Julian Vogel

Nature Chemistry, Published online: 22 October 2020; doi:10.1038/s41557-020-00564-3

Life requires a constant supply of energy, but the energy sources that drove the transition from prebiotic chemistry to biochemistry on the early Earth are unknown. Now, a potentially prebiotic chemical activating reagent has been shown to enable the synthesis, in aqueous conditions and catalysed by small molecules, of peptides, peptidyl–RNAs, RNA oligomers and primordial phospholipids.

Chemically fueled emulsions are solutions with droplets made of phase‐separated molecules activated and deactivated by a chemically‐fueled reaction cycle. Such systems are present in biology, but synthetic analogues are limited. Here, we describe human‐made chemically fueled emulsions, and we find a surprising behavior, i.e., the dynamics of droplet growth is regulated by the kinetics of the fuel‐driven reaction cycle. Combining experiments and theory, we elucidate the underlying mechanism, which relies on the acceleration of Ostwald ripening.

Abstract

Chemically fueled emulsions are solutions with droplets made of phase‐separated molecules that are activated and deactivated by a chemical reaction cycle. These emulsions play a crucial role in biology as a class of membrane‐less organelles. Moreover, theoretical studies show that droplets in these emulsions can evolve to the same size or spontaneously self‐divide when fuel is abundant. All of these exciting properties, i. e., emergence, decay, collective behavior, and self‐division, are pivotal to the functioning of life. However, these theoretical predictions lack experimental systems to test them quantitively. Here, we describe the synthesis of synthetic emulsions formed by a fuel‐driven chemical cycle, and we find a surprising new behavior, i. e., the dynamics of droplet growth is regulated by the kinetics of the fuel‐driven reaction cycle. Consequently, the average volume of these droplets grows orders of magnitude faster compared to Ostwald ripening. Combining experiments and theory, we elucidate the underlying mechanism.

Make and break: Molecular models provide a unique insight into the ATP‐driven self‐assembly and hydrolysis‐triggered disassembly of fuel‐regulated bioinspired supramolecular polymers.

Abstract

Fuel‐regulated self‐assembly is a key principle by which Nature creates spatiotemporally controlled materials and dynamic molecular systems that are in continuous communication (molecular exchange) with the external environment. Designing artificial materials that self‐assemble and disassemble via conversion/consumption of a chemical fuel is a grand challenge in supramolecular chemistry, which requires a profound knowledge of the factors governing these complex systems. Here we focus on recently reported metal‐coordinated monomers that polymerise in the presence of ATP and depolymerise upon ATP hydrolysis, exploring their fuel‐regulated self‐assembly/disassembly via multiscale molecular modelling. We use all‐atom simulations to assess the role of ATP in stabilising these monomers in assemblies, and we then build on a minimalistic model to investigate their fuel‐driven polymerisation and depolymerisation on a higher scale. In this way, we elucidate general aspects of fuel‐regulated self‐assembly that are important toward the rational design of new types of bioinspired materials.

Connecting parts of a resorcin[4]arene derivative through stepwise intramolecular acylation, reduction, and intramolecular acylation reactions produces a diketone‐bearing zigzag hydrocarbon belt. Further chemical modifications result in the formation of diverse functional molecules with different belt structures.

Abstract

Described in this paper are the synthesis and structure of novel and edge‐functionalized zigzag hydrocarbon belts. A stepwise “fjord‐stitching” strategy featuring repetitive intramolecular acylation reactions of a resorcin[4]arene derivative as the key steps afforded a biscarbonyl‐functionalized octahydrobelt[8]arene product. Facile ketone reduction with NaBH₄ and nucleophilic addition with n‐butyllithium produced secondary and tertiary alcohol‐containing molecular belts, respectively. Selective oxidation reactions of biscarbonyl‐bearing octahydrobelt[8]arene with m‐CPBA and (PhSeO)₂O furnished the corresponding lactone‐ and 1,4‐quinone‐embedded molecular belts. Depending on the functional groups on the edges, the acquired belt molecules adopt different shapes such as square prism, truncated cone, and elliptical cylinder.

