Modulation of the Gloeobacter violaceus Ion Channel by Fentanyl: A Molecular Dynamics Study.

Fentanyl is an opioid analgesic, which is routinely used in general surgery to suppress the sensation of pain and as the analgesic component in the induction and maintenance of anesthesia. Fentanyl is also used as the main component to induce anesthesia and as a potentiator to the general anesthetic propofol. The mechanism by which fentanyl induces its anesthetic action is still unclear, and we have therefore employed fully atomistic molecular dynamics simulations to probe this process by simulating the interactions of fentanyl with the Gloeobacter violaceus ligand-gated ion channel (GLIC). In this paper, we identify multiple extracellular fentanyl binding sites, which are different from the transmembrane general anesthetic binding sites observed for propofol and other general anesthetics. Our simulations identify a novel fentanyl binding site within the GLIC that results in conformational changes that inhibit conduction through the channel.

Using density functional theory to interpret the infrared spectra of flexible cyclic phosphazenes.

The cyclic phosphazene trimer P(3)N(3)(OCH(2)CF(3))(6)and the related cyclic tetramer P(4)N(4)(OCH(2)CF(3))(8) have been synthesized, isolated and their vapor-phase absorption spectra recorded at moderate resolution using an FTIR spectrometer. The interpretation of these spectra is achieved primarily by comparison with the results of high-precision density functional calculations, which enable the principal absorption features to be assigned and conclusions to be drawn regarding the geometries and conformations adopted by both molecules. These in turn allow interesting comparisons to be made with analogous cyclic halo-phosphazenes (such as P(3)N(3)Cl(6)) and other related ring compounds. The highly flexible nature of the two cyclic phosphazenes precludes a complete theoretical study of their potential energy hypersurfaces and a novel alternative approach involving the analysis of a carefully selected subset of the possible molecular conformations has been shown to produce satisfactory results. The two cyclic phosphazene oligomers have been proposed as the major low-to-medium temperature pyrolysis products of the parent polyphosphazene (PN(OCH(2)CF(3))(2))(n), and the identification of vibrational absorption features characteristic of each molecule will enable future studies to test the validity of this proposition.

Atomistic Molecular Dynamics Simulations of Propofol and Fentanyl in Phosphatidylcholine Lipid Bilayers.

Atomistic molecular dynamics (MD) and steered MD simulations in combination with umbrella sampling methodology were utilized to study the general anesthetic propofol and the opioid analgesic fentanyl and their interaction with lipid bilayers, which is not yet fully understood. These molecules were inserted into two different fully hydrated phospholipid bilayers, namely, dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC), to investigate the effects that these drugs have on the bilayer. We determined the role of the lipid chain length and saturation on the behavior of the two drugs. Pure, fully hydrated DOPC and DPPC bilayers were also simulated, and the results were in excellent agreement with the experimental values. Various structural and mechanical properties of each system, such as the area per lipid, area compressibility modulus, order parameter, lateral lipid diffusion, hydrogen bonds, and radial distribution functions, have been calculated to assess how the drug molecules affect the different bilayers. From the calculated results, we show that fentanyl and propofol generally follow similar trends in each bilayer but adopt different favorable positions close to the headgroup/chain interface at the carbonyl groups. Propofol was shown to selectively form hydrogen bonds at the carbonyl carbon in each bilayer, whereas fentanyl interacts with water molecules at the headgroup interface. From the calculated free-energy profiles, we determined that both molecules show a preference for the low-density, low-order acyl chain region of the bilayers and both significantly preferred the DOPC bilayer with propofol and fentanyl having energy minima at -6.66 and -43.07 kcal mol-1, respectively. This study suggests that different chain lengths and levels of saturation directly affect the properties of these two important molecules, which are seen to work together to control anesthesia in surgical applications.

Diffusion of methanol in zeolite NaY: a molecular dynamics study.

Molecular dynamics simulations were performed in order to obtain a detailed understanding of the self-diffusion mechanisms of methanol in the zeolite NaY system. We derived a new force-field term to describe the interactions between the methanol molecules and the extraframework cations. From the simulations, we show that diffusive behavior in the high-temperature range consists of a combination of both short- and long-range motions at low and intermediate loadings. This type of motion is characterized by an activation energy that decreases as the loading increases. At low loadings, we also observe short-range diffusive behavior based on a surface-mediated mechanism. The short-range behavior corresponds to motion only on the length scale of an FAU supercage, whereas the long-range behavior involves intercage diffusion. For the saturation loading corresponding to 96 methanol molecules per unit cell, only short-range motions within the same supercage predominate. Finally, the preferential arrangement of the adsorbate molecules around the extraframework cations are examined and compared with those previously deduced from experimental data.

Adsorption of methanol on zeolites X and Y. An atomistic and quantum chemical study.

The adsorption of methanol on basic zeolites X and Y was investigated with both atomistic and quantum chemical methods. The Monte Carlo docking method was used to localize preferred adsorption sites within the framework. Sites were found adjacent to the interstitial alkali cations in the sites SI, SII, and SIII. We investigated the influence on adsorption behavior of all possible interstitial alkali metal cations, i.e., Li(+), Na(+), K(+), Rb(+), and Cs(+), and in the case of site SII also the influence of varying the Si/Al ratio and distribution. Clusters were cut from the periodic framework in a way that the topological character of the different sites was preserved. DFT calculations yielded geometries and energetic data, which are analyzed with respect to the nature of the cation and to the Si/Al ratio. Adsorption of the methanol molecule is influenced mainly by the identity of the alkali metal cation. Other factors, including Si/Al ratio, are of secondary importance, though there is evidence of weak hydrogen bonding between methanol hydrogen and framework. Cation positions are displaced only slightly by interaction with methanol, although somewhat more at the SIII sites than the SII. We propose that the SIII sites may be a more likely location for methanol activation, particularly in the reaction with toluene, which favors the SII site.

Thermal rearrangement mechanisms in icosahedral carboranes and metallocarboranes.

Ab initio MD and potential energy surface sampling has been used to study the rearrangement processes in carboranes and their derivatives. A new mechanism is found, in addition to those previously proposed. The fact that theoretical activation energies are lower than those observed experimentally, and the differing activity of technetium and rhenium complexes, are rationalised by orbital symmetry constraints.