Joint density-functional theory for electronic structure of solvated systems

We introduce a new form of density functional theory for the {\em ab initio} description of electronic systems in contact with a molecular liquid environment. This theory rigorously joins an electron density-functional for the electrons of a solute with a classical density-functional theory for the liquid into a single variational principle for the free energy of the combined system. A simple approximate functional predicts, without any fitting of parameters to solvation data, solvation energies as well as state-of-the-art quantum-chemical cavity approaches, which require such fitting.Comment: Fixed typos and minor updates to tex

Molecular dynamics simulations of elementary chemical processes in liquid water using combined density functional and molecular mechanics potentials. II. Charge separation processes

A new approach to carry out molecular dynamics simulations of chemical reactions in solution using combined density functional theory/molecular mechanics potentials is presented. We focus our attention on the analysis of reactive trajectories, dynamic solvent effects and transmission coefficient rather than on the evaluation of free energy which is another important topic that will be examined elsewhere. In a previous paper we have described the generalities of this hybrid molecular dynamics method and it has been employed to investigate low energy barrier proton transfer process in water. The study of processes with activation energies larger than a few kT requires the use of specific techniques adapted to “rare events” simulations. We describe here a method that consists in the simulation of short trajectories starting from an equilibrated transition state in solution, the structure of which has been approximately established. This calculation is particularly efficient when carried out with parallel computers since the study of a reactive process is decomposed in a set of short time trajectories that are completely independent. The procedure is close to that used by other authors in the context of classical molecular dynamics but present the advantage of describing the chemical system with rigorous quantum mechanical calculations. It is illustrated through the study of the first reaction step in electrophilic bromination of ethylene in water. This elementary process is representative of many charge separation reactions for which static and dynamic solvent effects play a fundamental [email protected]

Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor

G protein–coupled receptors (GPCRs) signal through a limited number of G-protein pathways and play crucial roles in many biological processes. Studies of their in vivo functions have been hampered by the molecular and functional diversity of GPCRs and the paucity of ligands with specific signaling effects. To better compare the effects of activating different G-protein signaling pathways through ligand-induced or constitutive signaling, we developed a new series of RASSLs (receptors activated solely by synthetic ligands) that activate different G-protein signaling pathways. These RASSLs are based on the human 5-HT4b receptor, a GPCR with high constitutive Gs signaling and strong ligand-induced G-protein activation of the Gs and Gs/q pathways. The first receptor in this series, 5-HT4-D100A or Rs1 (RASSL serotonin 1), is not activated by its endogenous agonist, serotonin, but is selectively activated by the small synthetic molecules GR113808, GR125487, and RO110-0235. All agonists potently induced Gs signaling, but only a few (e.g., zacopride) also induced signaling via the Gq pathway. Zacopride-induced Gq signaling was enhanced by replacing the C-terminus of Rs1 with the C-terminus of the human 5-HT2C receptor. Additional point mutations (D66A and D66N) blocked constitutive Gs signaling and lowered ligand-induced Gq signaling. Replacing the third intracellular loop of Rs1 with that of human 5-HT1A conferred ligand-mediated Gi signaling. This Gi-coupled RASSL, Rs1.3, exhibited no measurable signaling to the Gs or Gq pathway. These findings show that the signaling repertoire of Rs1 can be expanded and controlled by receptor engineering and drug selection

Modélisation des systèmes complexes. Effets de solvant sur les modes de vibration d'un soluté au sein d'une solution

Le modèle du milieu continu polarisable, dans le formalisme du champ de réaction self consistant, est étendu pour permettre le calcul des vibrations moléculaires au sein d'un liquide au moyen des méthodes de la chimie quantique. Appliqué aux vibrations νC=O d'une série de composés carbonylés en solution dans le cyclohexane et dans l'acétonitrile, le modèle se révèle tout-à-fait apte à permettre le calcul des fréquences de vibrations d'un soluté. L'origine moléculaire de l'effet de solvant est discutée

Influence de la présence d'un ménisque dans la détermination des propriétés diélectriques par la méthode de Hippel en ligne coaxiale

The meniscus shaped surface of a coaxial sample is treated as a perturbation of a plane surface. It is shown that when the losses are high (tan δ > 0.4), the method of von Hippel, used with the assumption of an average plane of incidence, is very uncertain. In the case of medium or low losses, the sample lengths which lead to the best accuracy, are determined. They are not the same as those which are deduced from the influence of the sample length on the accuracy of the method. In the usual conditions (ε'/ε0 0,4) la méthode de von Hippel appliquée à un plan d'entrée moyen est très aléatoire. Pour des pertes moyennes et faibles, les longueurs qui réalisent les meilleures conditions de mesure sont déterminées. Elles ne correspondent toutefois pas à celles qui sont déduites de l'étude de l'influence de l'épaisseur sur la précision de la méthode. Dans les conditions usuelles : ε'/ε0 < 10, tg 8 < 0,1, l'effet du ménisque peut être négligé jusqu'aux fréquences de l'ordre de 2 000 MHz et introduit une incertitude inférieure à 2 % sur ε'' à 4 000 MHz