Pendant Proton-Relays Systematically Tune the Rate and Selectivity of Electrocatalytic Ammonia Generation in a Fe-Porphyrin Based Metal-Organic Framework.

Electrocatalytic nitrite reduction (eNO2RR) is a promising alternative route to produce ammonia (NH3). Until now, several molecular catalysts have shown capability to homogeneously reduce nitrite to NH3, while taking advantage of added secondary-sphere functionalities to direct catalytic performance. Yet, realizing such control over heterogeneous electrocatalytic surfaces remains a challenge. Herein, we demonstrate that heterogenization of a Fe-porphyrin molecular catalyst within a 2D Metal-Organic Framework (MOF), allows efficient eNO2RR to NH3. On top of that, installation of pendant proton relaying moieties proximal to the catalytic site, resulted in significant improvement in catalytic activity and selectivity. Notably, systematic manipulation of NH3 faradaic efficiency (up to 90%) and partial current (5-fold increase) was achieved by varying the proton relay-to-catalyst molar ratio. Electrochemical and spectroscopic analysis show that the proton relays simultaneously aid in generating and stabilizing of reactive Fe-bound NO intermediate. Thus, this concept offers new molecular tools to tune heterogeneous electrocatalytic systems.

Why Are Left-Handed G-Quadruplexes Scarce?

G-quadruplexes (G4s) are nucleic acid structures crucial for the regulation of gene expression and genome maintenance. While they hold promise as nanodevice components, achieving desired G4 folds requires understanding the interplay between stability and structural properties, like helicity. Although right-handed G4 structures dominate the experimental data, the molecular basis for this preference over left-handed helicity is unclear. To address this, we employ all-atom molecular dynamics simulations and quantum chemical methods. Our results reveal that right-handed G4s exhibit greater thermodynamic and kinetic stability as a result of favorable sugar-phosphate backbone conformations in guanine tracts. Moreover, while hydrogen-bonding patterns influence helicity-specific G4 loop conformations, they minimally affect stability differences. We also elucidate the strong correlation between helicity and the strand progression direction, essential for G4 structures. These findings deepen our understanding of G4s, providing molecular-level insights into their structural and energetic preferences, which could inform the design of novel nanodevices.

Low-Barrier Hydrogen Bond Determines Target-Binding Affinity and Specificity of the Antitubercular Drug Bedaquiline.

The role of short strong hydrogen bonds (SSHBs) in ligand-target binding remains largely unexplored, thereby hindering a potentially important avenue in rational drug design. Here we investigate the interaction between the antituberculosis drug bedaquiline (Bq) and the mycobacterial ATP synthase to unravel the role of a specific hydrogen bond to a conserved acidic residue in the target affinity and specificity. Our ab initio molecular dynamics simulations reveal that this bond belongs to the SSHB category and accounts for a substantial fraction of the target binding free energy. We also demonstrate that the presence of an extra acidic residue, i.e., aspartic acid at position 32 (D32), found exclusively in mycobacteria, cooperatively enhances the HB strength, ensuring specificity for the mycobacterial target. Consistently, we show that the removal of D32 markedly weakens the affinity, leading to Bq resistance associated with mutations of D32 to nonacidic residues. By designing simple Bq analogs, we then explore the possibility to overcome the resistance and potentially broaden the Bq antimicrobial spectrum by making the SSHB independent of the presence of the extra acidic residue.

Engineering TADF, mechanochromism, and second harmonic up-conversion properties in regioisomeric substitution space.

