Revealing elusive conformations of sucrose from hydrogen bond J-coupling in H2O: A combined NMR and quantum mechanics study.

Hydrogen bonding is a crucial feature of biomolecules, but its characterization in glycans dissolved in aqueous solutions is challenging due to rapid hydrogen exchange between hydroxyl groups and H2O. In principle, the scalar (J) coupling constant can reveal the relative orientation of the atoms in the molecule. In contrast to J-coupling through H-bonds reported in proteins and nucleic acids, research on J-coupling through H-bonds in glycans dissolved in water is lacking. Here, we use sucrose as a model system for H-bonding studies; its structure, which consists of glucose (Glc) and fructose (Frc), is well-studied, and it is readily available. We apply the in-phase, antiphase-HSQC-TOCSY and quantify previously unreported through H-bond J-values for Frc-OH1-Glc-OH2 in H2O. While earlier reports of Brown and Levy indicate this H-bond as having only a single direction, our reported findings indicate the potential presence of two involving these same atoms, namely, G2OH âž” F1O and F1OH âž” G2O (where F and G stand for Frc and Glc, respectively). The calculated density functional theory J-values for the G2OH âž” F1O agree with the experimental values. Additionally, we detected four other possible H-bonds in sucrose, which require different phi, psi (ϕ, ψ) torsion angles. The ϕ, ψ values are consistent with previous predictions of du Penhoat et al. and Venable et al. Our results will provide new insights into the molecular structure of sucrose and its interactions with proteins.

Mechanism of the antimicrobial activity induced by phosphatase inhibitor sodium ortho-vanadate.

The present study describes a novel antimicrobial mechanism based on Sodium Orthovanadate (SOV), an alkaline phosphatase inhibitor. Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and atomic force microscopy (AFM) were employed to examine the surface morphologies of the test organism, Escherichia coli (E. coli), during various antibacterial phases. Our results indicated that SOV kills bacteria by attacking cell wall growth and development, leaving E. coli's outer membrane intact. Our antimicrobial test indicated that the MIC of SOV for both E. coli and Lactococcus lactis (L. lactis) is 40 µM. A combination of quantum mechanical calculations and vibrational spectroscopy revealed that divanadate from SOV strongly coordinates with Ca2+ and Mg2+, which are the activity centers for the phosphatase that regulates bacterial cell wall synthesis. The current study is the first to propose the antibacterial mechanism caused by SOV attacking cell wall.

A Novel Abiotic Pathway for Phosphine Synthesis over Acidic Dust in Venus' Atmosphere.

Recent ground-based observations of Venus have detected a single spectral feature consistent with phosphine (PH3) in the middle atmosphere, a gas which has been suggested as a biosignature on rocky planets. The presence of PH3 in the oxidized atmosphere of Venus has not yet been explained by any abiotic process. However, state-of-the-art experimental and theoretical research published in previous works demonstrated a photochemical origin of another potential biosignature-the hydride methane-from carbon dioxide over acidic mineral surfaces on Mars. The production of methane includes formation of the HC · O radical. Our density functional theory (DFT) calculations predict an energetically plausible reaction network leading to PH3, involving either HC · O or H· radicals. We suggest that, similarly to the photochemical formation of methane over acidic minerals already discussed for Mars, the origin of PH3 in Venus' atmosphere could be explained by radical chemistry starting with the reaction of ·PO with HC·O, the latter being produced by reduction of CO2 over acidic dust in upper atmospheric layers of Venus by ultraviolet radiation. HPO, H2P·O, and H3P·OH have been identified as key intermediate species in our model pathway for phosphine synthesis.

Identification of novel CA IX inhibitor: Pharmacophore modeling, docking, DFT, and dynamic simulation.