Single and double cyclophenylene–ethynylenes (CPEs) with stable axial and helical chirality have been synthesized, which possess highly twisted bent structures and interesting chiroptical properties. Orbital interactions are observed along the biphenyl axis in both the single and double CPEs. Boosting of the g _abs value occurs in the biphenyl‐based double CPE and in the binaphthyl‐based single CPE, in contrast with the biphenyl‐based single CPE.

Abstract

Single and double cyclophenylene–ethynylenes (CPEs) with axial and helical chirality have been synthesized by the Sonogashira cross‐coupling of di‐ and tetraethynyl biphenyls with a U‐shaped prearomatic diiodoparaphenylene followed by reductive aromatization. X‐ray crystallographic analyses and DFT calculations revealed that the CPEs possess highly twisted bent structures. Bend angles on the edge of the paraphenylene units were close to the value of [5]cycloparaphenylene (CPP)—the smallest CPP to date. The double and single CPEs possessed stable chirality despite flexible biphenyl structures because of the high strain in the diethynyl–paraphenylene moiety. In both the single and double CPEs, orbital interactions along the biphenyl axis were observed by DFT calculations in LUMO and LUMO+2 of the single CPE and LUMO+1 of the double CPE, which likely cause lowering of these orbital energies. Concerning chiroptical properties: boosting of the g _abs value was observed in the biphenyl‐based double CPE, as well as the binaphthyl‐based single CPE, compared to the biphenyl‐based single CPE.

Glued by guanines: In this work, we show that the unique aggregation properties of H‐form 3′,5′ cyclic guanosine monophosphate molecules enable the sustainable non‐enzymatic template‐free synthesis of oligonucleotide sequences from nucleotide precursors on timescales of several days even in the presence of water.

Abstract

Polymerization of 3′,5′ cyclic guanosine monophosphate (3′,5′ cGMP) was previously reported to afford short RNA sequences from a plausible mildly activated prebiotic precursor in a non‐enzymatic and template‐free manner. In the current paper we analyze the reaction with PAGE as well as by infrared micro‐ and nanospectroscopy on time scales not considered before. We provide evidence that a preliminary oligomerization step in dry state allows for a continued synthesis of RNA oligomers even in the presence of subsequently added water. On a longer time scale, the oligomerization yield oscillates in an apparently chaotic fashion hinting at the importance of some non‐reversible phase‐separation processes on the experimentally observed outcome of the polymerization/degradation chemistries. The long‐lasting (hundreds of hours) intrinsic sustainability and resilience of the process gives a robust prebiotic potential to this unique oligomerization reaction, which could lead to the very first oligonucleotide sequences on the primordial Earth.

Nature Chemistry, Published online: 25 August 2020; doi:10.1038/s41557-020-0535-z

Stay-at-home policies invoked in response to COVID-19 have led to well-publicized drops in some air pollutants. The extent to which such reductions translate to improved air quality is dictated by not only emissions and meteorology, but also chemical transformations in the atmosphere.

Micellar shape changes of sodium dodecyl sulfate are associated with different binding modes of the counterions. Morphological changes are caused by symmetry breaking of the irreducible building blocks, with the formation of transient surfactant dimers mediated by the counterions that promote the stabilization of cylindrical instead of spherical micelles.

Abstract

The shape and size of self‐assembled structures upon local organization of their molecular building blocks are hard to predict in the presence of long‐range interactions. Combining small‐angle X‐ray/neutron scattering data, theoretical modelling, and computer simulations, sodium dodecyl sulfate (SDS), over a broad range of concentrations and ionic strengths, was investigated. Computer simulations indicate that micellar shape changes are associated with different binding of the counterions. By employing a toy model based on point charges on a surface, and comparing it to experiments and simulations, it is demonstrated that the observed morphological changes are caused by symmetry breaking of the irreducible building blocks, with the formation of transient surfactant dimers mediated by the counterions that promote the stabilization of cylindrical instead of spherical micelles. The present model is of general applicability and can be extended to all systems controlled by the presence of mobile charges.

