science. The de novo synthesis and origin of life both require the functional integration of three key characteristics — replication, metabolism and compartmentalization — into a system that is maintained out of equilibrium and is capable of open-ended Darwinian evolution. This Review takes systems of self-replicating molecules as starting points and describes the steps necessary to integrate additional characteristics of life. We analyse how far experimental self-replicators have come in terms of Darwinian evolution. We also cover models of replicator communities that attempt to solve Eigen’s paradox, whereby accurate replication needs complex machinery yet obtaining such complex self-replicators through evolution requires accurate replication. Successful models rely on a collective metabolism and a way of (transient) compartmentalization, suggesting that the invention and integration of these two characteristics is driven by evolution. Despite our growing knowledge, there remain numerous key challenges that may be addressed by a combined theoretical and experimental approach. Self-replicating systems play a central role in the emergence of life. This Review describes the features that self-replicating systems need to acquire to transition from chemistry to biology and surveys the progress made in theoretical and experimental approaches.

Establishing how life can emerge from inanimate matter is among the grand challenges of contemporary science. Chemical systems that capture life’s essential characteristics—replication, metabolism and compartmentalization—offer a route to understanding this momentous process. The synthesis of life, whether based on canonical biomolecules or fully synthetic molecules, requires the functional integration of these three characteristics. Here we show how a system of fully synthetic self-replicating molecules, on recruiting a cofactor, acquires the ability to transform thiols in its environment into disulfide precursors from which the molecules can replicate. The binding of replicator and cofactor enhances the activity of the latter in oxidizing thiols into disulfides through photoredox catalysis and thereby accelerates replication by increasing the availability of the disulfide precursors. This positive feedback marks the emergence of light-driven protometabolism in a system that bears no resemblance to canonical biochemistry and constitutes a major step towards the highly challenging aim of creating a new and completely synthetic form of life. [Figure not available: see fulltext.].

The conditions that led to the formation of the first organisms and the ways that life originates from a lifeless chemical soup are poorly understood. The recent hypothesis of ''RNA-peptide coevolution'' suggests that the current close relationship between amino acids and nucleobases may well have extended to the origin of life. We now show how the interplay between these compound classes can give rise to new self-replicating molecules using a dynamic combinatorial approach. We report two strategies for the fabrication of chimeric amino acid/nucleobase self-replicating macrocycles capable of exponential growth. The first one relies on mixing nucleobase- and peptide-based building blocks, where the ligation of these two gives rise to highly specific chimeric ring structures. The second one starts from peptide nucleic acid (PNA) building blocks in which nucleobases are already linked to amino acids from the start. While previously reported nucleic acid-based self-replicating systems rely on pre-synthesis of (short) oligonucleotide sequences, self-replication in the present systems start from units containing only a single nucleobase. Self-replication is accompanied by self-assembly, spontaneously giving rise to an ordered one-dimensional arrangement of nucleobase nanostructures.

Prebiotic chemistry has dominated the origins of life (OoL) field to such an extent that often these terms have been used interchangeably. While prebiotic chemistry has benefited from cross-seeding with other disciplines (e.g., biochemistry, biophysics, computational sciences, geosciences), the OoL problem is still primarily a chemical one. The range of possible non-enzymatic pathways provisioning important biomolecules is becoming clearer, and the problem can now be cast in terms of understanding how the constructive interplay between such pathways is underlying the mechanisms controlling their self-organization into systems. Those systems must be capable of producing their constituent parts and reproducing as a result, with a degree of maintaining and transferring their information content. This chapter provides a concise historical overview of the research field, presents a comprehensive panorama of the possible synthesis pathways for each biomolecular domain, discusses the homochirality conundrum, argues a case for experimentation using non-classical materials, and models, and finally considers current and future trends.

Self-replicating systems play an important role in research on the synthesis and origin of life. Monitoring of these systems has mostly relied on techniques such as NMR or chromatography, which are limited in throughput and demanding when monitoring replication in real time. To circumvent these problems, we now developed a pattern-generating fluorescent molecular probe (an ID-probe) capable of discriminating replicators of different chemical composition and monitoring the process of replicator formation in real time, giving distinct signatures for starting materials, intermediates and final products. Optical monitoring of replicators dramatically reduces the analysis time and sample quantities compared to most currently used methods and opens the door for future high-throughput experimentation in protocell environments.