Human Carbonic anhydrase IX (hCA IX) is found to be an essential biomarker for the treatment of hypoxic tumors in both the early and metastatic stages of cancer. Due to its active function in maintaining pH levels and overexpression in hypoxic conditions, hCA IX inhibitors can be a potential candidate specifically designed to target cancer development at various stages. In search of selective hCA IX inhibitors, we developed a pharmacophore model from the existing natural product inhibitors with IC50 values less than 50 nm. The identified hit molecules were then investigated on protein-ligand interactions using molecular docking experiments followed by molecular dynamics simulations. Among the zinc database 186 hits with an RMSD value less than 1 were obtained, indicating good contact with key residues HIS94, HIS96, HIS119, THR199, and ZN301 required for optimum activity. The top three compounds were subjected to molecular dynamics simulations for 100 ns to know the protein-ligand complex stability. Based on the obtained MD simulation results, binding free energies are calculated. Density Functional Theory (DFT) studies confirmed the energy variation between the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO). The current study has led to the discovery of lead compounds that show considerable promise as hCA IX inhibitors and suggests that three compounds with special molecular features are more likely to be better-inhibiting hCA IX. Compound S35, characterized by a higher stability margin and a smaller energy gap in quantum studies, is an ideal candidate for selective inhibition of CA IX.

Quantum mechanical study of transition metal hydrides: Comparison of determined molecular properties with experimental data.

This study compares results of four relativistic pseudopotential basis sets, which differ mainly by their size: double-zeta introduced by Hay and Wadt from Los Alamos National Laboratory (LANL2DZ), triple-zeta based on Stuttgart energy-consistent scalar-relativistic pseudopotential (SDD3), its extension with 2fg polarization functions, and combination of Stuttgart pseudopotentials with quintuple-zeta cc-pV5Z base (SDD5). Hydrides of transition metals from Cr to Zn group are chosen as reference molecules. The coupled cluster method (CCSD(T)) is used for evaluation of selected molecular characteristics. Interatomic distances, dissociation energies, vibration modes, and anharmonicity constants are determined and compared with available experimental data. As expected, the accuracy of basis depends mainly on its size. However, only moderate modification of SDD3 basis set significantly improves its accuracy, which becomes comparable to the largest basis set. Nevertheless, the time consumption is significantly lower.

Biophysical and structural characterization of tetramethrin serum protein complex and its toxicological implications.

Tetramethrin (TMT) is a commonly used insecticide and has a carcinogenic and neurodegenerative effect on humans. The binding mechanism and toxicological implications of TMT to human serum albumin (HSA) were examined in this study employing a combination of biophysical and computational methods indicating moderate binding affinity and potential hepato and renal toxicity. Fluorescence quenching experiments showed that TMT binds to HSA with a moderate affinity, and the binding process was spontaneous and predominantly enthalpy-driven. Circular dichroism spectroscopy revealed that TMT binding did not induce any significant conformational changes in HSA, resulting in no changes in its alpha-helix content. The binding site and modalities of TMT interactions with HSA as computed by molecular docking and molecular dynamics simulations revealed that it binds to Sudlow site II of HSA via hydrophobic interactions through its dimethylcyclopropane carboxylate methyl propanyl group. The structural dynamics of TMT induce proper fit into the binding site creating increased and stabilizing interactions. Additionally, molecular mechanics-Poisson Boltzmann surface area calculations also indicated that non-polar and van der Waals were found to be the major contributors to the high binding free energy of the complex. Quantum mechanics (QM) revealed the conformational energies of the binding confirmation and the degree of deviation from the global minimum energy conformation of TMT. The results of this study provide a comprehensive understanding of the binding mechanism of TMT with HSA, which is important for evaluating the toxicity of this insecticide in humans.

Aluminium 8-Hydroxyquinolinate N-Oxide as a Precursor to Heterometallic Aluminium-Lanthanide Complexes.