This research article explores the distinct TADF efficiency of three donor-acceptor based regio-isomers: DPAOCN (ortho-isomer), DPAMCN (meta-isomer), and DPAPCN (para-isomer). DPAPCN exhibits maximum TADF efficiency in both solution and solid-state with an impressive reverse inter-system crossing (RISC) rate of ∼106 s-1; the underlying cause being the minimum singlet-triplet splitting energy or ΔEST and maximum SOC (spin-orbit coupling) between the S1 & T1 states. Apart from TADF, differences in crystal packing of the regio-isomers result in intriguing bulk phase properties. DPAOCN, with its non-centrosymmetric P212121 space group and substantial crystal void volume, exhibits reversible tri-color mechanochromic luminescence behavior, while the meta and para isomers, due to their centrosymmetric packing and diminished crystal void volume, remain inert to mechanical pressure. Expanding the horizon of possibilities, the non-centrosymmetric nature of ortho-isomer further renders it an excellent SHG material, with a χ(2) value of 0.19 pm V-1 at 1220 nm and a laser-induced damage threshold (LIDT) value of 13.27 GW cm-2. Overall, a comprehensive investigation into the regio-isomers has been carried out, encompassing their TADF, SHG, and mechanochromic luminescent properties.

An insight into the mixed quantum mechanical-molecular dynamics simulation of a ZnII-Curcumin complex with a chosen DNA sequence that supports experimental DNA binding investigations.

An important aspect of research pertaining to Curcumin (HCur) is the need to arrest its degradation in aqueous solution and in biological milieu. This may be achieved through complex formation with metal ions. For this reason, a complex of HCur was prepared with ZnII, that is not likely to be active in redox pathways, minimizing further complications. The complex is monomeric, tetrahedral, with one HCur, an acetate and a molecule of water bound to ZnII. It arrests degradation of HCur to a considerable extent that was realized by taking it in phosphate buffer and in biological milieu. The structure was obtained by DFT calculations. Stable adduct formation was identified between optimized structures of HCur and [Zn(Cur)] with DNA (PDB ID: 1BNA) through experiments validated with multiscale modeling approach. Molecular docking studies provide 2D and 3D representations of binding of HCur and [Zn(Cur)] through different non-covalent interactions with the nucleotides of the chosen DNA. Through molecular dynamics simulation, a detailed understanding of binding pattern and key structural characteristics of the generated DNA-complex was obtained following analysis by RMSD, RMSF, radius of gyration, SASA and aspects like formation of hydrogen bonds. Experimental studies provide binding constants for [Zn(Cur)] with calf thymus DNA at 25 °C that effectively helps one to realize its high affinity towards DNA. In the absence of an experimental binding study of HCur with DNA, owing to its tendency to degrade in solution, a theoretical analysis of the binding of HCur to DNA is extremely helpful. Besides, both experimental and simulated binding of [Zn(Cur)] to DNA may be considered as a case of pseudo-binding of HCur to DNA. In a way, such studies on interaction with DNA helps one to identify HCur's affinity for cellular target DNA, not realized through experiments. The entire investigation is an understanding of experimental and theoretical approaches that has been compared continuously, being particularly useful when a molecule's interaction with a biological target cannot be realized experimentally.

A first-principles study of electronic and magnetic properties of 4d transition metals doped in Wurtzite GaN for spintronics applications.

We studied the electronic and magnetic properties of wurtzite GaN (w-GaN) doped with different concentrations of the 4d transition metal ions Nb, Mo, and Ru. We incorporated spin-polarized plane-wave density functional theory within an ultrasoft pseudopotential formalism. The 4d transition metals were doped at different geometrical sites to determine the geometry with the lowest total energy and the one that induced the largest magnetization. A spin-spin interaction study was performed to determine whether the doped compound was ferromagnetic or antiferromagnetic. The origin of magnetization in the transition metal-doped w-GaN compounds is due to the p-d hybridization of the nitrogen and 4d transition metals. From the bulk modulus results, we inferred that the structural integrity is preserved under compressive loads after doping w-GaN with these 4d transition metal ions. Our results indicate that these compounds can be used in spintronic applications.

Mangiferin Affects Melanin Synthesis by an Influence on Tyrosinase: Inhibition, Mechanism of Action and Molecular Docking Studies.

