Duplex vs. folding: tuning the self-assembly of synthetic recognition-encoded aniline oligomers.

One of the challenges in the realization of synthetic oligomers capable of sequence-selective duplex formation is intramolecular folding interaction between complementary recognition units. To assess whether complementary hetero-oligomers can assemble into high fidelity duplex structures, the competing folding equilibria must be carefully considered. A family of recognition-encoded aniline oligomers were assembled via reductive amination of dianiline linkers and dialdehyde monomers, which were equipped with either a 2-trifluoromethylphenol or a phosphine oxide H-bond recognition unit. To test the possibility of 1,2-folding in mixed sequence oligomers, the self-assembly properties of the homo- and hetero-dimers were characterised by 19F and 1H NMR titration and dilution experiments in toluene and in chloroform. Three different systems were investigated with variations in the steric bulk around the H-bond acceptor unit and the length of the dianiline linker. For two systems, the hetero-dimers folded with intramolecular H-bonding in the monomeric state, reducing stability of the intermolecular duplex by two to three orders of magnitude compared with the corresponding homo-oligomers. However, the use of a long rigid linker as the backbone connecting two monomer units successfully prevents 1,2-folding and leads to the formation of a stable mixed sequence duplex in toluene.

Nanoparticle-Assisted NMR Spectroscopy: Enhanced Detection of Analytes by Water-Mediated Saturation Transfer.

Nanoparticle-assisted "NMR chemosensing" is an experimental protocol that exploits the selective recognition abilities of nanoparticle receptors to detect and identify small molecules in complex mixtures by nuclear Overhauser effect magnetization transfer. Although the intrinsic sensitivity of the first reported protocols was modest, we have now found that water spins in long-lived association at the nanoparticle monolayer constitute an alternative source of magnetization that can deliver a remarkable boost of sensitivity, especially when combined with saturation transfer experiments. The approach is general and can be applied to analyte-nanoreceptor systems of different compositions. In this work, we provide an account of the new method and we propose a generalized procedure based on a joint water-nanoparticle saturation to further upgrade the sensitivity, which ultimately endows selective analyte detection down to the micromolar range on standard instrumentation.

Sequence-selective duplex formation and template effect in recognition-encoded oligoanilines.

A new family of duplex-forming recognition encoded oligomers, capable of sequence selective duplex formation and template directed synthesis, was developed. Monomers equipped with both amine and aldehyde groups were functionalized with 2-trifluoromethylphenol or phosphine oxide as H-bond recognition units. Duplex formation and assembly properties of homo- and hetero-oligomers were studied by 19F and 1H NMR experiments in chloroform. The designed backbone prevents the undesired 1,2-folding allowing sequence-selective duplex formation, and the stability of the antiparallel duplex is 3-fold higher than the parallel arrangement. Dynamic combinatorial chemistry was exploited for the templated synthesis of complementary oligomers, showing that an aniline dimer can template the formation of the complementary imine. The key role of the H-bond recognition confers to the system the ability to discriminate a mutated donor monomer incapable of H-bonding. Sequence selective duplex formation combined with the template effect makes this system an attractive target for further studies.

Intracluster ligand rearrangement: an NMR-based thermodynamic study.

Ligand and metal exchange reactions are powerful methods to tailor the properties of atomically precise metal nanoclusters. Hence, a deep understanding of the mechanisms behind the dynamics that rule the ligand monolayer is crucial for its specific functionalization. Combining variable-temperature NMR experiments and dynamic-NMR simulations, we extract the thermodynamic activation parameters of a new exchange reaction: the intracluster ligand rearrangement between the two symmetry-unique positions in [Ag25(DMBT)18]- and [Ag24Au(DMBT)18]- clusters. We report for the first time that this peculiar intracluster modification does not seem to proceed via metal-sulphur bond breaking and follows a first-order rate law, being therefore a process independent from the well-described collisional ligand exchange.