A reaction in anhydrous toluene between the formally unsaturated fragment [Ln(hfac)3] (Ln3+ = Eu3+, Gd3+ and Er3+; Hhfac = hexafluoroacetylacetone) and [Al(qNO)3] (HqNO = 8-hydroxyquinoline N-oxide), here prepared for the first time from [Al(OtBu)3] and HqNO, affords the dinuclear heterometallic compounds [Ln(hfac)3Al(qNO)3] (Ln3+ = Eu3+, Gd3+ and Er3+) in high yields. The molecular structures of these new compounds revealed a dinuclear species with three phenolic oxygen atoms bridging the two metal atoms. While the europium and gadolinium complexes show the coordination number (CN) 9 for the lanthanide centre, in the complex featuring the smaller erbium ion, only two oxygens bridge the two metal atoms for a resulting CN of 8. The reaction of [Eu(hfac)3] with [Alq3] (Hq = 8-hydroxyquinoline) in the same conditions yields a heterometallic product of composition [Eu(hfac)3Alq3]. A recrystallization attempt from hot heptane in air produced single crystals of two different morphologies and compositions: [Eu2(hfac)6Al2q4(OH)2] and [Eu2(hfac)6(µ-Hq)2]. The latter compound can be directly prepared from [Eu(hfac)3] and Hq at room temperature. Quantum mechanical calculations confirm (i) the higher stability of [Eu(hfac)3Al(qNO)3] vs. the corresponding [Eu(hfac)3Alq3] and (ii) the preference of the Er complexes for the CN 8, justifying the different behaviour in terms of the Lewis acidity of the metal centre.

Computational study of inclusion complexes of V-type nerve agents (VE, VG, VM, VR and VX) with ß-cyclodextrin.

The effective detoxification of organophosphate (OP) nerve agents (OPNAs) is a challenging issue for scientists. The host-guest inclusion complexes of five V-type nerve agents (VE, VG, VM, VR and VX) with ß-cyclodextrin (ß-CD) have been studied by combining quantum mechanical (QM) calculations and molecular dynamics (MD) simulations. The frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) have been analyzed to describe the reactivity parameters and electronic properties. The obtained results clearly reveal that stable complexes were formed in both vacuum and water media, and the complexation process occurred spontaneously. To understand non-covalent interactions, natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) have been used. IR and Raman spectra have been calculated to confirm the formation of complexes and also thermodynamic parameters have been investigated. It was demonstrated that in addition to van der Waals interactions, the presence of intermolecular hydrogen bonds enhances the stability of these complexes. Furthermore, MD simulations were carried out to get a better insight into the inclusion process of the above complexes. From MD simulations, all simulated systems reached full equilibration at 1000 ps and the V-agent molecules consistently remained in the ß-CD cavity and only had vibrational motion inside the cavity. More importantly, MD simulations support the findings of QM calculations and indicate that hydrogen bonding can help the leaving groups of V-agents to be released and them to be hydrolyzed. All results have shown that the VR agent formed the most stable complex with ß-CD molecule than that of other agents.Communicated by Ramaswamy H. Sarma.

RotNet: A Rotationally Invariant Graph Neural Network for Quantum Mechanical Calculations.

Deep learning has proven promising in biological and chemical applications, aiding in accurate predictions of properties such as atomic forces, energies, and material band gaps. Traditional methods with rotational invariance, one of the most crucial physical laws for predictions made by machine learning, have relied on Fourier transforms or specialized convolution filters, leading to complex model design and reduced accuracy and efficiency. However, models without rotational invariance exhibit poor generalization ability across datasets. Addressing this contradiction, this work proposes a rotationally invariant graph neural network, named RotNet, for accurate and accelerated quantum mechanical calculations that can overcome the generalization deficiency caused by rotations of molecules. RotNet ensures rotational invariance through an effective transformation and learns distance and angular information from atomic coordinates. Benchmark experiments on three datasets (protein fragments, electronic materials, and QM9) demonstrate that the proposed RotNet framework outperforms popular baselines and generalizes well to spatial data with varying rotations. The high accuracy, efficiency, and fast convergence of RotNet suggest that it has tremendous potential to significantly facilitate studies of protein dynamics simulation and materials engineering while maintaining physical plausibility.

Kinetic and structural details of urease inactivation by thiuram disulphides.