Mangiferin is a strong antioxidant that presents a wide range of biological activities. The aim of this study was to evaluate, for the first time, the influence of mangiferin on tyrosinase, an enzyme responsible for melanin synthesis and the unwanted browning process of food. The research included both the kinetics and molecular interactions between tyrosinase and mangiferin. The research proved that mangiferin inhibits tyrosinase activity in a dose-dependent manner with IC50 290 +/- 6.04 µM, which was found comparable with the standard kojic acid (IC50 217.45 +/- 2.54 µM). The mechanism of inhibition was described as mixed inhibition. The interaction between tyrosinase enzyme and mangiferin was confirmed with capillary electrophoresis (CE). The analysis indicated the formation of two main, and four less significant complexes. These results have also been supported by the molecular docking studies. It was indicated that mangiferin binds to tyrosinase, similarly to L-DOPA molecule, both in the active center and peripheral site. As it was presented in molecular docking studies, mangiferin and L-DOPA molecules can interact in a similar way with surrounding amino acid residues of tyrosinase. Additionally, hydroxyl groups of mangiferin may interact with amino acids on the tyrosinase external surface causing non-specific interaction.

How acidic amino acid residues facilitate DNA target site selection.

Despite the negative charge of the DNA backbone, acidic residues (Asp/Glu) commonly participate in the base readout, with a strong preference for cytosine. In fact, in the solved DNA/protein structures, cytosine is recognized almost exclusively by Asp/Glu through a direct hydrogen bond, while at the same time, adenine, regardless of its amino group, shows no propensity for Asp/Glu. Here, we analyzed the contribution of Asp/Glu to sequence-specific DNA binding using classical and ab initio simulations of selected transcription factors and found that it is governed by a fine balance between the repulsion from backbone phosphates and attractive interactions with cytosine. Specifically, Asp/Glu lower the affinity for noncytosine sites and thus act as negative selectors preventing off-target binding. At cytosine-containing sites, the favorable contribution does not merely rely on the formation of a single H-bond but usually requires the presence of positive potential generated by multiple cytosines, consistently with the observed excess of cytosine in the target sites. Finally, we show that the preference of Asp/Glu for cytosine over adenine is a result of the repulsion from the adenine imidazole ring and a tendency of purine-purine dinucleotides to adopt the BII conformation.

Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants.

The genome feature of SARS-CoV-2 leads the virus to mutate and creates new variants of concern. Tackling viral mutations is also an important challenge for the development of a new vaccine. Accordingly, in the present study, we undertook to identify B- and T-cell epitopes with immunogenic potential for eliciting responses to SARS-CoV-2, using computational approaches and its tailoring to coronavirus variants. A total of 47 novel epitopes were identified as immunogenic triggering immune responses and no toxic after investigation with in silico tools. Furthermore, we found these peptide vaccine candidates showed a significant binding affinity for MHC I and MHC II alleles in molecular docking investigations. We consider them to be promising targets for developing peptide-based vaccines against SARS-CoV-2. Subsequently, we designed two efficient multi-epitopes vaccines against the SARS-CoV-2, the first one based on potent MHC class I and class II T-cell epitopes of S (FPNITNLCPF-NYNYLYRLFR-MFVFLVLLPLVSSQC), M (MWLSYFIASF-GLMWLSYFIASFRLF), E (LTALRLCAY-LLFLAFVVFLLVTLA), and N (SPRWYFYYL-AQFAPSASAFFGMSR). The second candidate is the result of the tailoring of the first designed vaccine according to three classes of SARS-CoV-2 variants. Molecular docking showed that the protein-protein binding interactions between the vaccines construct and TLR2-TLR4 immune receptors are stable complexes. These findings confirmed that the final multi-epitope vaccine could be easily adapted to new viral variants. Our study offers a shortlist of promising epitopes that can accelerate the development of an effective and safe vaccine against the virus and its adaptation to new variants.Communicated by Ramaswamy H. Sarma.

