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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.

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.

The mechanism and the reactive species involved in the oxidation of alkenes, and alcohols with H2O2, catalysed by an in situ prepared mixture of a MnII salt, pyridine-2-carboxylic acid and a ketone is elucidated using substrate competition experiments, kinetic isotope effect (KIE) measurements, and atom tracking with 18O labelling. The data indicate that a single reactive species engages in the oxidation of both alkenes and alcohols. The primary KIE in the oxidation of benzyl alcohols is ca. 3.5 and shows the reactive species to be selective despite a zero order dependence on substrate concentration, and the high turnover frequencies (up to 30 s−1) observed. Selective 18O labelling identifies the origin of the oxygen atoms transferred to the substrate during oxidation, and is consistent with a highly reactive, e. g., [MnV(O)(OH)] or [MnV(O)2], species rather than an alkylperoxy or hydroperoxy species.

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.

International audience; Non-linear effects between the enantiomeric excesses of both the ligand and the product are ubiquitous phenomena in asymmetric catalysis, allowing asymmetric amplification (or depletion) and are widely used tools for mechanistic investigations. Non-linear effects are caused by catalyst aggregation; however, the effect of catalyst precipitation on NLEs has not been systematically investigated to date, except in special cases such as ternary phase systems. In this article, we show through simulations and with several literature cases at hand how precipitation affects shape and amplitude of NLE curves. The limit of solubility of the homo- or heterochiral dimeric species causes broken-shaped NLE curves or very pronounced NLEs even though the equilibria between the different species in solution are not favorable, at first sight. Peculiar features such as horizontal segments, inverse S-shaped curves and a strong effect of total catalyst concentration are also observed. Overall, this study allows to get a better understanding of chiral catalytic systems and gives an outlook at other types of phase separation leading to NLEs.

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.

For over 25 years the chemistry community has puzzled over the mechanism of the Soai reaction, a fascinating chemical process which achieves chiral symmetry breaking by combining autocatalysis with asymmetric amplification. In 2020, the groups of Denmark and Trapp each made a proposal, based on extensive experimental work, on what is the catalytic species there: either a tetrameric product alkoxide aggregate (“SMS tetramer”) or a product-substrate dimer (“hemiacetal”). These models seemingly oppose and exclude each other; however, they might also be both valid since the studies were conducted on different substrates which are not necessarily equivalent. This is shown in this Viewpoint by an in-depth comparison of the two studies and of data from earlier reports, which opens up to a discussion on this scenario's far-reaching implications on the fundamental understanding of asymmetry-amplifying autocatalysis.

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.

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.

This thesis presents a few contributions to the field of systems chemistry, ranging from dynamic combinatorial chemistry to photoizomerization. In the preface and the first chapter the reader is introduced to the general concepts and recent developments in systems chemistry. In Chapter 2 the concept of antiparallel dynamic covalent chemistry is introduced as a new kind of interaction between different combinatorial chemistries, and also as a tool to control the behaviour of dynamic combinatorial libraries. In Chapter 3 the interface between dynamic combinatorial chemistries is again explored, as well as a new kind of interaction between different combinatorial chemistries – in particular the catalysis of E/Z-isomerization of hydrazones by thiols. In Chapter 4 a long standing problem of slow hydrazone exchange is tackled. In particular, using UV irradiation as a means of introducing energy into system enables faster exchange due to the presence of reactants richer in energy. In Chapter 5 UV irradiation is used to establish photostationary states between two isomers of a hydrazone distributed between two immiscible solvents. Such a system is very easy to prepare, and yet shows complex emergent behaviour. In the final chapter all results are summarized and put in the perspective of possible future developments.

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 present invention relates to the use of compounds of formula (I) as inhibitors of RNA guided endonucleases, e.g., Cas9 and Cpfl, and methods for the inhibition of the function of such RNA guided endonucleases, including their use in the treatment and prevention of conditions or diseases.

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.

