RESUMO
The lasso peptide benenodin-1, a naturally occurring and bacterially produced [1]rotaxane, undergoes a reversible zip tie-like motion under heat activation, in which a peptidic wheel stepwise translates along a molecular thread in a cascade of "tail/loop pulling" equilibria. Conformational and structural analyses of four translational isomers, in solution and in the gas phase, reveal that the equilibrium distribution is controlled by mechanical and non-covalent forces within the lasso peptide. Furthermore, each dynamic pulling step is accompanied by a major restructuring of the intramolecular hydrogen bonding network between wheel and thread, which affects the peptide's physico-chemical properties.
Assuntos
Peptídeos , Rotaxanos , Ligação de Hidrogênio , Isomerismo , Conformação MolecularRESUMO
Lasso peptides are a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) defined by their threaded structure. Besides the class-defining isopeptide bond, other post-translational modifications (PTMs) that further tailor lasso peptides have been previously reported. Using genome mining tools, we identified a subset of lasso peptide biosynthetic gene clusters (BGCs) that are colocalized with genes encoding protein l-isoaspartyl methyltransferase (PIMT) homologues. PIMTs have an important role in protein repair, restoring isoaspartate residues formed from asparagine deamidation to aspartate. Here we report a new function for PIMT enzymes in the post-translational modification of lasso peptides. The PIMTs associated with lasso peptide BGCs first methylate an l-aspartate side chain found within the ring of the lasso peptide. The methyl ester is then converted into a stable aspartimide moiety, endowing the lasso peptide ring with rigidity relative to its unmodified counterpart. We describe the heterologous expression and structural characterization of two examples of aspartimide-modified lasso peptides from thermophilic Gram-positive bacteria. The lasso peptide cellulonodin-2 is encoded in the genome of actinobacterium Thermobifida cellulosilytica, while lihuanodin is encoded in the genome of firmicute Lihuaxuella thermophila. Additional genome mining revealed PIMT-containing lasso peptide BGCs in 48 organisms. In addition to heterologous expression, we have reconstituted PIMT-mediated aspartimide formation in vitro, showing that lasso peptide-associated PIMTs transfer methyl groups very rapidly as compared to canonical PIMTs. Furthermore, in stark contrast to other characterized lasso peptide PTMs, the methyltransferase functions only on lassoed substrates.
Assuntos
Ácido Aspártico/análogos & derivados , Bacillales/genética , Peptídeos/metabolismo , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Bacillales/metabolismo , Peptídeos/química , Peptídeos/genética , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/metabolismo , Processamento de Proteína Pós-Traducional , Thermobifida/genética , Thermobifida/metabolismoRESUMO
"Naphthocage", a naphthalene-based organic cage, reveals very strong binding (up to 1010 M-1) to aromatic (di)cationic guests, i.e., the tetrathiafulvalene mono- and dication and methyl viologen. Intercalation of the guests between two naphthalene walls is mediated by C-H···O, C-H···π, and cation···π interactions. The guests can be switched into and out of the cage by redox processes with high binding selectivity. Oxidation of the flexible cage itself in the absence of a guest leads to a stable radical cation with the oxidized naphthalene intercalated between and stabilized by the other two. Encapsulated guest cations are released from the cavity upon cage oxidation, paving the way to future applications in redox-controlled guest release or novel stimuli-responsive materials.
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Crown ethers are common building blocks in supramolecular chemistry and are frequently applied as cation sensors or as subunits in synthetic molecular machines. Developing switchable and specifically designed crown ethers enables the implementation of function into molecular assemblies. Seven tailor-made redox-active crown ethers incorporating tetrathiafulvalene (TTF) or naphthalene diimide (NDI) as redox-switchable building blocks are described with regard to their potential to form redox-switchable rotaxanes. A combination of isothermal titration calorimetry and voltammetric techniques reveals correlations between the binding energies and redox-switching properties of the corresponding pseudorotaxanes with secondary ammonium ions. For two different weakly coordinating anions, a surprising relation between the enthalpic and entropic binding contributions of the pseudorotaxanes was discovered. These findings were applied to the synthesis of an NDI-[2]rotaxane, which retains similar spectroelectrochemical properties compared to the corresponding free macrocycle. The detailed understanding of the thermodynamic and electrochemical properties of the tailor-made crown ethers lays the foundation for the construction of new types of molecular redox switches with emergent properties.
