Programmed catalysis within stimuli-responsive mechanically unlocked nanocavities in DNA origami tiles

The assembly of reversible stimuli-responsive locked DNA origami tiles being unlocked, in the presence of appropriate triggers, to form nanocavities in the origami rafts, is introduced. In the presence of ATP, K⁺-ion-stabilized G-quadruplexes or pH-responsive T-A·T triggers and appropriately engineered “helper units”, the origami rafts are unlocked to form nanocavities. By the application of appropriate counter-triggers, the nanocavities are relocked, thus establishing the switchable and reversible “mechanical” opening and closure mechanism of the nanocavities. The interconnection of the stimuli-responsive origami tiles into dimer structures enables the programmed triggered unlocking of each of the origami tiles, or both of the origami tiles, to yield dictated nanocavity-containing tiles. In addition, the functionalization of the opposite faces of the origami tiles with Mg²⁺-ion-dependent DNAzyme subunits leads, upon the triggered unlocking of the nanocavities, to the self-assembly of the active DNAzymes in the confined cavities. By the cyclic opening and closure of the cavities the reversible “ON”/“OFF” activation of the Mg²⁺-ion-dependent DNAzyme is demonstrated. Furthermore, upon the tethering of different Mg²⁺-ion-dependent subunits to the opposite faces of stimuli-responsive dimer origami tiles, the triggered programmed catalytic operation of different Mg²⁺-ion-dependent DNAzymes in the confined nanocavities, associated with the origami tiles, is demonstrated.

Programmed unlocking of nanocavities in origami dimer structures using different auxiliary triggers.     

Low-entropy lattices engineered through bridged DNA origami frames

The transformation from disorder to order in self-assembly is an autonomous entropy-decreasing process. The spatial organization of nanoscale anisotropic building blocks involves the intrinsic heterogeneity in three dimensions and requires sufficiently precise control to coordinate intricate interactions. Only a few approaches have been shown to achieve the anisotropic extension from components to assemblies. Here, we demonstrate the ability to engineer three-dimensional low-entropy lattices at the nucleotide level from modular DNA origami frames. Through the programmable DNA bridging strategy, DNA domains of the same composition are periodically arranged in the crystal growth directions. We combine the site-specific positioning of guest nanoparticles to reflect the anisotropy control, which is validated by small-angle X-ray scattering and electron microscopy. We expect that our DNA origami-mediated crystallization method will facilitate both the exploration of refined self-assembly platforms and the creation of anisotropic metamaterials.

Through the bridging principle, DNA origami building blocks are integrated into ordered self-assembled structures. Periodically arranged DNA domains can locate the nanoparticles in a uniform site to achieve precise control of the contents.     

DNAzyme- and light-induced dissipative and gated DNA networks

Nucleic acid-based dissipative, out-of-equilibrium systems are introduced as functional assemblies emulating transient dissipative biological transformations. One system involves a Pb²⁺-ion-dependent DNAzyme fuel strand-driven network leading to the transient cleavage of the fuel strand to “waste” products. Applying the Pb²⁺-ion-dependent DNAzyme to two competitive fuel strand-driven systems yields two parallel operating networks. Blocking the competitively operating networks with selective inhibitors leads, however, to gated transient operation of dictated networks, yielding gated catalytic operations. A second system introduces a “non-waste” generating out-of-equilibrium, dissipative network driven by light. The system consists of a trans-azobenzene-functionalized photoactive module that is reconfigured by light to an intermediary state consisting of cis-azobenzene units that are thermally recovered to the original trans-azobenzene-modified module. The cyclic transient photoinduced operation of the device is demonstrated. The kinetic simulation of the systems allows the prediction of the transient behavior of the networks under different auxiliary conditions.

Functional DNA modules are triggered in the presence of appropriate inhibitors to yield transient gated catalytic functions, and a photoresponsive DNA module leads to “waste-free” operation of transient, dissipative dynamic transitions.     

“Click handle”-modified 2′-deoxy-2′-fluoroarabino nucleic acid as a synthetic genetic polymer capable of post-polymerization functionalization

The functions of natural nucleic acids such as DNA and RNA have transcended genetic information carriers and now encompass affinity reagents, molecular catalysts, nanostructures, data storage, and many others. However, the vulnerability of natural nucleic acids to nuclease degradation and the lack of chemical functionality have imposed a significant constraint on their ever-expanding applications. Herein, we report the synthesis and polymerase recognition of a 5-(octa-1,7-diynyl)uracil 2′-deoxy-2′-fluoroarabinonucleic acid (FANA) triphosphate. The DNA-templated, polymerase-mediated primer extension using this “click handle”-modified FANA (cmFANA) triphosphate and other FANA nucleotide triphosphates consisting of canonical nucleobases efficiently generated full-length products. The resulting cmFANA polymers exhibited excellent nuclease resistance and the ability to undergo efficient click conjugation with azide-functionalized molecules, thereby becoming a promising platform for serving as a programmable and evolvable synthetic genetic polymer capable of post-polymerization functionalization.