Molecular Mechanisms Underlying Detection Sensitivity in Nanoparticle-Assisted NMR Chemosensing.

Nanoparticle-assisted nuclear magnetic resonance (NMR) chemosensing exploits monolayer-protected nanoparticles as supramolecular hosts to detect small molecules in complex mixtures via nuclear Overhauser effect experiments with detection limits down to the micromolar range. Still, the structure-sensitivity relationships at the basis of such detection limits are little understood. In this work, we integrate NMR spectroscopy and atomistic molecular dynamics simulations to examine the covariates that affect the sensitivity of different NMR chemosensing experiments [saturation transfer difference (STD), water STD, and high-power water-mediated STD]. Our results show that the intensity of the observed signals correlates with the number and duration of the spin-spin interactions between the analytes and the nanoparticles and/or between the analytes and the nanoparticles' solvation molecules. In turn, these parameters depend on the location and dynamics of each analyte inside the monolayer. This insight will eventually facilitate the tailoring of experimental and computational setups to the analyte's chemistry, making NMR chemosensing an even more effective technique in practical use.

Selective NMR detection of N-methylated amines using cavitand-decorated silica nanoparticles as receptors.

We report a strategy for the realization of NMR chemosensors based on the spontaneous self-assembly of lower rim pyridinium-functionalized tetraphopshonate cavitands on commercial silica nanoparticles. These nanohybrids enable the selective detection of physiologically relevant N-methylated amines, with a limit of detection of 31 µM, via STD-based NMR experiments, achieving for the first time fine structural selectivity in nanoparticle-assisted NMR chemosensing.

Hybrid nanoreceptors for high sensitivity detection of small molecules by NMR chemosensing.

"Nanoparticle-assisted NMR chemosensing" combines magnetization transfer NMR techniques with the recognition abilities of gold nanoparticles (AuNPs) to isolate the NMR spectrum of relevant organic species in mixtures. The efficiency of the magnetization transfer is crucial to set the detection limit of the technique. To this aim, a second generation of nanoreceptors obtained by the self-organization of 2 nm AuNPs onto the surface of bigger silica nanoparticles shows better magnetization transfer performances, allowing the detection of analytes in water down to 10 µM concentration using standard instrumentation.

On the Metal-Aided Catalytic Mechanism for Phosphodiester Bond Cleavage Performed by Nanozymes.

Recent studies have shown that gold nanoparticles (AuNPs) functionalized with Zn(II) complexes can cleave phosphate esters and nucleic acids. Remarkably, such synthetic nanonucleases appear to catalyze metal (Zn)-aided hydrolytic reactions of nucleic acids similar to metallonuclease enzymes. To clarify the reaction mechanism of these nanocatalysts, here we have comparatively analyzed two nanonucleases with a >10-fold difference in the catalytic efficiency for the hydrolysis of the 2-hydroxypropyl-4-nitrophenylphosphate (HPNP, a typical RNA model substrate). We have used microsecond-long atomistic simulations, integrated with NMR experiments, to investigate the structure and dynamics of the outer coating monolayer of these nanoparticles, either alone or in complex with HPNP, in solution. We show that the most efficient one is characterized by coating ligands that promote a well-organized monolayer structure, with the formation of solvated bimetallic catalytic sites. Importantly, we have found that these nanoparticles can mimic two-metal-ion enzymes for nucleic acid processing, with Zn ions that promote HPNP binding at the reaction center. Thus, the two-metal-ion-aided hydrolytic strategy of such nanonucleases helps in explaining their catalytic efficiency for substrate hydrolysis, in accordance with the experimental evidence. These mechanistic insights reinforce the parallelism between such functionalized AuNPs and proteins toward the rational design of more efficient catalysts.

Exploiting Double Exchange Diels-Alder Cycloadditions for Immobilization of Peptide Nucleic Acids on Gold Nanoparticles.

