New insights on the molecular recognition of imidacloprid with Aplysia californica AChBP: a computational study

The binding of imidacloprid (IMI), the forerunner of neonicotinoid insecticides, with the acetylcholine binding protein (AChBP) from Aplysia californica, the established model for the extracellular domain of insects nicotinic acetylcholine receptors, has been studied with a two-layer ONIOM partition approach (M06-2X/6-311G(d):PM6). Our calculations allow delineating the contributions of the key residues of AChBP for IMI binding. In particular, the importance of Trp147 and Cys190-191, through weak CH...pi interactions and both van der Waals and hydrogen-bond (H-bond) interactions, respectively, are highlighted. Furthermore, H-bonds between hydroxyl groups of both Ser189 and Tyr55 and the IMI nitro group are pointed out. The participation of Ile118, whose main chain NH and carbonyl group are hydrogen-bonded with the IMI pyridinic nitrogen through a water molecule, is characterized. Our simulations also indicate the presence of a significant contribution of this residue through van der Waals interactions. The various trends obtained by the calculations of the pairwise interaction energies are confirmed through a complementary noncovalent interaction (NCI) analysis of selected IMI-AChBP amino acid pairs. Indeed, the contribution of a halogen-bond interaction between IMI and AChBP, recently proposed in the literature, is corroborated by our NCI analysis

Similar Comparative Low and High Doses of Deltamethrin and Acetamiprid Differently Impair the Retrieval of the Proboscis Extension Reflex in the Forager Honey Bee (Apis mellifera)

In the present study, the effects of low (10 ng/bee) and high (100 ng/bee) doses of acetamiprid and deltamethrin insecticides on multi-trial learning and retrieval were evaluated in the honey bee Apis mellifera. After oral application, acetamiprid and deltamethrin at the concentrations used were not able to impair learning sessions. When the retention tests were performed 1 h, 6 h, and 24 h after learning, we found a significant difference between bees after learning sessions when drugs were applied 24 h before learning. Deltamethrin-treated bees were found to be more sensitive at 10 ng/bee and 100 ng/bee doses compared to acetamiprid-treated bees, only with amounts of 100 ng/bee and at 6 h and 24 h delays. When insecticides were applied during learning sessions, none of the tested insecticides was able to impair learning performance at 10 ng/bee or 100 ng/bee but retention performance was altered 24 h after learning sessions. Acetamiprid was the only one to impair retrieval at 10 ng/bee, whereas at 100 ng/bee an impairment of retrieval was found with both insecticides. The present results therefore suggest that acetamiprid and deltamethrin are able to impair retrieval performance in the honey bee Apis mellifera

Imidacloprid and thiacloprid neonicotinoids bind more favourably to cockroach than to honeybee alpha6 nicotinic acetylcholine receptor: insights from computational studies

The binding interactions of two neonicotinoids, imidacloprid (IMI) and thiacloprid (THI) with the extracellular domains of cockroach and honeybee alpha6 nicotinic acetylcholine receptor (nAChR) subunits in an homomeric receptor have been studied through docking and molecular dynamics (MD) simulations. The binding mode predicted for the two neonicotinoids is validated through the good agreement observed between the theoretical results with the crystal structures of the corresponding complexes with Ac-AChBP, the recognized structural surrogate for insects nAChR extracellular ligand binding domain. The binding site of the two insect alpha6 receptors differs by only one residue of loop D, a serine residue (Ser83) in cockroach being replaced by a lysine residue (Lys108) in honeybee. The docking results show very close interactions for the two neonicotinoids with both alpha6 nAChR models, in correspondence to the trends observed in the experimental neonicotinoid-Ac-AChBP complexes. However, the docking parameters (scores and energies) are not significantly different between the two insect alpha6 nAChRs to draw clear conclusions. The MD results bring distinct trends. The analysis of the average interaction energies in the two insects alpha6 nAChRs shows indeed better affinity of neonicotinoids bound to alpha6 cockroach compared to honeybee nAChR. This preference is explained by tighter contacts with aromatic residues (Trp and Tyr) of the binding pocket. Interestingly, the non-conserved residue Lys108 of loop D of alpha6 honeybee nAChR interacts through van der Waals contacts with neonicotinoids, which appear more favourable than the direct or water mediated hydrogen-bond interaction between the OH group of Ser83 of alpha6 cockroach nAChR and the electronegative terminal group of the two neonicotinoids (nitro in IMI and cyano in THI). Finally, in both insects nAChRs, THI is consistently found to bind more favourably than IMI

