Julian Vogel

Without catalyst! A non-enzymatic, spontaneous route to the formation of short, mixed-sequence RNA strands from 2′,3′-cyclic ribonucleotides is shown. The reaction occurs by drying at the air–water interfaces.

Abstract

For the emergence of life, the abiotic synthesis of RNA from its monomers is a central step. We found that in alkaline, drying conditions in bulk and at heated air-water interfaces, 2′,3′-cyclic nucleotides oligomerised without additional catalyst, forming up to 10-mers within a day. The oligomerisation proceeded at a pH range of 7–12, at temperatures between 40–80 °C and was marginally enhanced by K⁺ ions. Among the canonical ribonucleotides, cGMP oligomerised most efficiently. Quantification was performed using HPLC coupled to ESI-TOF by fitting the isotope distribution to the mass spectra. Our study suggests a oligomerisation mechanism where cGMP aids the incorporation of the relatively unreactive nucleotides C, A and U. The 2′,3′-cyclic ribonucleotides are byproducts of prebiotic phosphorylation, nucleotide syntheses and RNA hydrolysis, indicating direct recycling pathways. The simple reaction condition offers a plausible entry point for RNA to the evolution of life on early Earth.

Dissipative Dynamic Libraries: In this Concept, the fundamental features of Dissipative Dynamic Libraries (DDLs) maintained out-of-equilibrium by the consumption of a fuel are described with particular emphasis on the factors that govern the composition of the libraries over time.

Abstract

This Concept is focused on the key features of dissipative dynamic combinatorial chemistry (DDCC). DDCC deals with transient libraries of compounds, maintained out-of-equilibrium by the consumption of a fuel, whose composition changes upon the selection pressure of kinetic and/or thermodynamic processes. Concepts and definitions of kinetic and thermodynamic dissipative dynamic libraries (“KDDL” and “TDDL”), are introduced and illustrated by a number of actual cases, thus showing the consistency of the present approach. Such concepts and definitions can help establish a common language for this emerging field, which, in our view, has the potential to become highly relevant to supramolecular chemistry.

Coupling multiphase coacervate droplets to a chemical reaction cycle allows access to regimes inside the phase diagram not possible under thermodynamic control. Control over the stability, liquidity, and localization of the multiphases makes it a great synthetic platform to study the organization of membraneless organelles.

Abstract

Membraneless organelles are droplets in the cytosol that are regulated by chemical reactions. Increasing studies suggest that they are internally organized. However, how these subcompartments are regulated remains elusive. Herein, we describe a complex coacervate-based model composed of two polyanions and a short peptide. With a chemical reaction cycle, we control the affinity of the peptide for the polyelectrolytes leading to distinct regimes inside the phase diagram. We study the transitions from one regime to another and identify new transitions that can only occur under kinetic control. Finally, we show that the chemical reaction cycle controls the liquidity of the droplets offering insights into how active processes inside cells play an important role in tuning the liquid state of membraneless organelles. Our work demonstrates that not only thermodynamic properties but also kinetics should be considered in the organization of multiple phases in droplets.

Nature Chemistry, Published online: 26 August 2022; doi:10.1038/s41557-022-01028-6

The application of machine learning to big data, to make quantitative predictions about reaction outcomes, has been fraught with failure. This is because so many chemical-reaction data are not fit for purpose, but predictions would be less error-prone if synthetic chemists changed their reaction design and reporting practices.

Phosphorylation reactions in an aqueous medium on the early Earth: Prebiotically plausible organocatalyst 2,5-dimethylimidazolidine-4-thione is able to function as phosphorylation agent under exceptionally mild reactions conditions in an aqueous mixture without condensation agent. Depending on the surrounding conditions, the stereo selective formation of all canonical non-cyclic mono-phosphorylated nucleosides is possible.

