The limited scope of DNA-compatible chemistry restricts the types of chemical features that can be incorporated into DNA-encoded libraries (DELs). Here, a method to synthesize DNAconjugated polycyclic isoxazolidines via a [3+2] nitrone-olefin cycloaddition is described. The reaction is compatible with many olefin-containing substrates and diverse N-alkylhydroxylamines. The ability to perform subsequent DNA ligation and PCR amplification was also confirmed. This methodology facilitates the synthesis of DELs containing topographically complex compounds with underexplored chemical features.
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.
Molecular machines, such as ATPases or motor proteins, couple the catalysis of a chemical reaction, most commonly hydrolysis of nucleotide triphosphates, to their conformational change. In essence, they continuously convert a chemical fuel to drive their motion. An outstanding goal of nanotechnology remains to synthesize a nanomachine with similar functions, precision, and speed. The field of DNA nanotechnology has given rise to the engineering precision required for such a device. Simultaneously, the field of systems chemistry developed fast chemical reaction cycles that convert fuel to change the function of molecules. In this work, we thus combined a chemical reaction cycle with the precision of DNA nanotechnology to yield kinetic control over the conformational state of a DNA hairpin. Future work on such systems will result in out-of-equilibrium DNA nanodevices with precise functions.
In life, molecular architectures, like the cytoskeletal proteins or the nucleolus, catalyze the conversion of chemical fuels to perform their functions. For example, tubulin catalyzes the hydrolysis of GTP to form a dynamic cytoskeletal network. In contrast, myosin uses the energy obtained by catalyzing the hydrolysis of ATP to exert forces. Artificial examples of such beautiful architectures are scarce partly because synthetic chemically fueled reaction cycles are relatively rare. Here, we introduce a new chemical reaction cycle driven by the hydration of a carbodiimide. Unlike other carbodiimide-fueled reaction cycles, the proposed cycle forms a transient 5(4H)-oxazolone. The reaction cycle is efficient in forming the transient product and is robust to operate under a wide range of fuel inputs, pH, and temperatures. The versatility of the precursors is vast, and we demonstrate several molecular designs that yield chemically fueled droplets, fibers, and crystals. We anticipate that the reaction cycle can offer a range of other assemblies and, due to its versatility, can also be incorporated into molecular motors and machines.
Liquid-liquid phase separation is the process in which two immiscible liquids demix. This spontaneous phenomenon yields spherical droplets that eventually coarsen to one large, stable droplet governed by the principle of minimal free energy. In chemically fueled phase separation, the formation of phase-separating molecules is coupled to a fuel-driven, non-equilibrium reaction cycle. Chemically fueled phase separation yields dissipative structures sustained by a continuous fuel conversion. Such dissipative structures are ubiquitous in biology but poorly understood as they are governed by non-equilibrium thermodynamics. Here, we bridge the gap between passive, close-to-equilibrium, and active, dissipative structures with chemically fueled phase separation. We observe that spherical, active droplets can transition into a new morphology, i.e., a liquid, spherical shell of droplet material. A spherical shell would be highly unstable at equilibrium. Only by continuously converting chemical energy, this dissipative structure can be sustained. We demonstrate the transition mechanism, which is related to the activation of a product outside of the droplet, and the deactivation within the droplets leading to gradients of droplet material. We characterize how far out of equilibrium the spherical shell state is and the chemical power necessary to sustain it. Our work suggests new avenues for assembling complex stable morphologies, which might already be exploited to form membraneless organelles by cells.
Combining the selectivity of G‐quadruplex (G4) ligands with the spatial and temporal control of photochemistry is an emerging strategy to elucidate the biological relevance of these structures. In this work, we developed six novel V‐shaped G4 ligands that can, upon irradiation, form stable covalent adducts with G4 structures via the reactive intermediate, quinone methide (QM). We thoroughly investigated the photochemical properties of the ligands and their ability to generate QMs. Subsequently, we analyzed their specificity for various topologies of G4 and discovered a preferential binding towards the human telomeric sequence. Finally, we tested the ligand ability to act as photochemical alkylating agents, identifying the covalent adducts with G4 structures. This work introduces a novel molecular tool in the chemical biology toolkit for G4s.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.