Interpretation of experimental hydrogen-bond enthalpies and entropies from COSMO polarisation charge densities

In this work, experimental hydrogen-bond (HB) enthalpies measured in previous works for a wide range of acceptor molecules in dilute mixtures of 4-fluorophenol in non-polar solvents are quantified from COSMO polarisation charge densities σ of HB acceptors (HBA). As well as previously demonstrated for quantum chemically calculated HB enthalpies, a good correlation of the experimental data with the polarisation charge densities is observed, covering an extended range of HBA (O, N, S, π systems and halogens) ranging from very weak to strong hydrogen bonds. Furthermore, for the first time, a quantitative analysis of experimental HB entropies is performed for such a chemical diversity of HBA. A good quantification of these entropies is achieved using the polarisation charge density σ as a descriptor in combination with the logarithm of a directional partition function ΩHB. This partition function covers the directional and multiplicity entropy of HBA and is based on the σ-proportional HB enthalpy expression taken from COSMO-RS. As a result, the experimental HB enthalpies and free energies of the ∼300 HB complexes are quantified with an accuracy of ∼2 kJ mol−1 based on COSMO polarisation charge densities

Pretreatment of the cockroach cercal afferent/giant interneuron synapses with nicotinoids and neonicotinoids differently affects acetylcholine and nicotine-induced ganglionic depolarizations

We have recently demonstrated that neonicotinoid insecticides were able to act as agonists of postsynaptic nicotinic acetylcholine receptors (nAChRs) expressed at the synapse between the cercal nerve XI and the giant interneurons, in the sixth abdominal ganglion. In this work, we demonstrated that nicotinoids such as nornicotine acted as an agonist of nicotinic acetylcholine receptors expressed at cercal afferent/giant interneurons while cotinine was a poor agonist. Indeed, nornicotine induced a ganglionic depolarization which was blocked by the nicotinic antagonist mecamylamine. In addition, we found that pretreatment of the sixth abdominal ganglion with 1 and 10 muM nornicotine and cotinine had no significant effect on acetylcholine and nicotine-induced depolarization. But pretreatment with 1 and 10 muM acetamiprid and imidacloprid had a strong effect. 1 and 10 muM acetamiprid completely blocked acetylcholine-induced depolarization, whereas imidacloprid had a partial effect. The present work therefore suggests, in agreement with previous studies, that nornicotine and cotinine bind to distinct cockroach postsynaptic nAChRs, whereas acetamiprid and imidacloprid have competitive effects with acetylcholine and nicotine on ganglionic depolarization

New insights on the molecular features and electrophysiological properties of dinotefuran, imidacloprid and acetamiprid neonicotinoid insecticides