Abstract

Nucleotides play a fundamental role in organisms, from adenosine triphosphate (ATP), the body‘s main source of energy, to cofactors of enzymatic reactions (e. g. coenzyme A), to nucleoside monophosphates as essential building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Although nucleotides play such an elemental role, there is no pathway to date for the selective formation of nucleoside 5′-monophosphates. Here, we demonstrate a selective reaction pathway for 5’ mono-phosphorylation for all canonical purine and pyrimidine bases under exceptionally mild prebiotic relevant conditions in water and without using a condensing agent. The pivotal reaction step involves activated imidazolidine-4-thione phosphates. The selective formation of non-cyclic mono-phosphorylated nucleosides represents a novel and unique route to nucleotides and opens exciting perspectives in the study of the origins of life.

Transient polyether cages have been generated from macrocyclic diacids using carbodiimide-induced anhydride formation. The formation of the cages, studied by NMR spectroscopy, is sensitive to the presence of alkali metal cations, with both positive and negative templation effects.

Abstract

The use of “fuel” compounds to drive chemical systems out of equilibrium is currently of interest because of the potential for temporally controlled, responsive behavior. We have recently shown that transiently formed crown ethers exhibit counterintuitive templation effects when generated in the presence of alkali metal cations: “matched” cations, such as K⁺ with an 18-crown-6 analogue, suppress the formation of the macrocycles (negative templation). In this work, we describe two macrocyclic diacids that, on treatment with carbodiimides, give transient macrobicyclic cages analogous to polyether cages. Negative templation effects are observed for the smaller cage when generated in the presence of K⁺ and Na⁺, but there is a weak, but reproducible, positive templation effect in the presence of Li⁺. The larger cage behaves similarly in the presence of Li⁺, K⁺, Rb⁺, and Cs⁺, but differently with Na⁺, which appears to bind to both the cage and the initial macrocycle.

Nature Chemistry, Published online: 06 June 2022; doi:10.1038/s41557-022-00957-6

The emerging field of dissipative DNA nanotechnology aims at developing synthetic devices and nanomaterials with life-like properties such as directional motion, transport, communication or adaptation. This Review surveys how dissipative DNA systems combine the programmability of nucleic-acid reactions with the consumption of energy stored in chemical fuel molecules to perform work and cyclical tasks.

Nature Chemistry, Published online: 06 June 2022; doi:10.1038/s41557-022-00962-9

Explaining the controlled emergence and growth of molecular complexity at life’s origins is one of prebiotic chemistry’s grand challenges. Now, it has been shown that we can observe how the self-organization of a complex carbohydrate network can be modulated by its environment.

The solvent-free synthesis of core-functionalised naphthalene diimide (c-NDI) residues in a vibratory ball mill is reported. Twenty-one naphthalene diimide-based products were produced by using Suzuki, Sonogashira and Buchwald-Hartwig palladium coupling reactions, including dimeric diimide products that are constituents in functioning organic photovoltaic solar cells. These reactions are rapid (60 to 90 minutes), do not require additional heating, and are tolerant of air and atmospheric moisture.

Abstract

Solvent-free synthesis by using a vibratory ball mill (VBM) offers the chance to access new chemical reactivity, whilst reducing solvent waste and minimising reaction times. Herein, we report the core functionalisation of N,N’-bis(2-ethylhexyl)-2,6-dibromo-1,4,5,8-naphthalenetetracarboxylic acid (Br₂-NDI) by using Suzuki, Sonogashira and Buchwald–Hartwig coupling reactions. The products of these reactions are important building blocks in many areas of organic electronics including organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs) and organic photovoltaic cells (OPVCs). The reactions proceed in as little as 1 h, use commercially available palladium sources (frequently Pd(OAc)₂) and are tolerant to air and atmospheric moisture. Furthermore, the real-world potential of this green VBM protocol is demonstrated by the double Suzuki coupling of a monobromo(NDI) residue to a bis(thiophene) pinacol ester. The resulting dimeric NDI species has been demonstrated to behave as an electron acceptor in functioning OPVCs.

