Theoretical study of the novel sandwich compound [Au<Subscript>3</Subscript>Cl<Subscript>3</Subscript>Tr<Subscript>2</Subscript>]<Superscript>2+</Superscript>

A theoretical study of a sandwich compound with a metal monolayer sheet between two aromatic ligands is presented. A full geometry optimization of the [Au₃Cl₃Tr₂]²⁺ (1) compound, which is a triangular gold(I) monolayer sheet capped by chlorines and bounded to two cycloheptatrienyl (Tr) ligands was carried out using perturbation theory at the MP2 computational level and DFT. Compound (1) is in agreement with the 18–electron rule, the bonding nature in the complex may be interpreted from the donation interaction coming from the Tr rings to the Au array, and from the back-donation from the latter to the former. NICS calculations show a strong aromatic character in the gold monolayer sheet and Tr ligands; calculations done with HOMA, also report the same aromatic behavior on the cycloheptatrienyl fragments giving us an insight on the stability of (1). The Au –Au bond lengths indicate that an intramolecular aurophilic interaction among the Au(I) cations plays an important role in the bonding of the central metal sheet. Figure (a) Ground state geometry of complex 1; (b) Top view of compound 1 and Wiberg bond orders computed with the MP2/B1 computational method; (c) Lateral view of compound 1 and NICS values calculated with the MP2/B1 method; the values in parenthesis were obtained at the VWN/TZP level     

Molecular modeling of the intercalation of porphyrins into α-zirconium phosphate

In this work, n-alkylamines (number of carbon atoms ranging from 3 to 10) were investigated in detail by molecular modeling as spacers for intercalating porphyrins into α-zirconium phosphate (α-ZrP). Pre-intercalated n-alkylamines can form either a flat monolayer or a canted bilayer in the gallery of α-ZrP. Based on the interlayer state and intercalative potential of the two modes in α-ZrP, it is suggested that the flat monolayer is a better spacer than the bilayer and that n-propylamine (PA) and n-butylamine (BA) in mobile monolayers are the best spacers among the n-alkylamines studied, as is also found experimentally. The intercalation behavior of TMPyP [5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin] and several other porphyrins was investigated by calculating the intercalative potential. The calculated results showed that the porphyrins were densely packed in a canted monolayer model, and an increase of polarity of the substituent would facilitate the intercalation of the porphyrins. Figure Schematic representation of platform of intercalated spacers and guests taking n-butylamine and TMPyP as an example, respectively: a a flat monolayer of n-bultylamine in α-ZrP; b a canted monolayer of TMPyP in α-ZrP; c the top layer of the canted bilayer n-bultylamine in α-ZrP (the gray area indicates the amphiphilic distribution on the interface between α-ZrP layers and n-alkylamine/porphyrin).      

Adsorption and phase transitions in adsorbed systems: structural properties of CCl<Subscript>4</Subscript> layers adsorbed on a graphite surface

We present the results of simulations of a CCl₄ monolayer adsorbed on a graphite surface. The CCl₄ molecule was represented either by a shapeless superatom or by its atomic sites. The simulations were carried out over a large range of temperatures, from 20 K up to 340 K. We address the following problems: (1) the influence of molecular shape on the structure and stability of phases (particularly at low temperatures), and (2) the influence of the graphite corrugation on layer stability and mechanism of phase transitions. In particular, we discuss the possibility and conditions of the appearance of hexatic phase in the system. Figure Temperature dependence of Φ6 order parameter for CCl₄ monolayer adsorbed onsmooth and corrugated surfaces, in the spherical Lennard Jones (LJ) approximation.For comparison, the order parameter calculated for MacDonald’s five-site potential is also presented     

Structures of inclusion complexes of halogenbenzoic acids and α-cyclodextrin based on AM1 calculations

Semi-empirical quantum mechanics calculations using AM1 (Austin Method 1) were carried out for various host-guest combinations of α-cyclodextrin and mono-halogen benzoic acids. The energetically favorable inclusion structures were identified. The AM1 results show that α-cyclodextrin complexes with mono-halogen benzoic acid acids (where the halogen is chlorine, bromide, iodine) as guest compounds are more stable in the “head first” position than in the “tail-first” position for meta and para isomers while ortho mono-halogen benzoic acids complexes with α-cyclodextrin are more stable in “tail-first” position. The calculated structures were found to be in good agreement with those obtained from crystalographic databases.      