The ability of molecules and systems to make copies of themselves and the ability of molecules to fold into stable, well-defined three-dimensional conformations are of considerable importance in the formation and persistence of life. The question of how, during the emergence of life, oligomerization reactions become selective and channel these reactions toward a small number of specific products remains largely unanswered. Herein, we demonstrate a fully synthetic chemical system where structurally complex foldamers and self-replicating assemblies emerge spontaneously and with high selectivity from pools of oligomers as a result of forming noncovalent interactions. Whether foldamers or replicators form depends on remarkably small differences in building block structures and composition and experimental conditions. We also observed the dynamic transformation of a foldamer into a replicator. These results show that the structural requirements/design criteria for building blocks that lead to foldamers are similar to those that lead to replicators. What determines whether folding or replication takes place is not necessarily the type of noncovalent interaction, but only whether they occur intra- or intermolecularly. This work brings together, for the first time, the fields of replicator and foldamer chemistry.

Ultra-performance liquid chromatography is a common analysis tool, and stirring is common in many laboratory setups. Here we show a device which enables continuous stirring of samples whilst inside an ultra-performance liquid chromatography system. Utilizing standard magnetic stirring bars that fit standard vials, the device allows for the automation of experimental setups that require stirring. The device is designed such that it can replace the standard sample holder and fits in its place, while being battery operated. The use of three-dimensional (3D) printing and commercially available parts enables low-effort and low-cost device production, as well as easy modifications. Testing the device was performed by video analysis and by following the kinetics of a dynamic combinatorial library that is known to be exquisitely sensitive to agitation, as a result of involving a fiber growth-breakage mechanism. Design files and schematics are provided. High- and ultra-performance liquid chromatography are valuable tools for the identification of components in complex mixtures, but these instruments lack sample stirring capabilities. Here the authors design an automated device that enables continuous stirring of samples inside an ultra-performance liquid chromatography system, and can be reproduced and modified using 3D printing technology.

A device is presented, which enables continuous stirring of samples whilst inside an ultra-performance liquid chromatography system. Utilizing standard magnetic stirring bars that fit standard vials, the device allows for the automation of experimental setups that require stirring. The device is designed such that it can replace the standard sample holder and fits in its place, while being battery operated. The use of 3D printing and commercially available parts enables low-effort and low-cost device production, as well as easy modifications. Various tests were performed by following the kinetics of a dynamic combinatorial library that is known for exhibiting self-replication under mechanical agitation, via fiber growth-breakage mechanism. Design files and schematics are available.

This work addressed how self-replicating molecules can evolve to become more complex. Subjecting a system in which two self-replicating molecules compete for a common food source to a regime in which they are both degraded leads to survival of the most complex of the two replicators, even though this replicator is less efficient at replicating. These results show that chemical fueling of a replication process can drive the complexification of the replicator. The more complex replicator is also more proficient at catalyzing a model reaction, showing that complexification can also enhance (catalytic) function.

Self-assembly is a powerful method to obtain large discrete functional molecular architectures. When using a single building block, self-assembly generally yields symmetrical objects in which all the subunits relate similarly to their neighbours. Here we report the discovery of a family of self-constructing cyclic macromolecules with stable folded conformations of low symmetry, which include some with a prime number (13, 17 and 23) of units, despite being formed from a single component. The formation of these objects amounts to the production of polymers with a perfectly uniform length. Design rules for the spontaneous emergence of such macromolecules include endowing monomers with a strong potential for non-covalent interactions that remain frustrated in competing entropically favoured yet conformationally restrained smaller cycles. The process can also be templated by a guest molecule that itself has an asymmetrical structure, which paves the way to molecular imprinting techniques at the level of single polymer chains.

In this manuscript we describe how, by taking a systems approach, complex energy landscapes of supramolecular assemblies can be navigated using stoichiometry to control, with remarkable selectivity, which assembly gets populated. The perhaps counterintuitive finding is that it is not necessarily the assembly that, in a one-to-one comparison, is the most stable that wins the competition for common building blocks, even though the system is under thermodynamic control. Instead, an individually less stable assembly may completely dominate the system. This domination is possible when the building block stoichiometry in the system matches the stoichiometry of this specific assembly, allowing the system to maximize binding energy by making a large number of assemblies of moderate stability as opposed to a small number of more stable assemblies.