Enzyme mimics have broad applications in catalysis and can assist elucidation of the catalytic mechanism of natural enzymes. However, challenges arise from the design of catalytic sites, the selection of host molecules, and their integration into active three-dimensional structures. Herein, we describe the development of a photooxidase mimic by synergetic molecular self-assembly. 9-Fluorenylmethyloxycarbonyl-l-histidine undergoes efficient co-assembly with phthalocyanine into nanovesicles with tunable particle size and membrane thickness. The obtained nanovesicles can be used as catalysts for reactive-oxygen-mediated photosensitive oxidation with improved efficiency and stability. This work highlights the co-assembly of simple building blocks into a supramolecular photocatalyst, which might give insight into possible evolutionary paths of photocatalytic membrane systems, and might allow facile transfer into photosensitive nanoreactors or artificial organelles.

This dissertation is focused on two major investigations. The first one is about the mechanism with which a known self-replicator can create copies of itself. This study led to the first real-time visualization of a molecule capable of self-replication. The second is about the introduction of additional functionalities within self-replicating systems of molecules. Here, we were able to show emergent behavior: catalytic activity that would only start when the self-replication process takes place.

Inspired by nature, chemists have envisioned that it is possible to obtain organized structures (and functions) using complex networks of interacting molecules in a synthetic setting. Thus far, functional molecular systems have been recognized as fruitful platforms, suitable to challenge and complement prevalent strategies for innovation in areas ranging from biology and medicine to energy sustainability. To this end, this thesis describes studies on self-assembling systems and their emergent properties and functions. The research presented teeters at the interface of fundamental and applied research as we address conceptually very different topics from a unique starting point. The work in Chapters 3 and 4 utilizes reversibility of covalent and non-covalent interactions to explore the modes of organization in peptide-based systems. In particular, we investigated the tendency of self-assemblies towards post-modification, self-replication and folding. In Chapters 5 and 6 we explored an alternative synthetic mimic of the extracellular matrix (ECM). The basic scaffold was designed in such a way to facilitate chemical modifications on demand (easily and quickly). In this approach, only minimal synthetic efforts are required to readily diversify a polymeric material using various bioactive entities (e.g., cell adhesion ligands, RGD or LDV).In the future, functional systems that make use of dynamic bonds will continue to address highly compelling and challenging questions. By answering those, we aim to make advancements in fundamental topics such as the origin of life, as well as health and technology.

ConspectusAs 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 binding-induced 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 how life may have originated on earth, and for every-day life by opening up new vistas in the form living technology and materials.

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.

Unidirectional molecular rotation based on alternating photochemical and thermal isomerizations of overcrowded alkenes is well established, but rotary cycles based purely on photochemical isomerizations are rare. Herein we report three new second-generation molecular motors featuring a phosphorus center in the lower half, which engenders a unique element of axial chirality. These motors exhibit unusual behavior, in that all four diastereomeric states can interconvert solely photochemically. Kinetic analysis and modeling reveal that the behavior of the new motors is consistent with all-photochemical unidirectional rotation. Furthermore, X-ray crystal structures of all four diastereomeric states of two of these new motors were obtained, which constitute the first achievements of crystallographic characterization of the full 360° rotational cycle of overcrowded-alkene-based molecular motors. Finally, the axial phosphorus stereoelement in the phosphine motor can be thermally inverted, and this epimerization enables a “shortcut” of the traditional rotational cycle of these compounds.

Central to the origin of life is the question how a chemical system transitioned from interacting molecules to an entity with the capacity for self-replication, diversification and adaptive evolution. Here, we study a chemical system that is comprised of macrocycles that have been shown to spontaneously give rise to self-replicating entities. By combining experimental and theoretical approaches, we strive to understand the evolutionary potential of this system. In particular, we apply eco-evolutionary reasoning to investigate whether and when this system of chemical replicators can diversify. Here, we report first results of a simplified stochastic chemical reaction model that is parameterized on the basis of experimental data. The model considers the competition of two replicators that do not interact directly but need similar building blocks for their growth and reproduction. Interestingly, the replicator that emerges first is being overtaken by the later one. By means of stochastic simulations, we will explore how the competitive ability of a replicator is determined by its chemical characteristics, and under which conditions replicators can coexist. The results will subsequently inform the design of future experiments.