Structural features and hydrogen-bond interactions of dinotefuran (DIN), imidacoloprid (IMI) and acetamiprid (ACE) have been investigated experimentally through analyses of new crystal structures and observations in structural databases, as well as by Density Functional Theory quantum chemical calculations. Several conformations are observed experimentally in the solid state, highlighting the large flexibility of these compounds. This feature is confirmed by the theoretical calculations in the gas phase, the numerous and different energetic minima of the three neonicotinoids being located within a 10kJ/mol range. Comparisons of the observed and simulated data sheds light on the hydrogen-bond (HB) strength of the functional group at the tip of the electronegative fragment of each pharmacophore (NO(2) for DIN and IMI and CN for ACE). This effect originates in the \u27push-pull\u27 nature of these fragments and the related extensive electron delocalization. Molecular electrostatic potential calculations provide a ranking of the two fragments of the three neonicotinoid in terms of HB strength. Thus, the NO(2) group of DIN is the strongest HB acceptor of the electronegative fragment, closely followed by the cyano group of ACE. These two groups are significantly more potent than the NO(2) group of IMI. With respect to the other fragments of the three neonicotinoids, the nitrogen atom of the pyridine of IMI and ACE are stronger HB acceptors than the oxygen atom of the furanyl moiety of DIN. Finally, compared to electrophysiological studies obtained from cockroach synaptic and extrasynaptic receptors, DIN appears more effective than IMI and ACE because it strongly increases dose-dependently the ganglionic depolarisation and the currents amplitudes. These data suggest that DIN, IMI and ACE belong to two subgroups which act differently as agonists of insect nicotinic receptors

Predictive Models for Halogen-bond Basicity of Binding Sites of Polyfunctional Molecules

© 2016 Wiley-VCH Verlag GmbH & Co. KGaA.Halogen bonding (XB) strength assesses the ability of an electron-enriched group to be involved in complexes with polarizable electrophilic halogenated or diatomic halogen molecules. Here, we report QSPR models of XB of particular relevance for an efficient screening of large sets of compounds. The basicity is described by pKBI2, the decimal logarithm of the experimental 1 : 1 (B :I2) complexation constant K of organic compounds (B) with diiodine (I2) as a reference halogen-bond donor in alkanes at 298K. Modeling involved ISIDA fragment descriptors, using SVM and MLR methods on a set of 598 organic compounds. Developed models were then challenged to make predictions for an external test set of 11 polyfunctional compounds for which unambiguous assignment of the measured effective complexation constant to specific groups out of the putative acceptor sites is not granted. At this stage, developed models were used to predict pKBI2 of all putative acceptor sites, followed by an estimation of the predicted effective complexation constant using the ChemEqui program. The best consensus models perform well both in cross-validation (root mean squared error RMSE=0.39-0.47logKBI2 units) and external predictions (RMSE=0.49). The SVM models are implemented on our website (http://infochim.u-strasbg.fr/webserv/VSEngine.html) together with the estimation of their applicability domain and an automatic detection of potential halogen-bond acceptor atoms

Microstructural evolution and trace element mobility in Witwatersrand pyrite

Microstructural analysis of pyrite from a single sample of Witwatersrand conglomerate indicates a complex deformation history involving components of both plastic and brittle deformation. Internal deformation associated with dislocation creep is heterogeneously developed within grains, shows no systematic relationship to bulk rock strain or the location of grain boundaries and is interpreted to represent an episode of pyrite deformation that predates the incorporation of detrital pyrite grains into the Central Rand conglomerates. In contrast, brittle deformation, manifest by grain fragmentation that transects dislocation-related microstructures, is spatially related to grain contacts and is interpreted to represent post-depositional deformation of the Central Rand conglomerates. Analysis of the low-angle boundaries associated with the early dislocation creep phase of deformation indicates the operation of {100} slip systems. However, some orientation boundaries have geometrical characteristics that are not consistent with simple {100} deformation.These boundaries may represent the combination of multiple slip systems or the operation of the previously unrecognized {120} slip system. These boundaries are associated with order of magnitude enrichments in As, Ni and Co that indicate a deformation control on the remobilization of trace elements within pyrite and a potential slip system control on the effectiveness of fast-diffusion pathways. The results confirm the importance of grain-scale elemental remobilization within pyrite prior to their incorporation into the Witwatersrand gold-bearing conglomerates. Since the relationship between gold and pyrite is intimately related to the trace element geochemistry of pyrite, the results have implications for the application of minor element geochemistry to ore deposit formation, suggest a reason for heterogeneous conductivity and localized gold precipitation in natural pyrite and provide a framework for improving mineral processing