Counting bricks in the wall: Chemically fueled assemblies are regulated by a chemical reaction cycle. A fast reaction cycle was recently introduced that shows exciting, dynamic self‐assembly behavior. However, analysis of its kinetic properties is challenging due to its speed. Thus, we introduce a simple, powerful method to quench all reactions in the reaction cycle. We show the accuracy and application for several reaction cycles and a range of molecular assemblies.

Abstract

In chemically fueled self‐assembly, the activation and deactivation of molecules for self‐assembly is coupled to a reaction cycle. In biological examples, these reactions are typically fast, such that the building blocks remain activated for mere seconds. In contrast, synthetic reaction cycles are slower for self‐assembly, i. e., with half‐lives on the order of minutes. In search of life‐like, dynamic behavior in synthetic systems, several groups explore faster reaction cycles that form transient labile building blocks with half‐lives of tens of seconds. These cycles show exciting properties, but brought about a new challenge, i. e., accurately analyzing the fast cycle is impossible with classical techniques. We thus introduce the notion of quenching chemical reaction cycles for self‐assembly. As a model, we use the fast carbodiimide‐fueled chemical reaction cycle and demonstrate a method that quenches all reactions immediately. We show its accuracy and demonstrate the application for several reaction cycles and a range of dissipative assemblies. Finally, we offer preliminary design rules to quench other chemically fueled reaction cycles.

Non‐enzymatic RNA Copying: Enhanced non‐enzymatic ligation allows the rapid copying of long RNA template and short RNA splinted templates, thus suggesting a potential route to the assembly of artificial systems capable of evolution.

Abstract

The non‐enzymatic replication of the primordial genetic material is thought to have enabled the evolution of early forms of RNA‐based life. However, the replication of oligonucleotides long enough to encode catalytic functions is problematic due to the low efficiency of template copying with mononucleotides. We show that template‐directed ligation can assemble long RNAs from shorter oligonucleotides, which would be easier to replicate. The rate of ligation can be greatly enhanced by employing a 3′‐amino group at the 3′‐end of each oligonucleotide, in combination with an N‐alkyl imidazole organocatalyst. These modifications enable the copying of RNA templates by the multistep ligation of tetranucleotide building blocks, as well as the assembly of long oligonucleotides using short splint oligonucleotides. We also demonstrate the formation of long oligonucleotides inside model prebiotic vesicles, which suggests a potential route to the assembly of artificial cells capable of evolution.

The mechanism of aggregation‐induced emission (AIE), which overcomes the common aggregation‐caused quenching (ACQ) problem in organic optoelectronics, is revealed by monitoring the real time structural evolution and dynamics of electronic excited state with frequency and polarization resolved ultrafast ultraviolet/infrared spectroscopy and theoretical calculations. The formation of Woodward‐Hoffmann cyclic intermediates upon ultraviolet excitation is observed within picoseconds in dilute solutions of AIE molecule tetraphenylethylene (TPE) and its derivatives but not in their respective solid. The ultrafast excited state cyclization by crossing a conical intersection (CI) provides an efficient nonradiative relaxation pathway in solutions. Without such a reaction mechanism, the electronic excitation is preserved in the molecular solids and the molecule fluoresces efficiently, aided by the very slow intermolecular charge and energy transfers due to the well separated molecular packing arrangement in solids. The mechanisms can be general for tuning the properties of chromophores in different phases for various important applications.