Structure-based 3D-QSAR studies on thiazoles as 5-HT<Subscript>3</Subscript> receptor antagonists

Structure-based 3D-QSAR studies were performed on 20 thiazoles against their binding affinities to the 5-HT₃ receptor with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The thiazoles were initially docked into the binding pocket of a human 5-HT_3A receptor homology model, constructed on the basis of the crystal structure of the snail acetylcholine binding protein (AChBP), using the GOLD program. The docked conformations were then extracted and used to build the 3D-QSAR models, with cross-validated values 0.785 and 0.744 for CoMFA and CoMSIA, respectively. An additional five molecules were used to validate the models further, giving satisfactory predictive values of 0.582 and 0.804 for CoMFA and CoMSIA, respectively. The results would be helpful for the discovery of new potent and selective 5-HT₃ receptor antagonists.      

Concentration-Dependent Effects on Intracellular and Surface pH of Exposing <Emphasis Type="Italic">Xenopus</Emphasis> oocytes to Solutions Containing NH<Subscript>3</Subscript>/NH<Subscript>4</Subscript><Superscript>+</Superscript>

Others have shown that exposing oocytes to high levels of (10–20 mM) causes a paradoxical fall in intracellular pH (pH_i), whereas low levels (e.g., 0.5 mM) cause little pH_i change. Here we monitored pH_i and extracellular surface pH (pH_S) while exposing oocytes to 5 or 0.5 mM NH₃/NH₄ ⁺. We confirm that 5 mM causes a paradoxical pH_i fall (−ΔpH_i ≅ 0.2), but also observe an abrupt pH_S fall (−ΔpH_S ≅ 0.2)—indicative of NH₃ influx—followed by a slow decay. Reducing [NH₃/NH₄ ⁺] to 0.5 mM minimizes pH_i changes but maintains pH_S changes at a reduced magnitude. Expressing AmtB (bacterial Rh homologue) exaggerates −ΔpH_S at both levels. During removal of 0.5 or 5 mM NH₃/NH₄ ⁺, failure of pH_S to markedly overshoot bulk extracellular pH implies little NH₃ efflux and, thus, little free cytosolic NH₃/NH₄ ⁺. A new analysis of the effects of NH₃ vs. NH₄ ⁺ fluxes on pH_S and pH_i indicates that (a) NH₃ rather than NH₄ ⁺ fluxes dominate pH_i and pH_S changes and (b) oocytes dispose of most incoming NH₃. NMR studies of oocytes exposed to ¹⁵N-labeled show no significant formation of glutamine but substantial accumulation in what is likely an acid intracellular compartment. In conclusion, parallel measurements of pH_i and pH_S demonstrate that NH₃ flows across the plasma membrane and provide new insights into how a protein molecule in the plasma membrane—AmtB—enhances the flux of a gas across a biological membrane.

The platinum-olefin binding energy in series of (PH<Subscript>3</Subscript>)<Subscript>2</Subscript>Pt(olefin) complexes - a theoretical study

Theoretical investigation of Pt(0)-olefin organometallic complexes containing tertiary phosphine ligands was focused on the strength of platinum-olefin electronic interaction. DFT theoretical study of electronic effects in a substantial number of ethylene derivatives was evaluated in terms of the Pt-olefin binding energy using MP2 correlation theory. Organometallics bearing coordinated olefins with general formula (R¹R²C = CR³R⁴)Pt(PH₃)₂ [R = various substituents] had been selected, including olefins containing both electron-donor substituents as well as electron-withdrawing groups. The stability of the corresponding complexes increases with a strengthening electron-withdrawal ability of the olefin substituents. Figure Representation of (CH₂ = CHR)Pt(PPh₃)₂ and the stability chart     

Computational studies of the binding site of α<Subscript>1A</Subscript>-adrenoceptor antagonists

Aimed at achieving a good understanding of the 3-dimensional structures of human α_1A-adrenoceptor (α_1A-AR), we have successfully developed its homology model based on the crystal structure of β₂-AR. Subsequent structural refinements were performed to mimic the receptor’s natural membrane environment by using molecular mechanics (MM) and molecular dynamics (MD) simulations in the GBSW implicit membrane model. Through molecular docking and further simulations, possible binding modes of subtype-selective α_1A-AR antagonists, Silodosin, RWJ-69736 and (+)SNAP-7915, were examined. Results of the modeling and docking studies are qualitatively consistent with available experimental data from mutagenesis studies. The homology model built should be very useful for designing more potent subtype-selective α_1A-AR antagonists and for guiding further mutagenesis studies. Figure The superposition of β₂-AR crystal structure (gold ribbons) and α_1A-AR homology model (blue ribbons)     

3D-QSAR study of microsomal prostaglandin E<Subscript>2</Subscript> synthase(mPGES-1) inhibitors

