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Darwinian evolution, including the selection of the fittest species under given environmental conditions, is a major milestone in the development of synthetic living systems. In this regard, generalist or specialist behavior (the ability to replicate in a broader or narrower, more specific food environment) are of importance. Here we demonstrate generalist and specialist behavior in dynamic combinatorial libraries composed of a peptide‐based and an oligo(ethylene glycol) based building block. Three different sets of macrocyclic replicators could be distinguished based on their supramolecular organization: two prepared from a single building block as well as one prepared from an equimolar mixture of them. Peptide‐containing hexamer replicators were found to be generalists, i. e. they could replicate in a broad range of food niches, whereas the octamer peptide‐based replicator and hexameric ethyleneoxide‐based replicator were proven to be specialists, i. e. they only replicate in very specific food niches that correspond to their composition. However, sequence specificity cannot be demonstrated for either of the generalist replicators. The generalist versus specialist nature of these replicators was linked to their supramolecular organization. Assembly modes that accommodate structurally different building blocks lead to generalist replicators, while assembly modes that are more restrictive yield specialist replicators. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 n m, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

New methodology for making novel materials is highly desirable. Here, an 'ingredients' approach to functional self-assembled hydrogels was developed. By designing a building block to contain the right ingredients, a multi-responsive, self-assembled hydrogel was obtained through a process of template-induced self-synthesis in a dynamic combinatorial library. The system can be switched between gel and solution by light, redox reactions, pH, temperature, mechanical energy and sequestration or addition of MgII salt. [ABSTRACT FROM AUTHOR]

In biology enzyme concentrations are continuously regulated, yet for synthetic catalytic systems such regulatory mechanisms are underdeveloped. We now report how a substrate of a chemical reaction induces the formation of its own catalyst from a dynamic molecular network. After complete conversion of the substrate, the network disassembles the catalyst. These results open up new opportunities for controlling catalysis in synthetic chemical systems. [ABSTRACT FROM AUTHOR]

Making receptors to order: A small dynamic combinatorial library (DCL), formed from two dithiols in water, provides a continuous range of six receptors of different sizes. The majority of the 30 tested amines and ammonium ions amplified receptors from this library, thus spanning the complete receptor‐size range and showing that this DCL provides a generic platform for the development of receptors for this important class of compounds. [ABSTRACT FROM AUTHOR]

Background: The assessment of molecular similarity is a key step in the drug discovery process that has thus far relied almost exclusively on computational approaches. We now report an experimental method for similarity assessment based on dynamic combinatorial chemistry. Results: In order to assess molecular similarity directly in solution, a dynamic molecular network was used in a twostep process. First, a clustering analysis was employed to determine the network's innate discriminatory ability. A classification algorithm was then trained to enable the classification of unknowns. The dynamic molecular network used in this work was able to identify thin amines and ammonium ions in a set of 25 different, closely related molecules. After training, it was also able to classify unknown molecules based on the presence or absence of an ethylamine group. Conclusions: This is the first step in the development of molecular networks capable of predicting bioactivity based on an assessment of molecular similarity. [ABSTRACT FROM AUTHOR]

Background: Molecular recognition at the environment provided by the phospholipid bilayer interface plays an important role in biology and is subject of intense investigation. Dynamic combinatorial chemistry is a powerful approach for exploring molecular recognition, but has thus far not been adapted for use in this special microenvironment. Results: Thioester exchange was found to be a suitable reversible reaction to achieve rapid equilibration of dynamic combinatorial libraries at the egg phosphatidyl choline bilayer interface. Competing thioester hydrolysis can be minimised by judicial choice of the structure of the thioesters and the experimental conditions. Comparison of the library compositions in bulk solution with those in the presence of egg PC revealed that the latter show a bias towards the formation of library members rich in membrane-bound building blocks. This leads to a shift away from macrocyclic towards linear library members. Conclusions: The methodology to perform dynamic combinatorial chemistry at the phospholipid bilayer interface has been developed. The spatial confinement of building blocks to the membrane interface can shift the ringchain equilibrium in favour of chain-like compounds. These results imply that interfaces may be used as a platform to direct systems to the formation of (informational) polymers under conditions where small macrocycles would dominate in the absence of interfacial confinement. [ABSTRACT FROM AUTHOR]