Polymerase-mediated incorporation of a “click handle”-modified fluoroarabinonucleic acid (cmFANA) triphosphate produces a new class of nuclease-resistant, evolvable genetic polymers that can be functionalized with azide-containing molecules.     

DNA-templated control of chirality and efficient energy transport in supramolecular DNA architectures with aggregation-induced emission

Two conjugates of tetraphenylethylene with d-2′-deoxyuridine (1d) and l-2′-deoxyuridine (1l) were synthesized to construct new supramolecular DNA-architectures by self-assembly. The non-templated assemblies of 1d and 1l show strong aggregation-induced emission and their chirality is exclusively controlled by the configuration of their sugar part. In contrast, the chirality of the DNA-templated assemblies is governed by the configuration of the DNA, and there is no configuration-selective binding of 1d to d-A₂₀ and 1l to l-A₂₀. The quantum yield of the assembly of 1d along the single-stranded DNA A₂₀ is 0.40; approximately every second available binding site on the DNA template is occupied by 1d. The strong aggregation-induced emission of these DNA architectures can be efficiently quenched and the excitation energy can be transported to Atto dyes at the 5′-terminus. A multistep energy transport “hopping” precedes the final energy transfer to the terminal acceptor. The building block 1d promotes this energy transport as stepping stones. This was elucidated by reference DNA double strands in which 1d was covalently incorporated at two distinct sites in the sequences, one near the Atto dye, and one farther away. This new type of completely self-assembled supramolecular DNA architecture is hierarchically ordered and the DNA template controls not only the binding but also the energy transport properties. The high intensity of the aggregation-induced emission and the excellent energy transport properties make these DNA-based materials promising candidates for optoelectronic applications.

DNA architectures with tetraphenylethylene are assembled in a non-covalent way. The strong aggregation-induced emission of the chromophores is quenched and the energy is transported to Atto dyes by a multistep energy “hopping”.     

Bioorthogonal regulation of DNA circuits for smart intracellular microRNA imaging

Catalytic DNA circuits represent a versatile toolbox for tracking intracellular biomarkers yet are constrained with low anti-interference capacity originating from their severe off-site activation. Herein, by introducing an unprecedented endogenous DNA repairing enzyme-powered pre-selection strategy, we develop a sequential and specific on-site activated catalytic DNA circuit for achieving the cancer cell-selective imaging of microRNA with high anti-interference capacity. Initially, the circuitry reactant is firmly caged by an elongated stabilizing duplex segment with a recognition/cleavage site of a cell-specific DNA repairing enzyme, which can prevent undesired signal leakage prior to its exposure to target cells. Then, the intrinsic DNA repairing enzyme of target cells can liberate the DNA probe for efficient intracellular microRNA imaging via the multiply guaranteed molecular recognition/activation procedures. This bioorthogonal regulated DNA circuit presents a modular and programmable amplification strategy for highly reliable assays of intracellular biomarkers, and provides a pivotal molecular toolbox for living systems.

An on-site bioorthogonal regulated DNA circuit was developed by introducing an endogenous DNA repairing enzyme-mediated sequential activation strategy to achieve cancer cell-selective microRNA imaging with high anti-interference ability.     

Design and recognition of cucurbituril-secured platinum-bound oligopeptides

Platinum terpyridyl complexes, stacked on top of one another and secured as dimers with cucurbit[8]uril (CB[8]) in aqueous medium, were functionalized quantitatively and in situ with a pair of pentapeptides Phe-(Gly)₃-Cys by grafting their cysteine residues to the Pt centers. The resulting CB[8]·(Pt·peptide)₂ assemblies were used to target secondary hosts CB[7] and CB[8] via their pair of phenylalanine residues, again in situ. A series of well-defined architectures, including a supramolecular “pendant necklace” with hybrid head-to-head and head-to-tail arrangements inside CB[8], were obtained during the self-sorting process after combining only 3 or 4 simple building units.

A platinum terpyridyl complex, pentapeptide Phe-(Gly)₃-Cys and cucurbit[8]uril assemble into a “pendant necklace” with hybrid head-to-head and head-to-tail arrangements in aqueous medium.     