Creating large objects from simple subunits rarely results in structures that are of low symmetry as well as of low polydispersity. We now report the spontaneous and uniquely selective oligomerization of simple monomer units into oligomers that are of uniform length, have complex low symmetry structures and are conformationally well-defined. The occurrence of such structures is both frequent and diverse. It is driven by the spontaneous folding into three-dimensional shapes akin to those exhibited by biopolymers. We also show that templates can direct the formation of new functional foldamers. The resulting structures carry imprints of the templates and are therefore capable of binding these. This behavior resembles that of molecularly imprinted polymers (MIPs), with the important distinction that the selected oligomers are uniform and conformationally well-defined, whereas MIPs suffer from heterogeneity in structure, shape and size.

Our knowledge regarding the early steps in the formation of evolvable life and what constitutes the minimal molecular basis of life remains far from complete. The recent emergence of systems chemistry reinvigorated the investigation of systems of self-replicating molecules to address these questions. Most of these studies focus on single replicators and the effects of replicators on the emergence of other replicators remains under-investigated. Here we show the cross-catalyzed emergence of a novel self-replicator from a dynamic combinatorial library made from a threonine containing peptide building block, which, by itself, only forms trimers and tetramers that do not replicate. Upon seeding of this library with different replicators of different macrocycle size (hexamers and octamers), we observed the emergence of hexamer replicator consisting of six units of the threonine peptide only when it is seeded with an octamer replicator containing eight units of a serine building block. These results reveal for the first time how a new replicator can emerge in a process that relies critically on the assistance by another replicator through cross-catalysis and that replicator composition is history dependent.

Photoisomerization provides a clean and efficient way of reversibly altering physical properties of chemical systems and injecting energy into them. These effects have been applied in development of systems such as photoresponsive materials, molecular motors, and photoactivated drugs. Typically, switching from more to less stable isomer(s) is performed by irradiation with UV or visible light, while the reverse process proceeds thermally or by irradiation using another wavelength. In this work we developed a method of rapid and tunable Z -> E isomerization of C = N bond in acyl hydrazones, using aromatic thiols as nucleophilic catalysts. As thiols can be oxidized into catalytically inactive disulfides, the isomerization rates can be controlled via the oxidation state of the catalyst, which, together with the UV irradiation, provides orthogonal means to control the E/Z state of the system. As a proof of this concept, we have applied this method to control the diversity of acyl hydrazone based dynamic combinatorial libraries.

Self-replication at the molecular level is often seen as essential to the early origins of life. Recently a mechanism of self-replication has been discovered in which replicator self-assembly drives the process. We have studied one of the examples of such self-assembling self-replicating molecules to a high level of structural detail using a combination of computational and spectroscopic techniques. Molecular Dynamics simulations of self-assembled stacks of peptide-derived replicators provide insights into the structural characteristics of the system and serve as the basis for semiempirical calculations of the UV-vis, circular dichroism (CD) and infrared (IR) absorption spectra that reflect the chiral organization and peptide secondary structure of the stacks. Two proposed structural models are tested by comparing calculated spectra to experimental data from electron microscopy, CD and IR spectroscopy, resulting in a better insight into the specific supramolecular interactions that lead to self-replication. Specifically, we find a cooperative self-assembly process in which β-sheet formation leads to well-organized structures, while also the aromatic core of the macrocycles plays an important role in the stability of the resulting fibers.

The ability to design reaction networks with high, but addressable complexity is a necessary prerequisite to make advanced functional chemical systems. Dynamic combinatorial chemistry has, proven to be a useful tool in achieving complexity, however with some limitations in controlling it. Herein we introduce the concept of antiparallel: chemistries, in which the same functional group can be channeled into one of two reversible chemistries depending on a controllable parameter. Such systems allow both for achieving complexity, by combinatorial chemistry,, and addressing it, by switching from one chemistry to another by controlling an external parameter. In our design the two antiparallel chemistries are thiol disulfide exchange and thio-Michael addition, sharing the thiol as the common building block. By means of oxidation and reduction the system can be reversibly switched from predominantly thio-Michael chemistry to predominantly disulfide chemistry, as well as to any intermediate state. Both chemistries operate in water, at room temperature, and at mildly basic pH, which makes them' a suitable platform for further development of systems chemistry.

With the advent of reversible covalent chemistry the study of the interplay between covalent bond formation and non-covalent interactions has become increasingly relevant. Here we report that the interplay between reversible disulfide chemistry and self-assembly can give rise either to molecular diversity, i.e. the emergence of a unprecedentedly large range of macrocycles or to molecular specificity, i.e. the autocatalytic emergence of a single species. The two phenomena are the result of two different modes of self-assembly, demonstrating that control over self-assembly pathways can enable control over covalent bond formation.