This paper reports on the molecular details of the reactivity of urease, a nickel-dependent enzyme that catalyses the last step of organic nitrogen mineralization, with thiuram disulphides, a class of molecules known to inactivate the enzyme with high efficacy but for which the mechanism of action had not been yet established. IC50 values of tetramethylthiuram disulphide (TMTD or Thiram) and tetraethylthiuram disulphide (TETD or Disulfiram) in the low micromolar range were determined for plant and bacterial ureases. The X-ray crystal structure of Sporosarcina pasteurii urease inactivated by Thiram, determined at 1.68 Å resolution, revealed the presence of a covalent modification of the catalytically essential cysteine residue. This is located on the flexible flap that modulates the size of the active site channel and cavity. Formation of a Cys-S-S-C(S)-N(CH3)2 functionality responsible for enzyme inactivation was observed. Quantum-mechanical calculations carried out to rationalise the large reactivity of the active site cysteine support the view that a conserved histidine residue, adjacent to the cysteine in the active site flap, modulates the charge and electron density along the thiol SH bond by shifting electrons towards the sulphur atom and rendering the thiol proton more reactive. We speculate that this proton could be transferred to the nickel-coordinated urea amide group to yield a molecule of ammonia from the generated Curea-NH3+ functionality during catalysis.

Induction of New Aromatic Polyketides from the Marine Actinobacterium Streptomyces griseorubiginosus through an OSMAC Approach.

Using the OSMAC (One Strain Many Compounds) approach, the actinobacterium Streptomyces griseorubiginosus, derived from an unidentified cnidarian collected from a reef near Pointe de Bellevue in Réunion Island (France), was subjected to cultivation under diverse conditions. This endeavour yielded the isolation of a repertoire of 23 secondary metabolites (1-23), wherein five compounds were unprecedented as natural products (19-23). Specifically, compounds 19 and 20 showcased novel anthrone backbones, while compound 23 displayed a distinctive tetralone structure. Additionally, compounds 21 and 22 presented an unusual naphtho [2,3-c]furan-4(9H)-one chromophore. Interestingly, the detection of all these novel compounds (19-23) was exclusively achieved when the bacterium was cultured in FA-1 liquid medium supplemented with the epigenetic modifier γ-butyrolactone. The elucidation of the structural features of the newfound compounds was accomplished through a combination of HRESIMS, 1D and 2D NMR spectroscopy, as well as QM-NMR (Quantum Mechanical-Nuclear Magnetic Resonance) methods and by comparison with existing literature. Moreover, the determination of the relative configuration of compound 23 was facilitated by employing the mix-J-DP4 computational approach.

Identification of hydrogen bonding network for proton transfer at the quinol oxidation site of Rhodobacter capsulatus cytochrome bc1.

Cytochrome bc1 catalyzes electron transfer from quinol (QH2) to cytochrome c in reactions coupled to proton translocation across the energy-conserving membrane. Energetic efficiency of the catalytic cycle is secured by a two-electron and two-proton bifurcation reaction leading to oxidation of QH2 and reduction of the Rieske cluster and heme bL. The proton paths associated with this reaction remain elusive. Here, we used site-directed mutagenesis and quantum mechanical calculations to analyze the contribution of protonable side chains located at the heme bL side of the QH2 oxidation site in Rhodobacter capsulatus cytochrome bc1. We observe that the proton path is effectively switched off when H276 and E295 are simultaneously mutated to the nonprotonable residues in the H276F/E295V double mutant. The two single mutants, H276F or E295V, are less efficient but still transfer protons at functionally relevant rates. Natural selection exposed two single mutations, N279S and M154T, that restored the functional proton transfers in H276F/E295V. Quantum mechanical calculations indicated that H276F/E295V traps the side chain of Y147 in a position distant from QH2, whereas either N279S or M154T induce local changes releasing Y147 from that position. This shortens the distance between the protonable groups of Y147 and D278 and/or increases mobility of the Y147 side chain, which makes Y147 efficient in transferring protons from QH2 toward D278 in H276F/E295V. Overall, our study identified an extended hydrogen bonding network, build up by E295, H276, D278, and Y147, involved in efficient proton removal from QH2 at the heme bL side of QH2 oxidation site.