RESUMO
We report a quite flexible naphthol-based cage (so-called "naphthocage") which adopts a self-inclusion conformation in its free state and is able to bind singly charged organic cations extremely strongly ( Ka > 107 M-1). Ion-selective electrodes prepared with this naphthocage show a super-Nernstian response to acetylcholine. In addition, the highly stable complex (1010 M-1) between ferrocenium and the naphthocage can be switched electrochemically, which lays a basis for its application in stimuli-responsive materials.
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Organic fluorophores, particularly stimuli-responsive molecules, are very interesting for biological and material sciences applications, but frequently limited by aggregation- and rotation-caused photoluminescence quenching. A series of easily accessible bipyridinium fluorophores, whose emission is quenched by a twisted intramolecular charge-transfer (TICT) mechanism, is reported. Encapsulation in a cucurbit[7]uril host gave a 1:1 complex exhibiting a moderate emission increase due to destabilization of the TICT state inside the apolar cucurbituril cavity. A much stronger fluorescence enhancement is observed in 2:2 complexes with the larger cucurbit[8]uril, which is caused by additional conformational restriction of rotations around the aryl/aryl bonds. Because the cucurbituril complexes are pH switchable, this system represents an efficient supramolecular ON/OFF fluorescence switch.
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Reversible oxidation reactions in electrochemically switchable oligorotaxanes with tetrathiafulvalene (TTF) decorated 24-crown-8 ether wheels generate intramolecular mixed-valence and radical-cation interactions between the wheels. This induces shuttling of the wheels and a contraction of inter-wheel distances. Further oxidation generates repulsive forces between the TTFs and maximizes the inter-wheel distances instead. These interactions and co-conformational changes were not observed for structurally similar controls in which acetyl groups along the axle prevent translational motion of the wheels. This operation mode of oligorotaxanes, which is reminiscent of an accordion-like motion, is promising for functional materials and nanodevices such as piston-type rotaxane motors.
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A rapid screening method based on traveling-wave ion-mobility spectrometry (TWIMS) combined with tandem mass spectrometry provides insight into the topology of interlocked and knotted molecules, even when they exist in complex mixtures, such as interconverting dynamic combinatorial libraries. A TWIMS characterization of structure-indicative fragments generated by collision-induced dissociation (CID) together with a floppiness parameter defined based on parent- and fragment-ion arrival times provide a straightforward topology identification. To demonstrate its broad applicability, this approach is applied here to six Hopf and two Solomon links, a trefoil knot, and a [3]catenate.
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Molecular recognition of stable organic radicals is a relatively novel, but important structural binding motif in supramolecular chemistry. Here, we report on a redox-switchable veratrole-fused tetrathiafulvalene derivative VTTF which is ideally suited for this purpose and for the incorporation into stimuli-responsive systems. As revealed by electrochemistry, UV/Vis measurements, X-ray analysis, and electrocrystallisation, VTTF can be reversibly oxidised to the corresponding radical-cation or dication which shows optoelectronic and structural propterties similar to tetrathiafulvalene and tetrakis(methylthio)tetrathiafulvalene. However, theoretical calculations, variable temperature EPR, and NIR spectroscopy indicate that the dispersion-driven binding in the mixed-valence dimer (VTTF2)Ë+ (KMV = 69 M-1 in CH2Cl2) and the radical-cation dimer (VTTFË+)2 (KRC = 38 M-1 in CH3CN) is significantly enhanced by the additional veratrole π-surface in comparison to pristine tetrathiafulvalene.