Enhancement of Chiroptical Responses of trans‐Bis[(β‐iminomethyl)naphthoxy]platinum(II) Complexes with Distorted Square Planar Coordination Geometry

Invited for this month''s cover picture are the groups of Masahiro Ikeshita and Takashi Tsuno at Nihon University and Yoshitane Imai at Kindai University (Japan). The cover picture shows the comparison of circularly polarized luminescence (CPL) properties of square planar platinum(II) complexes with different coordination geometry. Computational studies have been carried out to investigate these structure‐dependencies, and revealed that the distortion of the coordination geometry results into an enhancement the chiroptical responses of these compounds. Read the full text of their Research Article at 10.1002/open.202100277.

“… How does the stereochemistry of transition metal complexes affect their photophysical properties…” Find out more about the story behind the front cover research at 10.1002/open.202100277.     

Catalytic oxidative dehydrogenation of N-heterocycles with nitrogen/phosphorus co-doped porous carbon materials

A metal-free oxidative dehydrogenation of N-heterocycles utilizing a nitrogen/phosphorus co-doped porous carbon (NPCH) catalyst is reported. The optimal material is robust against traditional poisoning agents and shows high antioxidant resistance. It exhibits good catalytic performance for the synthesis of various quinoline, indole, isoquinoline, and quinoxaline ‘on-water’ under air atmosphere. The active sites in the NPCH catalyst are proposed to be phosphorus and nitrogen centers within the porous carbon network.

Green oxidations made easy. Metal-free dehydrogenation of N-heterocycles are possible in using N,P-co-doped porous carbon materials “on” water using air.     

The assemble,grow and lift-off (AGLO) strategy to construct complex gold nanostructures with pre-designed morphologies

The construction of metallic nanostructures with customizable morphologies and complex shapes has been an essential pursuit in nanoscience. DNA nanotechnology has enabled the fabrication of increasingly complex DNA nanostructures with unprecedented specificity, programmability and sub-nanometer precision, which makes it an ideal approach to rationally organize metallic nanostructures. Here we report an Assemble, Grow and Lift-Off (AGLO) strategy to construct robust standalone gold nanostructures with pre-designed customizable shapes in solution, using only a simple 2D DNA origami sheet as a versatile transient template. Gold nanoparticle (AuNP) seeds were firstly assembled onto the pre-designed binding sites of the DNA origami template and then additional gold was slowly deposited onto the AuNP seeds. The growing seed surfaces eventually merge with adjacent seeds to generate one continuous gold nanostructure in a pre-designed shape, which can then be lifted off the origami template. Diverse customized patterns of templated AuNP seeds were successfully transformed into corresponding gold nanostructures with the target structure transformation percentage over 80%. Moreover, the AGLO strategy can be incorporated with a magnetic bead separation platform to enable the easy recycling of the excess AuNP seeds and DNA components.

The AGLO strategy generates complex gold nanostructures with user-designed morphologies in solution, using only a simple 2D DNA origami sheet as a versatile transient template. The products are robust and stable as standalone gold nanostructures.     

Photo-modulation of supramolecular polymorphism in the self-assembly of a scissor-shaped azobenzene dyad into nanotoroids and fibers

Recent advances in the research field of supramolecularly engineered dye aggregates have enabled the design of simple one-dimensional stacks such as fibers and of closed structures such as nanotoroids (nanorings). More complex and advanced supramolecular systems could potentially be designed using a molecule that is able to provide either of these distinct nanostructures under different conditions. In this study, we introduced bulky but strongly aggregating cholesterol units to a scissor-shaped azobenzene dyad framework, which affords either nanotoroids, nanotubes, or 1D fibers, depending on the substituents. This new dyad with two trans-azobenzene arms shows supramolecular polymorphism in its temperature-controlled self-assembly, leading to not only oligomeric nanotoroids as kinetic products, but also to one-dimensional fibers as thermodynamic products. This supramolecular polymorphism can also be achieved via photo-triggered self-assembly, i.e., irradiation of a monomeric solution of the dyad with two cis-azobenzene arms using strong visible light leads to the preferential formation of nanotoroids, whereas irradiation with weak visible light leads to the predominant formation of 1D fibers. This is the first example of a successful light-induced modulation of supramolecular polymorphism to produce distinctly nanostructured aggregates under isothermal conditions.

Introduction of the bulky yet strongly aggregating cholesterol units to an azobenzene dyad lead to a supramolecular polymorphism not only in its temperature-controlled but also in photo-triggered self-assembly, leading to toroids and helical fibers.     