Generating combinatorial libraries under equilibrium conditions has the important advantage that the libraries are adaptive (i.e. they can respond to exterior influences in the form of molecular recognition events). Thus, a ligand will direct and amplify the formation of its ideal receptor and vice versa. Proof of principle of this approach has been established using small libraries showing highly efficient amplification of selected receptors. The approach has recently been extended to address folding of macromolecules, including peptides. [ABSTRACT FROM AUTHOR]

A combinatorial library that responds to its target by increasing the concentration of strong binders at the expense of weak binders sounds ideal. Dynamic combinatorial chemistry has the potential to achieve exactly this. In this review, we will highlight the unique features that distinguish dynamic combinatorial chemistry from traditional combinatorial chemistry, and that could make a useful addition to the set of combinatorial techniques used in drug discovery. [Copyright &y& Elsevier]

The article discusses the findings of studies on the effect of the size of dynamic combinatorial libraries on the detectability of molecular recognition induced amplification. The effect of library size on the probability of determining the strongest binding library member present and the binding affinity of the most amplified detectable library member is also examined. It tackles the optimal experimental conditions for large DCLs. It stresses the likelihood that larger DCLs will produce better binders.

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. [ABSTRACT FROM AUTHOR]

Dynamic combinatorial chemistry (DCC) is a subset of combinatorial chemistry where the library members interconvert continuously by exchanging building blocks with each other. Dynamic combinatorial libraries (DCLs) are powerful tools for discovering the unexpected and have given rise to many fascinating molecules, ranging from interlocked structures to self-replicators. Furthermore, dynamic combinatorial molecular networks can produce emergent properties at systems level, which provide exciting new opportunities in systems chemistry. In this perspective we will highlight some new methodologies in this field and analyze selected examples of DCLs that are under thermodynamic control, leading to synthetic receptors, catalytic systems, and complex self-assembled supramolecular architectures. Also reviewed are extensions of the principles of DCC to systems that are not at equilibrium and may therefore harbor richer functional behavior. Examples include self-replication and molecular machines. [ABSTRACT FROM AUTHOR]

A family of self-replicating macrocycles was developed using dynamic combinatorial chemistry. Replication is driven by self-assembly of the replicators into fibrils and relies critically on mechanically induced fibril fragmentation. Analysis of separate dynamic combinatorial libraries made from one of six peptide-functionalized building blocks of different hydrophobicity revealed two selection criteria that govern the emergence of replicators from these systems. First, the replicators need to have a critical macrocycle size that endows them with sufficient multivalency to enable their self-assembly into fibrils. Second, efficient replication occurs only for library members that are of low abundance in the absence of a replication pathway. This work has led to spontaneous emergence of replicators with unrivalled structural complexity, being built from up to eight identical subunits and reaching a MW of up to 5.6 kDa. The insights obtained in this work provide valuable guidance that should facilitate future discovery of new complex self-replicating molecules. They may also assist in the development of new self-synthesizing materials, where self-assembly drives the synthesis of the very molecules that self-assemble. To illustrate the potential of this concept, the present system enables access to self-assembling materials made from self-synthesizing macrocycles with tunable ring size ranging from trimers to octamers. [ABSTRACT FROM AUTHOR]

Designing synthetic receptors that bind biologically relevant guests in an aqueous solution remains a considerable challenge. We now report a new synthetic receptor for nicotine, selected from a dynamic combinatorial library, that binds this guest in water at neutral pH through a combination of hydrophobic and π–π interactions. [ABSTRACT FROM AUTHOR]

The article explores the developments on dynamic combinatorial chemistry, which is combinatorial chemistry under control. Topics discussed include its history, the exchange reactions, experimental considerations, applications, the theoretical studies of dynamic combinatorial libraries, and related approaches.

The article reports the discovery and highly diastereoselective amplification of a strongly binding induced-fit host from a dynamic combinatorial library of macrocyclic disulfides in water. Dynamic combinatorial chemistry is a particularly effective method, in which a pool of hosts is generated by linking relatively simple building blocks together using a reversible reaction. The continuous exchange of building blocks ensures that the library is under thermodynamic control. Upon adding a guest, the equilibrium shifts in the direction of the host(s) that bind(s) this guest with high affinity.