The spontaneous emergence of long RNA molecules on the early Earth, a phenomenon central to the RNA World hypothesis, continues to remain an enigma in the field of origins of life. Few studies have looked at the nonenzymatic oligomerization of cyclic mononucleotides under neutral to alkaline conditions, albeit in fully dehydrated state. In this study, we systematically investigated the oligomerization of cyclic nucleotides under prebiotically relevant conditions, wherein starting reactants were subjected to repeated dehydration–rehydration (DH–RH) regimes. DH–RH conditions, a recurring geological theme that was prevalent on prebiotic Earth, are driven by naturally occurring processes including diurnal cycles and tidal pool activity. These conditions have been shown to facilitate uphill oligomerization reactions. The polymerization of 2'–3' and 3'–5' cyclic nucleotides of a purine (adenosine) and a pyrimidine (cytidine) was investigated. Additionally, the effect of amphiphiles was also evaluated. Furthermore, to discern the effect of "realistic" conditions on this process, the reactions were also performed using a hot spring water sample from a candidate early Earth environment. Our study showed that the oligomerization of cyclic nucleotides under DH–RH conditions resulted in intact informational oligomers. Amphiphiles increased the stability of both the starting monomers and the resultant oligomers in selected reactions. In the hot spring reactions, both the oligomerization of nucleotides and the back hydrolysis of the resultant oligomers were pronounced. Altogether, this study demonstrates how nonenzymatic oligomerization of cyclic nucleotides, under both laboratory-simulated prebiotic conditions and in a candidate early Earth environment, could have resulted in RNA oligomers of a putative RNA World.

The importance of the whole picture : Aggregation‐induced emission (AIE) research demonstrates that many properties and functions that are absent in molecular species can be found in molecular aggregates. AIE research thus emphasizes the significance of aggregate science in addition to molecular science for materials development.

Abstract

Aggregation‐induced emission (AIE) describes a photophysical phenomenon in which molecular aggregates exhibit stronger emission than the single molecules. Over the course of the last 20 years, AIE research has made great strides in material development, mechanistic study and high‐tech applications. The achievements of AIE research demonstrate that molecular aggregates show many properties and functions that are absent in molecular species. In this review, we summarize the advances in the field of AIE and its related areas. We specifically focus on the new properties of materials attained by molecular aggregates beyond the microscopic molecular level. We hope this review will inspire more research into molecular ensembles at and beyond the meso level and lead to the significant progress in material and biological science.

Around the clock: A cationic polyelectrolyte is assembled with temporal control by means of the formaldehyde‐sulfite clock reaction. Electrostatic interactions template microscopic complexes, which are then crosslinked covalently to lock‐in a preformed structure. The final particle size can be controlled simply by tuning either the concentrations of components, or the initial pH value.

Abstract

Controlling the transient self‐assembly of (macro)molecular building blocks is of fundamental interest, both to understand the dynamic processes occurring in living systems and to develop new generations of functional materials. The subtle interplay between different types of physicochemical interactions, as well as the possible reaction pathways, are crucial when both thermodynamic and kinetic factors play substantial roles, as in the case of transient supramolecular assemblies. Clock reactions are a promising tool to achieve temporal control over self‐assembly in non‐living materials. Here, we report on the tunable association of poly(allylamine hydrochloride) (PAH) fueled by the formaldehyde‐sulfite clock reaction. The electrostatic interaction between the large macromolecules and the small, oppositely charged sulfite ions gives rise to micron‐sized coacervate‐like complexes. As the clock proceeds, sulfite is completely depleted and the complexes dissociate. However, under suitable conditions, a subsequent reaction between the polyelectrolyte and formaldehyde can lock‐in the preformed supramolecular structure, giving rise to covalently crosslinked colloidal particles.

Grow and learn: A new active material system was achieved by using a mild redox reaction network to fuel the dissipative self‐assembly of a disulfide‐based hydrogelator. The mild redox reactions simultaneously cause self‐assembled fibrils to grow and shrink, leading to transient, out‐of‐equilibrium dynamic behavior.

Abstract

This work reports a new transient self‐assembly of active materials fueled solely by a mild redox reaction network. Fuel‐driven dissipative, out‐of‐equilibrium assemblies are common in living systems but are challenging to mimic synthetically. Synthetic dissipative assembly systems developed thus far often use relatively toxic fuels and harsh conditions. Herein we report a transient, out‐of‐equilibrium self‐assembly system based on a new chemical reaction network using redox reactions. We use a mild redox chemical reaction network to simultaneously create and destroy a disulfide‐based hydrogelator, leading to transient, dynamic behavior. By closely regulating the reaction kinetics and reagent composition, the macroscopic properties of the active materials are fine‐tuned. The current work represents an important step toward the development of active materials operating under mild conditions.