Ligand-Induced Ground- and Excited-State Chirality in Silicon Nanoparticles: Surface Interactions Matter.

Silicon-based light-emitting materials have emerged as a favorable substitute to various organic and inorganic systems due to silicon's high natural abundance, low toxicity, and excellent biocompatibility. However, efforts on the design of free-standing silicon nanoparticles with chiral non-racemic absorption and emission attributes are rather scare. Herein, we unravel the structural requirements for ligand-induced chirality in silicon-based nanomaterials by functionalizing with D- and L-isomers of a bifunctional ligand, namely, tryptophan. The structural aspects of these systems are established using high-resolution high-angle annular dark-field imaging in the scanning transmission electron microscopy mode, solid-state nuclear magnetic resonance, Fourier transform infrared, and X-ray photoelectron spectroscopy. Silicon nanoparticles capped with L- and D-isomers of tryptophan displayed positive and negative monosignated circular dichroic signals and circularly polarized luminescence indicating their ground- and excited-state chirality. Various studies supported by density functional theory calculations signify that the functionalization of indole ring nitrogen on the silicon surface plays a decisive role in modifying the chiroptical characteristics by generating emissive charge-transfer states. The chiroptical responses originate from the multipoint interactions of tryptophan with the nanoparticle surface through the indole nitrogen and -CO2- groups that can transmit an enantiomeric structural imprint on the silicon surface. However, chiroptical properties are not observed in phenylalanine- and alanine-capped silicon nanoparticles, which are devoid of Si-N bonds and chiral footprints. Thus, the ground- and excited-state chiroptics in tryptophan-capped silicon nanoparticles originates from the collective effect of ligand-bound emissive charge-transfer states and chiral footprints. Being the first report on the circularly polarized luminescence in silicon nanoparticles, this work will open newer possibilities in the field of chirality.

Inhibition Ability of Natural Compounds on Receptor-Binding Domain of SARS-CoV2: An In Silico Approach.

The lack of medication to treat COVID-19 is still an obstacle that needs to be addressed by all possible scientific approaches. It is essential to design newer drugs with varied approaches. A receptor-binding domain (RBD) is a key part of SARS-CoV-2 virus, located on its surface, that allows it to dock to ACE2 receptors present on human cells, which is followed by admission of virus into cells, and thus infection is triggered. Specific receptor-binding domains on the spike protein play a pivotal role in binding to the receptor. In this regard, the in silico method plays an important role, as it is more rapid and cost effective than the trial and error methods using experimental studies. A combination of virtual screening, molecular docking, molecular simulations and machine learning techniques are applied on a library of natural compounds to identify ligands that show significant binding affinity at the hydrophobic pocket of the RBD. A list of ligands with high binding affinity was obtained using molecular docking and molecular dynamics (MD) simulations for protein-ligand complexes. Machine learning (ML) classification schemes have been applied to obtain features of ligands and important descriptors, which help in identification of better binding ligands. A plethora of descriptors were used for training the self-organizing map algorithm. The model brings out descriptors important for protein-ligand interactions.

Emergence of Aggregation Induced Emission (AIE), Room-Temperature Phosphorescence (RTP), and Multistimuli Response from a Single Organic Luminogen by Directed Structural Modification.

Multifunctional organic luminogens exhibiting simultaneous aggregation induced emission (AIE), room-temperature phosphorescence (RTP), and mechanochromism have recently attracted considerable attention owing to their potential applications in optoelectronics and bioimaging. However, a comprehensive correlation among these three distinguished properties is yet to be unveiled, which will help to decipher defined methodologies to design future generation multifunctional organic materials. Herein, we have demonstrated a route to obtain a multifunctional organic luminogen, starting from an ACQphore (TPANDI) by simple structural engineering. We have shown that a slight reduction in length of the planar acceptor moieties can effectively inhibit the undesirable π-π stacking interaction between molecules in the condensed state and thereby cause an ACQ to AIE type transformation from TPANDI to TPANMI and TPAPMI. Both TPANMI and TPAPMI exhibit RTP properties (even in ambient condition) because of the presence of a reasonably low singlet-triplet energy gap (ΔEST). In our study, these two luminogens were found to be mechano-inactive. Interestingly, an insertion of cyano-ethylene group and benzene linker in between the triphenylamine and phthalimide moieties introduced another luminogen TPACNPMI, which can simultaneously exhibit AIE, RTP, and mechanochromic properties.