RESUMO
With the rise of artificial molecular machines, control of motion on the nanoscale has become a major contemporary research challenge. Tetrathiafulvalenes (TTFs) are one of the most versatile and widely used molecular redox switches to generate and control molecular motion. TTF can easily be implemented as functional unit into molecular and supramolecular structures and can be reversibly oxidized to a stable radical cation or dication. For over 20 years, TTFs have been key building blocks for the construction of redox-switchable mechanically interlocked molecules (MIMs) and their electrochemical operation has been thoroughly investigated. In this review, we provide an introduction into the field of TTF-based MIMs and their applications. A brief historical overview and a selection of important examples from the past until now are given. Furthermore, we will highlight our latest research on TTF-based rotaxanes.
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Donor-acceptor materials with small HOMO-LUMO gaps are important in molecular electronics, but are often difficult to synthesise. A simple and efficient way to position tetrathiafulvalene (TTF) as the donor and naphthalene diamide (NDI) as the acceptor in close proximity to each other in a divalent crown/ammonium pseudo[2]rotaxane is presented. The divalent design provides high chelate cooperativity and much stronger binding compared with a monovalent analogue. The pseudo[2]rotaxane was then doubly interlocked by stoppering it in a catalyst-free 1,3-dipolar cycloaddition. UV/Vis and cyclic voltammetry experiments with the resulting [2]rotaxane revealed the optoelectronic properties of an intramolecular charge transfer with a small HOMO-LUMO energy gap. Redox-switching experiments showed the rotaxane to be pentastable. DFT calculations provided insights into the electronic structures of the five redox states.
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Mechanically interlocked molecules (MIMs), such as rotaxanes and catenanes, have captured the attention of chemists both from a synthetic perspective and because of their role as simple prototypes of molecular machines. Although examples exist in nature, most synthetic MIMs are made from artificial building blocks and assembled in organic solvents. The synthesis of MIMs from natural biomolecules remains highly challenging. Here, we report on a synthesis strategy for interlocked molecules solely made from peptides, that is, mechanically interlocked peptides (MIPs). Fully peptidic, cysteine-decorated building blocks were self-assembled in water to generate disulfide-bonded dynamic combinatorial libraries consisting of multiple different rotaxanes, catenanes and daisy chains as well as more exotic structures. Detailed NMR spectroscopy and mass spectrometry characterization of a [2]catenane comprising two peptide macrocycles revealed that this structure has rich conformational dynamics reminiscent of protein folding. Thus, MIPs can serve as a bridge between fully synthetic MIMs and those found in nature.
Assuntos
Substâncias Macromoleculares/química , Peptídeos/química , Sequência de Aminoácidos , Cisteína/química , Substâncias Macromoleculares/síntese química , Peptídeos/síntese química , Engenharia de ProteínasRESUMO
We present the synthesis of a porous, organic [4+4] imine cage containing perfluorinated aromatic panels. Gas adsorption experiments show an uptake of 19.0 wt% CO2 (4.2 mmol g-1, 273 K and at 1 bar) and 1.5 wt% H2 (7.5 mmol g-1, 77 K and at 1 bar) for the specific surface area of 536 m2 g-1 of the crystalline material obtained directly from the reaction mixture, combined with an outstanding thermal stability, making it a very interesting porous material suitable for gas adsorption.
RESUMO
Antibiotic resistance poses a serious threat to global health. To reinforce the anti-infective arsenal, many novel therapeutic strategies to fight bacterial infections are being explored. Among them, anti-virulence therapies, which target pathways important for virulence, have attracted much attention. Nitric oxide (NO) defense systems have been identified as critical for the pathogenesis of various bacteria, making them an appealing therapeutic target. In this study, we performed chemical screens to identify inhibitors of NO detoxification in Escherichia coli. We found that 2-mercaptobenzothiazole (2-MBT) can potently inhibit cellular detoxification of NO, achieving a level of inhibition that resembled the effect of genetically removing Hmp, the dominant detoxification enzyme under oxygenated conditions. Further analysis revealed that in the presence of NO, 2-MBT impaired the catalysis of Hmp and synthesis of Hmp and other proteins, whereas in its absence there were minimal perturbations to growth and protein synthesis. In addition, by studying the structure-activity relationship of 2-MBT, we found that both sulfur atoms in 2-MBT were vital for its inhibition of NO detoxification. Interestingly, when 2-mercaptothiazole (2-MT), which lacked the benzene ring, was used, differing biological activities were observed, although they too were NO dependent. Specifically, 2-MT could still prohibit NO detoxification, though it did not interfere with Hmp catalysis; rather, it was a stronger inhibitor of protein synthesis and it reduced the transcript levels of hmp, which was not observed with 2-MBT. Overall, these results provide a strong foundation for further exploration of 2-MBT and 2-MT for therapeutic applications.