Simulation and Synthesis of Cobalt (Co) Nanoparticles by Gamma Radiation Technique.

Cobalt nanoparticles were synthesized using the gamma radiolytic technique, and the particle size was found to be reduced from 12±1 to 7±1 nm by increasing the dose from 10 to 60 kGy. The UV-visible absorption spectra were measured and exhibited a steady absorption maxima at 517 nm in the UV region, which blue-shifted toward a lower wavelength with a decrease in particle size. By taking the conduction electrons of an isolated particle that are not entirely free but are instead bound to their respective quantum levels, the optical absorption of the cobalt nanoparticles can be calculated and simulated via intra-band quantum excitation for particle sizes comparable to the measured ones. We found that the simulated absorption maxima of electronic excitations corresponded to the measured absorption maxima. Moreover, the structural characterizations were performed utilizing dynamic light scattering (DLS), transmission electron microscopy (TEM), and X-ray diffraction (XRD).

A Competition between Relative Stability and Binding Energy in Caffeine Phenyl-Glucose Aggregates: Implications in Biological Mechanisms.

Hydrogen bonds and stacking interactions are pivotal in biological mechanisms, although their proper characterisation within a molecular complex remains a difficult task. We used quantum mechanical calculations to characterise the complex between caffeine and phenyl-ß-D-glucopyranoside, in which several functional groups of the sugar derivative compete with each other to attract caffeine. Calculations at different levels of theory (M06-2X/6-311++G(d,p) and B3LYP-ED=GD3BJ/def2TZVP) agree to predict several structures similar in stability (relative energy) but with different affinity (binding energy). These computational results were experimentally verified by laser infrared spectroscopy, through which the caffeine·phenyl-ß-D-glucopyranoside complex was identified in an isolated environment, produced under supersonic expansion conditions. The experimental observations correlate with the computational results. Caffeine shows intermolecular interaction preferences that combine both hydrogen bonding and stacking interactions. This dual behaviour had already been observed with phenol, and now with phenyl-ß-D-glucopyranoside, it is confirmed and maximised. In fact, the size of the complex's counterparts affects the maximisation of the intermolecular bond strength because of the conformational adaptability given by the stacking interaction. Comparison with the binding of caffeine within the orthosteric site of the A2A adenosine receptor shows that the more strongly bound caffeine·phenyl-ß-D-glucopyranoside conformer mimics the interactions occurring within the receptor.

Computational Methods for Molecular Understanding of the Antibiotic-Aminoacyl tRNA Synthetase Interaction.

Developing an understanding of the interactions between an antibiotic and its binding site in a pathogen cell is the key to antibiotic design-an important cost-saving methodology compared to the costly and time-consuming random trial-and-error approach. The rapid development of antibiotic resistance provides an impetus for such studies. Recent years have witnessed the beginning of the use of combined computational techniques, including computer simulations and quantum mechanical computations, to understand how antibiotics bind at the active site of aminoacyl tRNA synthetases (aaRSs) from pathogens. Such computational protocols assist the knowledge-based design of antibiotics targeting aaRSs, which are their validated targets. After the ideas behind the protocols and their strategic planning are discussed, the protocols are described along with their major outcomes. This is followed by an integration of results from the different basic protocols. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Analysis of active-site residues from primary sequence of synthetase and transfer RNAs Basic Protocol 2: Molecular dynamics simulation-based protocol to study the structure and dynamics of the aaRS active site:antibiotic complex Basic Protocol 3: Quantum mechanical method-based protocol to study the structure and dynamics of the aaRS active site:antibiotic complex.

Tuning the Photophysics of Two-Arm Bis[(dimethylamino)styryl]benzene Derivatives by Heterocyclic Substitution.