While tensions may lay between science and policy, we argue that dissemination and public engagement are key in alleviating those perceived tensions. Science being valued by society results in fact-based policy-making being demanded by constituents. Constituents’ demands will yield representatives who are familiar with the scientific process and research to inform policy decisions.

Making artificial (“de-novo”) life from completely synthetic molecules is a challenging endeavour that could help us understand life, detect it, and gain some insight on its origins. The aim of this thesis is to combine in a single system several properties that are fundamental to living systems – specifically self-replication, compartmentalization, and metabolism.This work is based on self-replicating fibres that emerge from a dynamic combinatorial library. Through the thesis, we study their self-replication mechanism using HS-AFM, use complex coacervates to compartmentalize them, and combine them with photocatalytic cofactors to obtain the first synthetic example of a light-driven protometabolism. Finally, we combine this protometabolic feedback loop with out-of-equilibrium conditions to design a synthetic oscillator.The results shown here are first steps towards the synthesis of de-novo life, and can lead in the future to more complex processes such as ecological relationships or Darwinian evolution.

Controlling the formation of ordered and predictable patterns in dissipative reaction-diffusion processes is challenging. Now, liquid vibrations induced by audible sound have been shown to direct the formation of spatiotemporal patterns in switchable chemical systems and assemblies.

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.

The work carried out in this thesis provides examples on how variations in building block design affect self-assembly and self-replication behavior in dynamic combinatorial libraries. Chapter 1 provides an introduction in which possible definitions of life are discussed, together with the main characteristics of living systems (like self-replication and metabolism) and an overview of recent developments on self-replicators based on peptides and nucleobases. In Chapter 2 we report two peptide-based self-replicators that were utilized to synthesize supramolecular polymers with controllable size and composition. Our observations indicated that the nature of the polymers was strongly affected by the morphology of the sheared seeds. In Chapter 3 we show how self-replication can be tuned by the length of the spacer in DCLs made from two structurally different building blocks. In Chapter 4 we discovered parasitic behavior between self-replicators formed from building blocks that differ by a single methylene unit. We observed that a 6-ring replicator can only emerge when assisted by a pre-existing 8-ring self-replicator. Aiming for diversification of self-replicators through a cross-catalytic pathway under out-from-equilibrium conditions, we used continuous flow-set-ups in Chapter 5. First, we set up a system with two building blocks and optimized the experimental conditions in terms of flow rate, time and starting replicator composition. We also report attempts to create a cross-catalytic cycle by introducing a third building block. Finally, in Chapter 6, our studies are placed in a broader perspective and future prospects are discussed.

This thesis intends to capture the processes of self-replication and folding individually or combined by using dynamic combinatorial chemistry. This thesis is composed of 6 chapters, each of them dealing with a different aspect of folding and replication.In Chapter 1, we briefly introduced the basic concepts of systems chemistry and the origin of life. In order to mimic some of life’s important features and to achieve life-like behavior, it is particularly important to construct complex systems that combine the processes of self-replication and folding. In Chapter 2, we described how a dynamic combinatorial selection approach allows access to a foldamer of remarkable complexity constituted by 15 identical peptide-nucleobase building blocks. In Chapter 3, we reported the discovery of foldamers that form autonomously in aqueous media based on simple dipeptides using a systems chemistry approach. In Chapter 4, we described the emergence of self-replicating molecules that contain both amino acids and nucleobase from DCLs. In Chapter 5 we described for the first time the self-sorting between self-replicating and folded molecules in a DCL composed of two building blocks. Furthermore, we developed a transient self-replicating system using the same building blocks. Conclusions are drawn in Chapter 6.