Nature Chemistry, Published online: 26 May 2022; doi:10.1038/s41557-022-00949-6

Oscillations are widespread throughout the natural world and a number of fascinating inorganic oscillating reactions are known—but the formation and control of oscillating, self-replicating synthetic systems has remained challenging. Now, it has been shown that chemically fuelled oscillations within a network of organic replicators can drive supramolecular assembly and disassembly.

A transient hydrogel based on dissipative host–guest interactions was prepared. The host molecules are used as the chemical fuel to maintain the transient supramolecular networks. This work provides a new method to regulate the nonequilibrium host–guest inclusion system by fueling it with host molecules.

Abstract

Inspired by the dissipative assembly in biological systems, transient hydrogels based on supramolecular interactions have been developed that are under thermodynamic nonequilibrium states. Host–guest interactions possess excellent properties including high selectivity and adjustable association constants, which are beneficial for controlling the properties and behaviors of transient colloidal materials. In this work, a host-fueled transient supramolecular hydrogel system is reported. The hydrogels based on host–guest interactions are formed by addition of a chemical fuel, α-cyclodextrin (α-CD), to the aqueous solutions containing Pluronic F127 and α-amylase. Meanwhile, as the host molecule of α-CD consumes, the hydrogel networks start to collapse. The lifetime of the transient supramolecular hydrogels can be precisely controlled by adjusting the temperature and hydrogel composition, and repeated sol-to-gel-to-sol transitions can be realized by refueling the system with α-CD. This study provides a new approach to regulate the nonequilibrium host–guest inclusion system by fueling it with host molecules.

Nature Chemistry, Published online: 17 March 2022; doi:10.1038/s41557-022-00899-z

Information is physical, but the flow between information, energy and mechanics in chemical systems remains largely unexplored. Now, an autonomous molecular motor has been analysed with information thermodynamics, which relates information to other thermodynamic parameters. This treatment provides a general thermodynamic understanding of molecular motors, with practical implications for machine design.

Multicolor molecular emission is controlled in a dynamic timing manner by introducing a temporal chemical lock. The temporal life-time of the systems can be encoded by molecularly engineering the structural information.

Abstract

Dynamic control over molecular emission, especially in a time-dependent manner, holds great promise for the development of smart luminescent materials. Here we report a series of dynamic multicolor fluorescent systems based on the time-encoded locking and unlocking of individual vibrational emissive units. The intramolecular cyclization reaction driven by adding chemical fuel acts as a chemical lock to decrease the conformational freedom of the emissive units, thus varying the fluorescence wavelength, while the resulting chemically locked state can be automatically unlocked by the hydrolysis reaction with water molecules. The dynamic molecular system can be driven by adding chemical fuels for multiple times. The emission wavelength and lifetime of the locking states can be readily controlled by elaborating the molecular structures, indicating this strategy as a robust and versatile way to modulate multi-color molecular emission in a time-encoded manner.

Two types of artificial ribose-based amphiphiles have been prepared and self-assembled into various supramolecular structures, exhibiting aggregation-induced emission. The molecularly dissolved amphiphiles can be converted selectively into dimeric pyrophosphates in the presence of carbodiimide EDC, giving rise to helical fibers with lengths at the micrometer scale.

Abstract

The aqueous self-assembly of amphiphiles into aggregates such as micelles and vesicles has been widely investigated over the past decades with applications ranging from materials science to drug delivery. The combination of characteristic properties of nucleic acids and amphiphiles is of substantial interest to mimic biological self-organization and compartmentalization. Herein, we present ribose- and ribonucleotide-based amphiphiles and investigate their self-assembly as well as their fundamental reactivity. We found that various types of aggregates are formed, ranging in size from nanometers to micrometers and all amphiphiles exhibit aggregation-induced emission (AIE) in solution as well as in the solid state. We also observed that the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) leads to rapid and selective dimerization of the amphiphiles into pyrophosphates, which decreases the critical aggregation concentration (CAC) by a factor of 25 when compared to the monomers. Since the propensity for amphiphile dimerization is correlated with their tendency to self-assemble, our results may be relevant for the formation of rudimentary compartments under prebiotic conditions.