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Are they still electrifying? Electrochemically switchable rotaxanes are well known for their ability to efficiently undergo changes of (co-)conformation and properties under redox-control. Thus, these mechanically interlocked assemblies represent an auspicious liaison between the fields of molecular switches and molecular electronics. Since the first reported example of a redox-switchable molecular shuttle in 1994, improved tools of organic and supramolecular synthesis have enabled sophisticated new architectures, which provide precise control over properties and function. This perspective covers recent advances in the area of electrochemically active rotaxanes including novel molecular switches and machines, metal-containing rotaxanes, non-equilibrium systems and potential applications.
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A tetrathiafulvalene (TTF)-containing crown ether macrocycle with C s symmetry was designed to implement planar chirality into a redox-active [2]rotaxane. The directionality of the macrocycle atom sequence together with the non-symmetric axle renders the corresponding [2]rotaxane mechanically planar chiral. Enantiomeric separation of the [2]rotaxane was achieved by chiral HPLC. The electrochemical properties - caused by the reversible oxidation of the TTF - are similar to a non-chiral control. Reversible inversion of the main band in the ECD spectra for the individual enantiomers was observed after oxidation. Experimental evidence, conformational analysis and DFT calculations of the neutral and doubly oxidised species indicate that mainly electronic effects of the oxidation are responsible for the chiroptical switching. This is the first electrochemically switchable rotaxane with a reversible inversion of the main ECD band.
RESUMO
In this study, the crown/ammonium [3]rotaxane R2 is reported which allows a switchable synchronisation of wheel pirouetting motions. The rotaxane is composed of a dumbbell-shaped axle molecule with two mechanically interlocked macrocycles which are decorated with a redox-active tetrathiafulvalene (TTF) unit. Electrochemical, spectroscopic, and electron paramagnetic resonance experiments reveal that rotaxane R2 can be reversibly switched between four stable oxidation states (R2, R2Ë+, R22(Ë+), and R24+). The oxidations enable non-covalent, cofacial interactions between the TTF units in each state-including a stabilised mixed-valence (TTF2)Ë+ and a radical-cation (TTFË+)2 dimer interaction-which dictate a syn (R2, R2Ë+, and R22(Ë+)) or anti (R24+) ground state co-conformation of the wheels in the rotaxane. Furthermore, the strength of these wheel-wheel interactions varies with the oxidation state, and thus electrochemical switching allows a controllable synchronisation of the wheels' pirouetting motions. DFT calculations explore the potential energy surface of the counter-rotation of the two interacting wheels in all oxidation states. The controlled coupling of pirouetting motions in rotaxanes can lead to novel molecular gearing systems which transmit rotational motion by switchable non-covalent interactions.
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The self-inclusion behavior of a tetrathiafulvalene-containing lasso-type pseudo[1]rotaxane can be reversibly switched between threaded and non-threaded states by redox-stimuli. The switching mechanism was investigated by cyclic voltammetry in solution and monitored by ion mobility mass spectrometry in the gas phase.
RESUMO
Switchable crown ether-ammonium [2]rotaxanes with a redox-active tetrathiafulvalene (TTF) unit implemented in their wheels were synthesised and fully characterised. Reversible operation in two modes is possible, in which the [2]rotaxane's axle is either charged or neutral. Cyclic voltammetry experiments reveal the effects of mechanical bonding on the electrochemical properties of TTF and show the [2]rotaxanes to perform a distinct function in both modes. In the charged mode, redox-switching is dominated by strong electrostatic repulsion in the [2]rotaxane which subsequently leads to a macrocycle translation along the axle. In the non-charged mode, a selective energetic stabilisation of TTF radical cations is observed, which can be attributed to an interplay of weak electrostatic interactions between wheel and axle.