The identification of novel molecular systems with high fluorescence and significant non-linear optical (NLO) properties is a hot topic in the continuous search for new emissive probes. Here, the photobehavior of three two-arm bis[(dimethylamino)styryl]benzene derivatives, where the central benzene was replaced by pyridine, furan, or thiophene, was studied by stationary and time-resolved spectroscopic techniques with ns and fs resolution. The three molecules under investigation all showed positive fluorosolvatochromism, due to intramolecular charge-transfer (ICT) dynamics from the electron-donor dimethylamino groups, and significant fluorescence quantum yields, because of the population of a planar and emissive ICT state stabilized by intramolecular hydrogen-bond-like interactions. The NLO properties (hyperpolarizability coefficient and TPA cross-section) were also measured. The obtained results allowed the role of the central heteroaromatic ring to be disclosed. In particular, the introduction of the thiophene ring guarantees high fluorescent quantum yields irrespective of the polarity of the medium, and the largest hyperpolarizability coefficient because of the increased conjugation. An important and structure-dependent involvement of the triplet state was also highlighted, with the intersystem crossing being competitive with fluorescence, especially in the thiophene derivative, where the triplet was found to significantly sensitize molecular oxygen even in polar environment, leading to possible applications in photodynamic therapy.

May the Force (Field) Be with You: On the Importance of Conformational Searches in the Prediction of NMR Chemical Shifts.

NMR data prediction is increasingly important in structure elucidation. The impact of force field selection was assessed, along with geometry and energy cutoffs. Based on the conclusions, we propose a new approach named mix-J-DP4, which provides a remarkable increase in the confidence level of complex stereochemical assignments-100% in our molecular test set-with a very modest increment in computational cost.

L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human ß2-Adrenergic Receptor.

The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to ß2-adrenergic receptor (ß2AR) inactive and active states has led us to investigate protein-ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human ß2AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible ß2AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into ß2AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 µs MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF.

Structural aspects of formetanate hydrochloride binding with human serum albumin using spectroscopic and molecular modeling techniques.

Formetanate Hydrochloride (FMT), a highly potent chemical, acts as an insecticide, acaricide, and miticide to protect various fruits and vegetables. The widespread use elevates concern about its presence in the ecosystem, impact upon human health via interaction with biological receptors. Spectroscopic and molecular modeling techniques at different temperatures were used to investigate the binding of FMT with Human serum albumin (HSA) at the molecular level. The experimental and computational results have provided the binding affinity, binding mode, conformational flexibility, and thermodynamic profile of FMT-HSA complex. The FMT binding appears to be spontaneous, and entropy driven. Overall binding affinity of FMT falls within -7.29 to -4.67 Kcal M-1. FMT binds in domain I, subdomain IA of HSA and is stabilized by hydrophobic interactions. Molecular dynamics simulations of the FMT-HSA complex over 100 ns at 288 K, 298 K and 308 K indicated that FMT showed minor adjustments in conformation and placement within the binding site. While, MM/PBSA analysis of the complex provided individual contributions of energy terms. Quantum mechanical (QM) calculations were used to calculate absolute energy values of different poses of FMT which in turn showed minor variations in energy suggesting slight conformational variation in the bound form. The computational results are in agreement with experimental findings.

Molecular networking-based discovery of anti-inflammatory chromene dimers from Melicope pteleifolia.

With the aid of a feature-based molecular networking strategy, five undescribed C2 and C1 symmetric chromene dimers, namely, melptelchromenes A-E, were isolated from the leaves of Melicope pteleifolia. Four asymmetric dimers were found to be racemates and were resolved by chiral phase HPLC analyses. Their structures, including absolute configurations, were elucidated by HRMS, NMR spectroscopy, and quantum mechanical calculations of ECD spectra and NMR chemical shifts. Melptelchromenes A-D possess a unique ethylidene linkage via two 2H-chromene cores, while melptelchromene E represents the first example of a dimeric chromene featuring a 1,3-diarylbutan-1-ol moiety. Of these compounds, 6,6'-linked dimeric chromenes showed nitric oxide inhibitory activities on lipopolysaccharide-induced RAW 264 cells, and (-)- and (+)-melptelchromene E were the two most potent compounds (IC50, 3.0 and 5.1 µM, respectively).