Proton-Coupled Electron Transfer in the Aqueous Nanochannels of Lyotropic Liquid Crystals: Interplay of H-Bonding and Polarity Effects.

A molecular-level description of the aqueous nanochannels in lyotropic liquid crystals (LLCs) is crucial for their widespread utilization in diverse fields. Herein, the polarity and hydrogen bonding effects of LLC water molecules have been simultaneously explored using a single probe, 4'-N,N-dimethylamino-3-hydroxyflavone (DMA3HF), by the unique multiparametric sensitivity of the excited state proton-coupled electron transfer (PCET) phenomenon. The decreased ESIPT efficiency and the significantly retarded ESIPT dynamics (>20 times) of DMA3HF in the LLC phases suggests the dominant influence of strong hydrogen-bonded solute-solvent complexes that leads to a high activation barrier for ESIPT in the mesophases. The effects of hydrogen bonding on ESIPT have been elucidated by enhanced sampling techniques based on classical MD simulations of DMA3HF in explicit water. ESIPT via an extended hydrogen-bonded water wire is associated with a significantly high ESIPT activation barrier, substantiating the experimentally observed slow ESIPT dynamics inside the LLCs.

Peculiar hydrogen bonding behaviour of water molecules inside the aqueous nanochannels of lyotropic liquid crystals.

In spite of the widespread utilizations of lyotropic liquid crystals (LLCs) in food technology, as nanoreactors and in biomedical fields, the exact nature of their aqueous nanochannels which are deemed to dictate these applications are not completely understood. In this context, elucidation of the hydrogen bonding properties of the water molecules inside the nanochannels will contribute towards obtaining a complete picture of the LLC materials. In this study, we use two molecules exhibiting an excited state intramolecular proton transfer (ESIPT), fisetin and 3-hydroxyflavone, to determine the hydrogen bond donating and accepting parameters of the LLC water molecules. The steady state results imply a heterogeneity in the hydrogen bond accepting and donating properties inside the LLC nanochannels. Upon photoexcitation of the normal form of the ESIPT molecules, we notice that despite a reported general alcohol like polarity of the LLC nanochannels, the hydrogen bonding behaviour of the water molecules is similar to that of moderately polar aprotic solvents such as acetonitrile. In contrast, on excitation of the anionic species we observe that the spectral pattern is similar to that in alcohols. Additionally, the effect of the LLC water molecules on the rate of the intramolecular hydrogen transfer process has been explored. The ESIPT rates of both the probes, which are ultrafast (<20 ps) in neat polar protic and aprotic solvents, get slowed down dramatically by almost 15 times inside the LLC phases. Such an extent of retardation in the ESIPT rate is extremely rare in the literature, which signals towards the unique behaviour of the water molecules inside the LLC nanochannels. The structural topology of the LLC phases also influences the ESIPT rate with the timescale of the process increasing from the cubic to the hexagonal phase.

Structural characteristics requisite for the ligand-based selective detection of i-motif DNA.

Here, we have explored the light-up property of coumarin 343 (C343) selectively towards various i-motif DNAs based on the recognition of hemi-protonated cytosine-cytosine base pairing, unlike other DNA structures. We have also demonstrated the versatile ability of this i-motif ligand, i.e., the affinity of C343 towards both intermolecular and intramolecular i-motif DNA differing in the chain lengths, molecularity and sizes, which is observed in various oncogene promoters. A systematic study between i-motif DNA and various coumarin derivatives helps in understanding the structural characteristics required for an ideal ligand, which can be useful for future design of any i-motif DNA ligands.

