A Theoretical Evaluation of the pK(HB) and Delta H-HB(circle minus) Hydrogen-Bond Scales of Nitrogen Bases

The experimental pK(HB) hydrogen-bond (HB) basicity scale and the corresponding Delta H-HB(circle minus) enthalpic scale of nitrogen compounds are extended and analysed in light of simple theoretical descriptors using the B3LYP density functional method and it medium-size basis set (6-31+G(d,p)). The selected training set includes 59 monofunctional unhindered nitrogen bases for which homogeneous and accurate experimental pK(HB) and Delta H-HB(circle minus) data have been determined by means of the association equilibrium of the bases with a reference hydrogen-bond acid, 4-fluorophenol, in CCl4. The three hybridisation states encountered in the nitrogen atom, sp, sp(2) and sp(3), are equally represented in this data set. A proper estimation of their experimental enthalpy (Delta H-HB(circle minus)) is directly attainable from the theoretical enthalpy of the complexation reaction with hydrogen fluoride (Delta H-circle minus(HF)). However, a second parameter is required to calculate with good accuracy the experimental free energy of association represented by pK(HB). About 99% of the variance of the pK(HB) scale is described by a bilinear equation using the minimum electrostatic potential (V-s.min) of the monomer in addition to the interaction energy (D-0((HF))). The equations are tested for an external set of 99 additional compounds including very different nitrogen bases such as ortho-substituted pyridines, polyazines and azoles. Theoretical calculations give a reliable estimation of hydrogen-bond basicity provided that the populations of the different isomers of the bases are taken into account by using the Boltzmann law, and that a specific halogen-bond interaction with the solvent CCl4 is considered for polybasic molecules. The pK(HB) scale can thus be extended to important classes of species experimentally inaccessible in CCl4, to polynitrogen compounds and to molecules of biological significance

An Overview of Lewis Basicity and Affinity Scales

The impossibility of establishing a universal scale of Lewis basicity does not prevent the determination of the quantitative behavior of Lewis bases, thanks to scales constructed against particular Lewis acids: BF(3), 4-FC(6)H(4)OH, I(2), Li(+), Na(+), K(+), Al(+), Mn(+), CpNi(+), and CH(3)NH(3)(+). These scales encompass important types of bonds formed in a Lewis acid-base adduct: the dative bond, the conventional and ionic hydrogen bonds, the halogen bond and cation-molecule bonds for metal cations of groups 1, 7, 10, 11, and 13. Moreover, although these scales are generally not interrelated, there exist family-dependent relationships that permit ranking, in a rather general order, of bases belonging to a given chemical family, for example, the family of oxygen bases. Therefore, the skepticism about the quantitative usefulness of the Lewis concept of acids and bases is no longer founded

Structure et interactions moléculaires d agonistes et de modulateurs allostériques des récepteurs nicotiniques de l acétylcholine

La découverte de l acétylcholine binding protein (AChBP) a permis des avancées majeures dans la caractérisation des récepteurs nicotiniques de l acétylcholine (nAChRs). Dans le cadre de ce travail, une approche combinant la mise en oeuvre de méthodes expérimentales et de calculs quantiques issus de la théorie de la fonctionnelle de la densité (DFT) a été utilisée pour (i) déterminer les conformations de basse énergie et les interactions d une série de ligands des nAChRs (l ACh, la nicotine, l épibatidine, la galanthamine et la codéine) (ii) mettre à jour un motif structural de l AChBP jouant un rôle majeur dans l interaction avec les agonistes (iii) étudier la complexation de trois ligands avec un modèle tridimensionnel du site de fixation par une méthode mixte QM/QM . Ainsi, malgré l importante similitude structurale de la galanthamine et de la codéine, la confrontation des résultats obtenus au cours de ce travail révèle des différences d interactions par liaison H significatives entre les deux composés. Par ailleurs, le motif structural mis à jour, qui comprend le Trp 143, impliqué dans la fixation des agonistes, et l Asp 85, hautement conservé dans la famille des canaux ioniques, a été caractérisé de façon approfondie, l influence d un effet coopératif sur le réseau de liaison H formé étant démontrée. Enfin, l ordre énergétique d interaction ACh<Nicotine<Epibatidine rapporté dans la littérature a été reproduit par nos simulations, validées par le bon accord des résultats obtenus avec les données expérimentales disponibles. Cette séquence d affinité a été rationalisée par une analyse fine de paramètres géométriques clés des interactions agonistes-AChBP.The discovery of the Acetylcholine Binding Protein (AChBP) has allowed major breakthroughs in the characterization of nicotinic acetylcholine receptors (nAChRs). In this work, a combined approach based on the use of various experimental methods and of theoretical calculations from density functional theory (DFT) has allowed to (i) determine the conformations and interactions of five nAChRs ligands (ACh, nicotine, epibatidine, galanthamine and codeine) in various environments (ii) shed light on a structural motif of AChBP playing a key role in the agonist binding (iii) study the complexation of ACh, nicotine and epibatidine with a three dimensional model of the AChBP binding site through a mixed QM/QM approach. Thus, despite the important similarities of galanthamine and codeine, the confrontation of the results obtained from the various approaches used in this work reveals significant differences of hydrogen-bond interactions of the two compounds. Furthermore, the structural motif we have found, which includes the Trp 143, involved in the agonists binding, and the Asp 85, highly conserved in the ion channels family, has been deeply characterized, the influence of a cooperative effect on the H-bond network formed being demonstrated. Finally, the energetic ranking of interaction of the three ligands ACh<Nicotine<Epibatidine reported in the literature has been reproduced by our simulations, the results obtained being validated by their good agreement with the experimental data available. This affinity sequence has been rationalized by a comprehensive analysis of key geometric parameters of agonists-AChBP interactions.NANTES-BU Sciences (441092104) / SudocSudocFranceF