A facile combinatorial approach to construct a ratiometric fluorescent sensor: application for the real-time sensing of cellular pH changes

Realtime monitoring of the cellular environment, such as the intracellular pH, in a defined cellular space provides a comprehensive understanding of the dynamics processes in a living cell. Considering the limitation of spatial resolution in conventional microscopy measurements, multiple types of fluorophores assembled within that space would behave as a single fluorescent probe molecule. Such a character of microscopic measurements enables a much more flexible combinatorial design strategy in developing fluorescent probes for given targets. Nanomaterials with sizes smaller than the microscopy spatial resolution provide a scaffold to assemble several types of fluorophores with a variety of optical characteristics, therefore providing a convenient strategy for designing fluorescent pH sensors. In this study, fluorescein (CF) and tetramethylrhodamine (CR) were assembled on a DNA nanostructure with controlling the number of each type of fluorophore. By taking advantage of the different responses of CF and CR emissions to the pH environment, an appropriate assembly of both CF and CR on DNA origami enabled a controlled intensity of fluorescence emission and ratiometric pH monitoring within the space defined by DNA origami. The CF and CR-assembled DNA origami was successfully applied for monitoring the intracellular pH changes.

A combinatorial assembly of two types of intensity-based fluorophores on a DNA nanostructure provided a ratiometric pH probe with high emission intensity for monitoring intracellular pH changes.     

Diboramacrocycles: reversible borole dimerisation–dissociation systems

We report that the outcome of the tin–boron exchange reaction of a mixed thiophene-benzo-fused stannole with aryldibromoboranes is associated with the steric bulk of the aryl substituent of the borane reagent, leading to either boroles or large diboracycles as products. NMR spectroscopic studies indicate that the two products can reversibly interconvert in solution, and mechanistic density functional theory (DFT) calculations reveal boroles to be intermediates in the formation of the diboracyclic products. The addition of Lewis bases to the diboracycles leads to the corresponding borole adducts, demonstrating that they react as “masked” boroles. Additionally, the reaction of the title compounds with a series of organic azides affords complex heteropropellanes, formally 2 : 1 borole-azide adducts, that deviate from the usual BN aromatic compounds formed via nitrogen atom insertion into the boroles.

Diboramacrocycles are a new form of borole dimers, participating in various addition reactions as “masked” boroles. The reaction of a less crowded diboramacrocycle with organic azides affords unprecedented complex heteropropellanes.     

Exploring Helical Folding in Oligomers of Cyclopentane‐Based ϵ‐Amino Acids: A Computational Study

Invited for this month''s cover picture is the group of Young Kee Kang at Chungbuk National University (Republic of Korea). The cover picture shows the preferred conformation of the hexamer of ϵ‐amino acid Amc₅a with a cyclopentane substituent in the backbone investigated using DFT methods in chloroform and water. The Amc₅a hexamer adopted a stable left‐handed conformation with a rise of 4.8 Å per turn both in chloroform and water. However, the hexamer of Ampa (an analogue of Amc₅a with replacing cyclopentane by pyrrolidine) adopted different conformations in chloroform and in water. Read the full text of their Research Article at 10.1002/open.202100253.

“…Finding the appropriate protocol is a crucial step for conformational prediction of peptides and peptide foldamers in solution…” Find out more about the story behind the front cover research at 10.1002/open.202100253.     

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pK_a limitation of “hard” nucleophiles in enantioselective transformations.

A variety of “hard” α-sulfonyl carbanions of aryl, heteroaryl and alkyl sulfones were successfully employed as nucleophiles in palladium-catalyzed asymmetric allylic alkylation with excellent enantioselectivities.     

New insights into the folding–unfolding mechanism and conformations of cytochrome C

Metalloproteins account for over one-third of all proteins in nature and play important roles in biological processes. The formation of the native structures of metalloproteins requires not only the correct folding of the polypeptide chains but also the proper incorporation of metal cofactors. Understanding the folding mechanism of metalloproteins has been challenging. Horse heart cytochrome C (cytc) is a classical model system for protein folding studies. Although a large number of ensemble studies have been carried out to characterize the folding mechanism of cytc, there is still a significant debate on the folding mechanism and the existence of the proposed “foldons”. Here, we used single-molecule optical tweezers to probe the mechanical folding–unfolding behaviors of cytc at the single-molecule level. By directly monitoring the folding and unfolding of holo-cytc, we revealed novel insights into the folding of cytc. Our results showed that the structural elements that are distant from the N- and C-termini can exist as a short-lived intermediate, a finding that contrasts with the general belief that the folding and packing of the N- and C-terminal helices are prerequisites for the folding of other structural elements in cytc. In addition, our results present strong evidence that apo-cytc, which has been long believed to be a random coil, is not a true random coil, and weak interactions within the unfolded polypeptide chain exist. Our results bring new insights into our understanding of the folding mechanisms of heme proteins as well as the role of heme in the folding process.