Nuclear quantum effects in a HIV/cancer inhibitor: The case of ellipticine.

Ellipticine is a natural product that is currently being actively investigated for its inhibitory cancer and HIV properties. Here we use path-integral molecular dynamics coupled with excited state calculations to characterize the role of nuclear quantum effects on the structural and electronic properties of ellipticine in water, a common biological solvent. Quantum effects collectively enhance the fluctuations of both light and heavy nuclei of the covalent and hydrogen bonds in ellipticine. In particular, for the ellipticine-water system, where the proton donor and acceptor have different proton affinities, we find that nuclear quantum effects (NQEs) strengthen both the strong and the weak H bonds. This is in contrast to what is observed for the cases where the proton affinity of the donors and acceptors is same. These structural fluctuations cause a significant red-shift in the absorption spectra and an increase in the broadening, bringing it into closer agreement with the experiments. Our work shows that nuclear quantum effects alter both qualitatively and quantitatively the optical properties of this biologically relevant system and highlights the importance of the inclusion of these effects in the microscopic understanding of their optical properties. We propose that isotopic substitution will produce a blue shift and a reduction in the broadening of the absorption peak.

Coordination polymers of Fe(iii) and Al(iii) ions with TCA ligand: distinctive fluorescence, CO2 uptake, redox-activity and oxygen evolution reaction.

Fe and Al belong to different groups in the periodic table, one from the p-block and the other from the d-block. In spite of their different groups, they have the similarity of exhibiting a stable 3+ oxidation state. Here we have prepared Fe(iii) and Al(iii) based coordination polymers in the form of metal-organic gels with the 4,4',4''-tricarboxyltriphenylamine (TCA) ligand, namely Fe-TCA and Al-TCA, and evaluated some important physicochemical properties. Specifically, the electrical conductivity, redox-activity, porosity, and electrocatalytic activity (oxygen evolution reaction) of the Fe-TCA system were noted to be remarkably higher than those of the Al-TCA system. As for the photophysical properties, almost complete quenching of the fluorescence originating from TCA was observed in case of the Fe-TCA system, whereas for the Al-TCA system a significant retention of fluorescence with red-shifted emission was observed. Quantum mechanical calculations based on density functional theory (DFT) were performed to unravel the origin of such discriminative behaviour of these coordination polymer systems.

Spectroscopy and Dynamics of Cryptolepine in the Nanocavity of Cucurbit[7]uril and DNA.

Herein, we explored the photophysical properties of the antimalarial, anticancer drug cryptolepine (CRYP) in the presence of the macrocyclic host cucurbit[7]uril (CB7) and DNA with the help of steady-state and time-resolved fluorescence techniques. Ground-state and excited-state calculations based on density functional theory were also performed to obtain insight into the shape, electron density distribution, and energetics of the molecular orbitals of CRYP. CRYP exists in two forms depending on the pH of the medium, namely, a cationic (charge transfer) form and a neutral form, which emit at λ=540 and 420 nm, respectively. In a buffer solution of pH 7, the drug exists in the cationic form, and upon encapsulation with CB7, it exhibits a huge enhancement in fluorescence intensity due to a decrement in nonradiative decay pathways of the emitting cryptolepine species. Furthermore, docking and quantum chemical calculations were employed to decipher the molecular orientation of the drug in the inclusion complex. Studies with natural DNA indicate that CRYP molecules intercalate into DNA, which leads to a huge quenching of the fluorescence of CRYP. Keeping this in mind, we studied the DNA-assisted release of CRYP molecules from the nanocavity of CB7. Strikingly, DNA alone could not remove the drug from the nanocavity of CB7. However, an external stimulus such as acetylcholine chloride was able to displace CRYP from the nanocavity, and subsequently, the displaced drug could bind to DNA.