The generation of PNA-decorated gold nanoparticles (AuNPs) has revealed to be more difficult as compared to the generation of DNA-functionalized ones. The less polar nature of this artificial nucleic acid system and the associated tendency of the neutral poly-amidic backbone to aspecifically adsorb onto the gold surface rather than forming a covalent bond through gold-thiol interaction, combined with the low solubility of PNAs itself, form the main limiting factors in the functionalization of AuNP. Here, we provide a convenient methodology that allows to easily conjugate PNAs to AuNP. Positively charged PNAs containing a masked furan moiety were immobilized via a double exchange Diels-Alder cycloaddition onto masked maleimide-functionalized AuNPs in a one-pot fashion. Conjugated PNA strands retain their ability to selectively hybridize with target DNA strands. Moreover, the duplexes resulting from hybridization can be detached through a retro-Diels-Alder reaction, thus allowing straightforward catch-and-release of specific nucleic acid targets.

Toward supramolecular nanozymes for the photocatalytic activation of Pt(IV) anticancer prodrugs.

A supramolecular nanozyme for the photocatalytic conversion of a Pt(iv) anticancer complex to cisplatin is described herein. We employed 1.9 nm Au nanoparticles decorated with thiol ligands bearing a TACN (1,4,7-triazacyclononane) headgroup to encapsulate FMN (riboflavin-5'-phosphate). In the presence of an electron donor, flavin-loaded nanoparticles photocatalyzed the reductive activation of the prodrug cis,cis,trans-[Pt(NH3)2(Cl2)(O2CCH2CH2COOH)2] to cisplatin, achieving turnover frequency values of 7.4 min-1.

1 H NMR Chemosensing of Potassium Ions Enabled by Guest-Induced Selectivity Switch of a Gold Nanoparticle/Crown Ether Nanoreceptor.

Invited for this month's cover is the group of Prof. Fabrizio Mancin from the University of Padova, Italy. The cover picture shows an 18-crown-6-functionalized gold nanoparticle that switches its molecular recognition preference from organic cations to organic anions in the presence of potassium ions, thus allowing 1 H NMR sensing of potassium. Read the full text of the article at 10.1002/cplu.201900028.

1 H NMR Chemosensing of Potassium Ions Enabled by Guest-Induced Selectivity Switch of a Gold Nanoparticle/Crown Ether Nanoreceptor.

A sensing protocol to detect potassium ions in water by 1 H NMR spectroscopy is described. The method exploits the K+ -modulated affinity of 18-crown-6 functionalized gold nanoparticles towards organic ions, combined with NOE magnetization transfer. Binding of K+ to the crown ether moieties switches the nanoreceptor preference (and its ability to transfer magnetization) from organic cations (tyramine) to organic anions (phloretate). In this way, a ratiometric NMR signal is produced with a detection limit of 0.6 mM. Detection can be performed in 20 min with standard instruments and with little interference from other alkali and alkaline earth metal ions present in the sample.

Detection and identification of designer drugs by nanoparticle-based NMR chemosensing.

Properly designed monolayer-protected nanoparticles (2 nm core diameter) can be used as nanoreceptors for selective detection and identification of phenethylamine derivatives (designer drugs) in water. The molecular recognition mechanism is driven by the combination of electrostatic and hydrophobic interactions within the coating monolayer. Each nanoparticle can bind up to 30-40 analyte molecules. The affinity constants range from 105 to 106 M-1 and are modulated by the hydrophobicity of the aromatic moiety in the substrate. Detection of drug candidates (such as amphetamines and methamphetamines) is performed by using magnetization (NOE) or saturation (STD) transfer NMR experiments. In this way, the NMR spectrum of the drug is isolated from that of the mixture, allowing broad-class multianalyte detection and even identification of unknowns. The introduction of a dimethylsilane moiety in the coating monolayer allows performing STD experiments in complex mixtures. In this way, a detection limit of 30 µM is reached with standard instruments.