Building on our ability to design and synthesise molecules and our understanding of the noncovalent interactions between these molecules, the chemical sciences are currently entering the new territory of Systems Chemistry. This young field aims to develop complex molecular systems showing emergent properties; i.e. properties that go beyond the sum of the characteristics of the individual consituents of the system. This review gives an impression of the state of the art of the field by showing a diverse number of recent highlights, including out-of-equilibrium self-assembly, chemically fuelled molecular motion, compartmentalised chemical networks and designed oscillators. Subsequently a number of current challenges related to the design of complex chemical systems are discussed, including those of creating concurrent formation-destruction systems, continuously maintaining chemical systems away from equilibrium, incorporating feedback loops and pushing replication chemistry away from equilibrium. Finally, the prospects for Systems Chemistry are discussed including the tantalizing vision of the de novo synthesis of life and the idea of self-synthesising and self-repairing chemical factories.

This work shows how a designed co-factor can be recruited and activated by a self-replicator to do photo-redox catalysis and generate the precursors from which the self-replicator can grow. It constitutes an important step in the direction of the de-novo synthesis of life by intergrating self-replication with a protometabolism.

How life can emerge from inanimate matter is one of the grand questions in science. Self-replicating molecules are necessary for the transition from chemistry to biology, but they need to acquire additional functions for life to emerge. Catalysis is one of the most essential of such functionalities, but mechanisms through which self-replicators can acquire catalytic and, in extension, metabolic properties have remained elusive. Here we show how catalytic activity and promiscuity in a self-replicator emerges through co-option: features that are selected to benefit replication inadvertently result in an arrangement of chemical functionalities that is conducive to catalysis. Specifically, we report self-assembly driven self-replicators that promote both a model retro-aldol reaction and the cleavage of fluorenylmethoxycarbonyl groups, with the latter transformation exerting a positive feedback on replication (protometabolism). Such chance invention of new function at the molecular level marks a pivotal step toward the de novo synthesis of life. In the development of chemical complexity—and the transition into biology—developing catalytic functionality is essential. Here the authors report the emergence of catalytic activity for two separate reactions (including one demonstrating a positive feedback on replication) in a self-replicating system.

We report dynamic combinatorial libraries made from a simple building block that is on the verge of enabling self-assembly driven self-replication. Adding a template provides a sufficient additional push yielding self-replication. Self-assembly and self-replication can emerge with building blocks that are considerably smaller than those reported thus far.

Fragmentbasiertes Wirkstoffdesign (FBWD) fuhrt zu pharmakologisch aktiven Substanzen fur biologische Targets. Obschon es zahlreiche Beispiele fur FBWD anhand von Fragmentwachstum und -optimierung gibt, wird die Verknupfung von Fragmenten nur selten verwendet. Dynamische kombinatorische Chemie (DKC) ist zu einer erfolgreichen Strategie fur die Identifizierung von Hits fur biologische Targets herangewachsen. Wir berichten hier uber die synergistische Kombination von Fragmentverknupfung und DKC, um Inhibitoren der Aspartylprotease Endothiapepsin zu identifizieren. Aufbauend auf Rontgenkristallstrukturen von Endothiapepsin im Komplex mit Fragmenten haben wir eine Bibliothek von Bisacylhydrazonen entworfen und DKC benutzt, um potente Hemmstoffe des Enzyms zu identifizieren: Der starkste Hemmstoff besitzt einen IC50-Wert von 54 nm, was eine 240-fache Steigerung der Affinitat im Vergleich zu den Ausgangstreffern darstellt. Anschliesend hat die Rontgenkristallographie den vorhergesagten Bindungsmodus bestatigt und somit die Effizienz der Kombination aus Fragmentverknupfung und DKC als Strategie fur die Identifizierung von Hits unterstrichen. Die Methode kann fur eine Reihe biologischer Targets Anwendung finden und sollte das Potenzial haben, die Optimierung eines Hits zu einer Leitstruktur zu vereinfachen.

We present a detailed study of self-assembled hydrogels of bundled and cross-linked networks consisting of positively charged amyloid-like nanofibers and a triblock copolymer with negatively charged end blocks as a cross-linker. In a first step small oligopeptides self-assemble into macrocycles which are held together by reversible disulfide bonds. Interactions between the peptides cause the macrocycles to assemble into nanofibers, which form a reversible hydrogel. The physical properties of the hydrogel are tuned using various methods such as control over the fibre length, addition of a cross-linking copolymer, and addition of salt. We establish a relationship between the bulk mechanical properties, the properties of the individual fibers and the hydrogel morphology using characterization techniques operating at different length scales such as rheology, atomic force microscopy (AFM) and cryo transmission electron microscopy (Cryo-TEM). This allows for a precise control of the elastic behaviour of these networks.