Can Quantum-Mechanical Calculations Yield Reasonable Estimates of Hydrogen-Bonding Acceptor Strength? The Case of Hydrogen-Bonded Complexes of Methanol

International audienceThe thermodynamics and some vibrational properties of hydrogen-bonded complexes of methanol with 23 hydrogen-bond acceptors (HBAs) have been determined in CCl4 by FTIR spectrometry. The experimental sample contains carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine organic bases and covers an energetic range of 13 kJ mol?1 in the basicity scale (??G), 22 kJ mol?1 in the affinity scale (??H), and 400 cm?1 in the spectroscopic scale (??(OH)) (from benzene to trimethylphosphane oxide and amines). The experimental results in CCl4 are compared to those computed in the gas phase at various levels of theory. Ninety five percent of the variance of the red shift and 89% of the variance of the intensification of the OH stretching upon hydrogen bonding are explained by gas-phase B3LYP/6-31+G(d,p) calculations. However, this level does not satisfactorily explain the thermodynamic properties. Only 68% of the variance of the methanol affinity (??H) is taken into account. MP2/aug-cc-pVTZ//B3LYP/6-31+G(d,p) affinity calculations raise the explanation to 77% for all HBAs and to 93% when three outliers (Me2SO, Me3PO, and tetrahydrothiophene) are excluded. Discrepancies are analyzed in terms of experimental errors, calculation approximations, and solvation

Insights into a highly conserved network of hydrogen bonds in the agonist binding site of nicotinic acetylcholine receptors: A structural and theoretical study

Structural and theoretical studies on the geometrical features of a hydrogen-bond network occurring in the binding site of nicotinic acetylcholine receptors (nAChRs) and composed of interconnected WxPD (Trp-x-Pro-Asp) and SWyz (Ser-Trp-yz) sequences from loops A and B, respectively, have been carried out. Multiple sequence alignments using as template the sequence of the apoform of Aplysia californica acetylcholine binding protein (Ac-AChBP) show the strict conservation of serine and tryptophan residues of the loop B SWyz sequence. Considering a sample of 19 high resolution AChBP structures, the strong conformational preferences of the key tryptophan residue has been pointing out, whatever the form, free or bounded, of AChBP. The geometry of the motif hydrogen-bond network has been characterized through the analyses of seven distances. The robustness of the various hydrogen-bond interactions is pointed out, the one involving the aspartate carboxylate group and the serine residue being the shortest of the network. The role of a cooperative effect involving a NH(His145)center dot center dot center dot OH (Ser142) hydrogen bond is highlighted. Density functional theory calculations on several simplified models based on the motif hydrogen-bond network allow probing the importance of the various hydrogen-bond interactions. The removal of the Ser142 hydroxyl group induces strong structural rearrangements, in agreement with the structural observations. Molecular electrostatic potential calculations on model systems highlight the importance of a cooperative effect in the whole hydrogen-bond network. More precisely, the key role of the Ser142 hydroxyl group, involved in several hydrogen bonds, is underlined. (C) 2014 Wiley Periodicals, Inc

New insights on the structural and molecular recognition properties of insecticides through computational chemistry: The challenging case of sulfoxaflor

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