Optical trapping experiments offer new insights into the folding and unfolding of cytochrome C.     

Experimental and Theoretical Study of the Ultrafast Dynamics of a Ni2Dy2‐Compound in DMF After UV/Vis Photoexcitation

Invited for this month''s cover picture are the groups of Wolfgang Hübner (TU Kaiserslautern, Germany), Annie Powell (Karlsruhe Institut of Technology, Germany), and Andreas‐Neil Unterreiner (Karlsruhe Institut of Technology, Germany). The cover picture shows the Dy₂Ni₂‐molecular magnet being excited with a UV/Vis laser pulse, together with its time‐resolved spectrum after the pulse. The comparison of the theoretical and the experimental spectra together with both the observed and the calculated relaxation times reveal, among others, three key points: the intermediate states participating in the laser‐induced dynamics, the partial metal‐to‐oxygen charge‐transfer excitations, and the order of magnitude of the coupling of the molecular magnet to the thermal bath of the environment. Read the full text of their Full Paper at 10.1002/open.202100153.

“… The comparison of the theoretical and the experimental spectra together with both the observed and the calculated relaxation times reveals three key points…” Find out more about the story behind the front cover research at 10.1002/open.202100153.     

Expanding organofluorine chemical space: the design of chiral fluorinated isosteres enabled by I(i)/I(iii) catalysis

Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena. Delineating their biological origins and significance have resulted in landmark developments in synthetic organic chemistry: Arigoni''s venerable synthesis of the chiral methyl group is a personal favourite. Whilst radioisotopes allow the steric footprint of the native group to be preserved, this strategy was never intended for therapeutic chemotype development. In contrast, leveraging H → F bioisosterism provides scope to complement the chiral, radioactive bioisostere portfolio and to reach unexplored areas of chiral chemical space for small molecule drug discovery. Accelerated by advances in I(i)/I(iii) catalysis, the current arsenal of achiral 2D and 3D drug discovery modules is rapidly expanding to include chiral units with unprecedented topologies and van der Waals volumes. This Perspective surveys key developments in the design and synthesis of short multivicinal fluoroalkanes under the auspices of main group catalysis paradigms.

Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena.     

Natural product drug discovery in the artificial intelligence era

Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets. Their unique characteristics and structural diversity continue to marvel scientists for developing NP-inspired medicines, even though the pharmaceutical industry has largely given up. High-performance computer hardware, extensive storage, accessible software and affordable online education have democratized the use of artificial intelligence (AI) in many sectors and research areas. The last decades have introduced natural language processing and machine learning algorithms, two subfields of AI, to tackle NP drug discovery challenges and open up opportunities. In this article, we review and discuss the rational applications of AI approaches developed to assist in discovering bioactive NPs and capturing the molecular “patterns” of these privileged structures for combinatorial design or target selectivity.

Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets.     

A pillar[5]arene-based covalent organic framework with pre-encoded selective host–guest recognition

It is highly desirable to maintain both permanent accessible pores and selective molecular recognition capability of macrocyclic cavitands in the solid state. Integration of well-defined discrete macrocyclic hosts into ordered porous polymeric frameworks (e.g., covalent organic frameworks, COFs) represents a promising strategy to transform many supramolecular chemistry concepts and principles well established in the solution phase into the solid state, which can enable a broad range of practical applications, such as high-efficiency molecular separation, heterogeneous catalysis, and pollution remediation. However, it is still a challenging task to construct macrocycle-embedded COFs. In this work, a novel pillar[5]arene-derived (P5) hetero-porous COF, denoted as P5-COF, was rationally designed and synthesized. Featuring the unique backbone structure, P5-COF exhibited selective adsorption of C₂H₂ over C₂H₄ and C₂H₆, as well as significantly enhanced host–guest binding interaction with paraquat, in comparison with the pillar[5]arene-free COF analog, Model-COF. The present work established a new strategy for developing COFs with customizable molecular recognition/separation properties through the bottom-up “pre-porous macrocycle to porous framework” design.

A novel pillar[5]arene-derived (P5) COF was rationally designed and synthesized, which exhibited superior performance in selective gas adsorption and paraquat binding.