How new species emerge in nature is still incompletely understood and difficult to study directly. Self-replicating molecules provide a simple model that allows us to capture the fundamental processes that occur in species formation. We have been able to monitor in real time and at a molecular level the diversification of self-replicating molecules into two distinct sets that compete for two different building blocks ('food') and so capture an important aspect of the process by which species may arise. The results show that the second replicator set is a descendant of the first and that both sets are kinetic products that oppose the thermodynamic preference of the system. The sets occupy related but complementary food niches. As diversification into sets takes place on the timescale of weeks and can be investigated at the molecular level, this work opens up new opportunities for experimentally investigating the process through which species arise both in real time and with enhanced detail.

The application of nanoparticles to the multivalent recognition of biomacromolecules or programmed self-assembly requires control over the relative placement of chemical groups on their surface. We have developed a method to direct the functionalization of surfaces of aldehyde-equipped gold nanoparticles using a DNA template. An error-correction mechanism is built into the functionalization process thanks to the thermodynamic control enabled by the hydrazone exchange reaction. This reversible reaction can be conveniently switched off by removing the catalyst, preserving the functionalization.

Self-replication plays a central role in the origin of life and in strategies to synthesize life de novo. Studies on self-replication have focused mostly on isolated systems, while the dynamics of systems containing multiple replicators have received comparatively little attention. Yet most evolutionary scenarios involve the interplay between different replicators. Here we report the emergence of parasitic behavior in a system containing self-replicators derived from two subtly different building blocks 1 and 2. Replicators from 2 form readily through cross-catalysis by pre-existing replicators made from 1. Once formed, the new replicators consume the original replicators to which they owe their existence. These results resemble parasitic and predatory behavior that is normally associated with living systems and show how such lifelike behavior has its roots in relatively simple systems of self-replicating molecules.

In living systems processes like genome duplication and cell division are carefully synchronized through subsystem coupling. If we are to create life de novo, similar control over essential processes such as self-replication need to be developed. Here we report that coupling two dynamic combinatorial subsystems, featuring two separate building blocks, enables effector-mediated control over self-replication. The subsystem based on the first building block shows only self-replication, whereas that based on the second one is solely responsive toward a specific external effector molecule. Mixing the subsystems arrests replication until the effector molecule is added, resulting in the formation of a host-effector complex and the liberation of the building block that subsequently engages in self-replication. The onset, rate and extent of self-replication is controlled by the amount of effector present.

Self-assembly of a specific member of a dynamic combinatorial library (DCL) may lead to self-replication of this molecule. However, if the concentration of the potential replicator in the DCL fails to exceed its critical aggregation concentration (CAC), then self-replication will not occur. We now show how addition of a template can raise the concentration of a library member-template complex beyond its CAC, leading to the onset of self-replication. Once in existence, the replicator aggregates promote further replication also in the absence of the template that induced the initial emergence of the replicator.

Directing self-assembly processes out-of-equilibrium to yield kinetically trapped materials with well-defined dimensions remains a considerable challenge. Kinetically controlled assembly of self-synthesizing peptide-functionalized macrocycles through a nucleation-growth mechanism is reported. Spontaneous fiber formation in this system is effectively shut down as most of the material is diverted into metastable non-assembling trimeric and tetrameric macrocycles. However, upon adding seeds to this mixture, well-defined fibers with controllable lengths and narrow polydispersities are obtained. This seeded growth strategy also allows access to supramolecular triblock copolymers. The resulting noncovalent assemblies can be further stabilized through covalent capture. Taken together, these results show that self-synthesizing materials, through their interplay between dynamic covalent bonds and noncovalent interactions, are uniquely suited for out-of-equilibrium self-assembly.

We have developed a method for the localized functionalization of gold nanoparticles using imine-based dynamic combinatorial chemistry. By using DNA templates, amines were grafted on the aldehyde-functionalized nanoparticles only if and where the nanoparticles interacted with the template molecules. Functionalization of the nanoparticles was controlled solely by the DNA template; only amines capable of interacting with DNA were bound to the surface. Interestingly, even though our libraries contained only a handful of simple amines, the DNA sequence influenced their attachment to the surface. Our method opens up new opportunities for the synthesis of multivalent, nanoparticle-based receptors for biomacromolecules.