5+(5×5+5×6)=hemisphere: An omphalos pentagon was decorated with 5 pentagons and 5 hexagons to form a hemispherical molecule by a polygon assembling strategy. Thirty phenine units were assembled to afford a large C₂₂₀H₁₈₀ molecule with a phenine framework isoreticular to a hemispherical, bisected segment of C₆₀.

Abstract

A synthetic strategy to construct large geodesic structures of phenine (1,3,5‐trisubstituted benzene) was devised. In this strategy, five pentagons were assembled on an omphalos pentagon, and bridging peripheral pentagons furnished five additional hexagons. Thirty phenine units were synthetically assembled to afford a large C₂₂₀H₁₈₀ molecule with a phenine framework isoreticular to a hemispherical, bisected segment of C₆₀. Although a hemispherical structure of the phenine framework was suggested by solution‐phase NMR spectra, crystallographic analysis revealed an oval‐like deformation of the molecular shape. In‐depth structural analyses, including theoretical calculations, showed that structural fluctuations observed as variations in the biaryl torsion angles allowed structural deformations and, at the same time, that the dynamic fluctuations resulted in the spectroscopic observation of a hemisphere as a time‐averaged structure.

The more the merrier: Phase separation triggers the stepwise oligomerization of two building blocks generating a library of dynamic species, leading to a structurally diverse, complex mixture of molecules. In contrast only two thermodynamically stable products are obtained with no phase separation.

Abstract

Chemical reactions occurring within liquid‐liquid phase separated systems drive numerous biological processes and have likely been involved in the emergence of first cellular compartments. Herein we report a reaction whose product distribution is drastically affected by the presence of a liquid‐liquid interface. Under phase separated conditions, the system produces a dynamic library of increasingly complex oligomeric structures. This reactivity is in sharp contrast to results under homogeneous conditions; when there is no phase separation only two thermodynamically stable products are formed. The reactivity observed using phase separated conditions stems from generating a dynamic out‐of‐equilibrium self‐assembling system. This work shows that relatively complex oligomeric products that would not be otherwise easily accessible can be made by biphasic out‐of‐equilibrium processes.

Molecules can be designed to interact with one another and form assemblies. Biology also uses molecular self-assembly to create its structural components. However, this biological process is tightly regulated by chemical reaction cycles that operate out of equilibrium. If we want to create life-like materials or even synthetic life, we should use an approach similar to molecular self-assembly. The focus of this review is to lay out design strategies toward the synthesis of molecular assemblies regulated by chemical reaction cycles.

Nature Chemistry, Published online: 18 March 2020; doi:10.1038/s41557-020-0451-2

Yujia Qing, an early-career researcher at the University of Oxford, talks to Nature Chemistry about winning the Dream Chemistry Award 2019, her chemistry dream of ‘Sequencing Life’, and the challenge this represents.

The oligomerization of ribonucleotides can produce short RNA strands in the absence of enzymes. This reaction gives one of two regioisomeric phosphodiester linkages, a 2′,5′- or a 3′,5′-diester. The former, non-natural linkage is detrimental for duplex stability, and is known to form preferentially in oligomerizations occurring in homogeneous solution with preactivated nucleotides in the presence of magnesium cations. We have studied ribonucleotide oligomerization with in situ activation, using NMR as monitoring technique. Unexpectedly, the known preference for 2′,5′-linkages in the oligomerization of AMP was reversed in the absence of magnesium ions at slightly basic pH. Further, oligomerization was surprisingly efficient in the absence of Mg²⁺ salts, producing oligomers long enough for duplex formation. A quantitative systems chemistry analysis then revealed that the absence of magnesium ions favors the activation of nucleotides, and that the high concentration of active species can compensate for slower coupling. Further, organocatalytic intermediates can help to overcome the unfavorable regioselectivity of the magnesium-catalyzed reactions. Our findings allay concerns that RNA may have been difficult to form in the absence of enzymes. They also show that there is an efficient path to genetic material that does not require mineral surfaces or cations known to catalyze RNA hydrolysis.