A new synthesis provides access to different sized substituted cycloparaphenylenes (CPPs). The use of a key synthon in a sequence of macrocyclization by cross-coupling with different reaction partners followed by aromatization allows a modular build-up. The controlled introduction of substituents enables a tube-like arrangement of these molecular carbon allotropes in the solid state.

Abstract

Herein, we report a modular synthesis providing access to substituted cycloparaphenylenes (CPPs) of different sizes. A key synthon introducing two geminal ester units was efficiently prepared by [2+2+2] cycloaddition. This building block can be conveniently converted to macrocyclic precursors controlling the ring size of the final CPP. Efficient reductive aromatization through single-electron transfer provided the substituted nanohoops in a straightforward manner. The tBu ester substitution pattern enables a tube-like arrangement in the solid-state governed by van der Waals interactions that exhibits one of the tightest packings of CPPs in tube direction, thus opening new avenues in the crystal design of CPPs.

Nature Chemistry, Published online: 29 November 2021; doi:10.1038/s41557-021-00825-9

The synthesis of chiral interlocked molecules in which the mechanical bond provides the only source of stereochemistry remains challenging. Now, a chiral interlocked auxiliary approach to mechanically planar chiral rotaxanes has been developed and its potential demonstrated through the synthesis of a range of difficult targets with high enantioselectivity.

Nature Chemistry, Published online: 06 December 2021; doi:10.1038/s41557-021-00830-y

Complex coacervate microdroplets have been proposed as primordial cells, but their ability to evolve by fusion, growth and fission has not yet been demonstrated. Now, it has been shown that gas bubbles inside heated rock pores can drive the growth, fusion, division and selection of coacervate microdroplets.

RNA molecules adopt three-dimensional structures that are critical to their function and of interest in drug discovery. Few RNA structures are known, however, and predicting them computationally has proven challenging. We introduce a machine learning approach that enables identification of accurate structural models without assumptions about their defining characteristics, despite being trained with only 18 known RNA structures. The resulting scoring function, the Atomic Rotationally Equivariant Scorer (ARES), substantially outperforms previous methods and consistently produces the best results in community-wide blind RNA structure prediction challenges. By learning effectively even from a small amount of data, our approach overcomes a major limitation of standard deep neural networks. Because it uses only atomic coordinates as inputs and incorporates no RNA-specific information, this approach is applicable to diverse problems in structural biology, chemistry, materials science, and beyond.

Nature Chemistry, Published online: 26 August 2021; doi:10.1038/s41557-021-00772-5

The correct function of ribozymes in a prebiotic world would be dependent on the presence of optimal salt compositions and concentrations. Now, local heat fluxes have been shown to create an ideal salt habitat for ribozyme activity based on geologically plausible salt-leaching processes.

We combine X-ray crystallography and kinetic measurements of modified nucleic acid constructs to determine the requirements for efficient template copying. The ³E conformation of the furanose rings is preferred in the formation of 3′–5′ phosphodiester bonds. Our findings may explain why RNA is a privileged substrate amongst other plausible candidates.

Abstract

The template-directed synthesis of RNA played an important role in the transition from prebiotic chemistry to the beginnings of RNA based life, but the mechanism of RNA copying chemistry is incompletely understood. We measured the kinetics of template copying with a set of primers with modified 3′-nucleotides and determined the crystal structures of these modified nucleotides in the context of a primer/template/substrate-analog complex. pH-rate profiles and solvent isotope effects show that deprotonation of the primer 3′-hydroxyl occurs prior to the rate limiting step, the attack of the alkoxide on the activated phosphate of the incoming nucleotide. The analogs with a ³E ribose conformation show the fastest formation of 3′–5′ phosphodiester bonds. Among those derivatives, the reaction rate is strongly correlated with the electronegativity of the 2′-substituent. We interpret our results in terms of differences in steric bulk and charge distribution in the ground vs. transition states.