This thesis focuses on the emergence of novel peptide self-replicators from dynamic combinatorial libraries. Thiol functionalised peptide building blocks, first reported by our group in 2010, form the basis of all chapters. The work performed here has two main objectives: First, to deepen the insights obtainable from self-replicating systems and second, to use peptide building blocks to mimic life-like features such as replication. Alongside this, we developed novel strategies to access novel replicators and to dictate their properties.

Complex (supra)molecular systems are ubiquitous in living organisms as well as in synthetic context but understanding them in depth is still out of reach, mainly because we do not have much insight into the gradual formation of complex behavior from more simple system elements. The motivation of this thesis is to show how complex chemical systems can be constructed and as a result, how the emergence of novel systems phenomena can be understood with the aid of the applied bottom-up approach.

Present studies on metal-organic frameworks (MOF) mainly focus on macro-scaled single crystals. However, the realization of MOF nanocrystals via a bottom-up one-step method still remains a significant challenge. Here, hierarchically assembled nanostructures of lanthanide-based MOFs with 1D and 3D morphologies have been successfully fabricated via a simple and rapid solution phase method at room temperature. Upon UV excitation, these nanomaterials exhibit highly efficient tunable luminescence properties, which come from the Eu3+ or Tb3+ ions. Moreover, white-light emission can be achieved by co-activating the organic ligand, Eu3+ and Tb3+ ions in the nano-MOFs. This journal is

Folding can bestow macromolecules with various properties, as evident from nature's proteins. Until now complex folded molecules are the product either of evolution or of an elaborate process of design and synthesis. We now show that molecules that fold in a well-defined architecture of substantial complexity can emerge autonomously and selectively from a simple precursor. Specifically, we have identified a self-synthesizing macrocyclic foldamer with a complex and unprecedented secondary and tertiary structure that constructs itself highly selectively from 15 identical peptide-nucleobase subunits, using a dynamic combinatorial chemistry approach. Folding of the structure drives its synthesis in 95% yield from a mixture of interconverting molecules of different ring sizes in a one-step process. Single-crystal X-ray crystallography and NMR reveal a folding pattern based on an intricate network of noncovalent interactions involving residues spaced apart widely in the linear sequence. These results establish dynamic combinatorial chemistry as a powerful approach to developing synthetic molecules with folding motifs of a complexity that goes well beyond that accessible with current design approaches. The fact that such molecules can form autonomously implies that they may have played a role in the origin of life at earlier stages than previously thought possible.

Life, as we know it today, requires the homochirality of its constituents. Yet it is likely that the prebiotic soup was a racemic mixture of molecules. It remains an open question at which point in evolution homochirality became necessary for life. Self-replicating molecules are expected to be a possible link between inanimate and animate matter. We here report the interplay between chirality and self-replication, and specifically investigated cross-catalysis between replicating species containing building blocks of different handedness. We find that, although replication of species from the same handedness is more efficient in isolated systems, nonstereoselective cross-catalysis dominates and leads to the formation of heterochiral self-replicators when a racemic mixture of building blocks is provided. These results demonstrate that homochirality is not a prerequisite for self-replication, and that chiral symmetry breaking could have occurred after the emergence of self-replicating systems from racemic mixtures.

The invention relates to self-assembling peptide (nano)fibers, hydrogels, and methods, uses and intermediate products and kits relating thereto. Provided is a method for providing peptide-based functionally modified (nano)fibers, comprising (i) providing a fiber forming solution comprising pseudopeptide building blocks of the formula A-Peptide-B, wherein: Peptide is a moiety of 1 to 8 amino acid residues having a sequence that is predisposed to form a one-dimensional array, such as β-sheet fibrils; A is an aromatic moiety carrying two reactive thiol groups; and B is a reactive α-nucleophile; (ii) exposing the fiber forming solution to oxidizing conditions to induce supramolecular self-assembly of the pseudopeptide building blocks into peptide-based (nano)fibers; and (iii) contacting said (nano)fibers with at least one biologically relevant functional group of interest comprising reactivity C forming a reactive pair with B to obtain covalently functionally modified nanofibers.