Microsomal prostaglandin E₂ synthase (mPGES-1) has been identified recently as a novel target for treating pain and inflammation. The aim of this study is to understand the binding affinities of reported inhibitors for mPGES-1 and further to design potential new mPGES-1 inhibitors. 3D-QSAR-CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) - techniques were employed on a series of indole derivatives that act as selective mPGES-1 inhibitors. The lowest energy conformer of the most active compound obtained from systematic conformational search was used as a template for the alignment of 32 compounds. The models obtained were used to predict the activities of the test set of eight compounds, and the predicted values were in good agreement with the experimental results. The 3D-QSAR models derived from the training set of 24 compounds were all statistically significant (CoMFA; q ² = 0.89, r ² = 0.95, , and CoMSIA; q ² = 0.84, r ² = 0.93, , ). Contour plots generated for the CoMFA and CoMSIA models reveal useful clues for improving the activity of mPGES-1 inhibitors. In particular, substitutions of an electronegative fluorine atom or a bulky hydrophilic phenoxy group at the meta or para positions of the biphenyl rings might improve inhibitory activity. A plausible binding mode between the ligands and mPGES-1 is also proposed.     

Exploring the binding features of rimonabant analogues and acyclic CB<Subscript>1</Subscript> antagonists: docking studies and QSAR analysis

In order to elucidate the structural requirements for human CB₁ receptor antagonism, 78 antagonists belonging to five different chemical classes were selected from the literature and docked into the receptor binding site, built by homology modeling techniques. To further explore the structure-activity relationships within the considered chemical classes, a pharmacophore model and a QSAR analysis were developed. In a first step five alignments, one for each group of compounds were generated. All of them were then submitted to a MOE pharmacophore search in order to obtain a final pharmacophore model representative of the whole dataset which was used to elaborate the following 3D-QSAR analysis, by means of the CoMFA methodology. The results of these investigations are expected to be useful in the process of design and development of new potent CB₁ antagonists. Figure Compounds 1-78 are aligned into the putative CB1 receptor binding site. The three key features shared by all of them are reported in coloured spheres. The hydrophobic/aromatic ones are depicted in purple while the acceptor functions are coloured in blue.     

Hologram and 3D-quantitative structure toxicity relationship studies of azo dyes

Amino azobenzenes are important dyes in the food and textile industry but their application is limited due to their mutagenicity. Computational modeling techniques were used to help understand the factors responsible for mutagenicity, and several quantitative structure toxicity relationship (QSTR) models have been derived. HQSTR (hologram QSTR) analyses indicated that different substituents at sites on both rings contribute to mutagenicity. Fragment parameters such as bond (B) and connectivity(C), as well as donor-acceptor (DA)-based model provide significant results (q² = 0.59, r² = 0.92, ) explaining these harmful effect. HQSTR results indicated that a bulky group at ring “Y” and small group at ring “X” might help to decrease mutagenicity. 3D-QSTR based on comparative molecular field analyses (CoMFA) and comparative molecular similarity index analyses (CoMSIA) are also in agreement with HQSTR. The 3D QSTR studies reveal that steric and electrostatic field effects have a strong relationship with mutagenicity (for CoMFA: q² = 0.51, r² = 0.95, and for CoMSIA: q² = 0.51, r² = 0.93 and ). In summary, negative groups and steric bulk at ring “Y” and small groups at carbon-3 of ring “X” might be helpful in reducing the mutagenicity of azo dyes.     

5,10,15,20-Tetra-(N-methyl-3-pyridyl)porphyrin destabilizes the antiparallel telomeric quadruplex d(TTAGGG)<Subscript>4</Subscript>

5,10,15,20-Tetra-(N-methyl-3-pyridyl)porphyrin (TMPyP3) is a DNA-binding derivative of porphyrins. A comparative study of the binding of this ligand to biologically significant DNA structures was performed. For this purpose, the interactions of TMPyP3 with the antiparallel telomeric G-quadruplex d(TTAGGG)₄, oligonucleotide dTTAGGGTTAGAG(TTAGGG)₂ (not forming a quadruplex structure), double-stranded d(AC)₈ · d(GT)₈, and single-stranded d(AC)₈ and d(GT)₈ DNA molecules have been studied. Analysis of absorption isotherms has demonstrated that the binding constants and the number of binding sites for the complexes TMPyP3: DNA increase in the following order: d(AC)₈ < d(GT)₈ < d(AC)₈ · d(GT)₈ = d(TTAGGG)₄ < dTTAGGGTTAGAG(TTAGGG)₂. It has been for the first time demonstrated that the constant for TMPyP3 binding to unfolded dTTAGGGTTAGAG(TTAGGG)₂ strand (1.3 × 10⁷ M⁻¹) is approximately threefold higher than for the G-quadruplex d(TTAGGG)₄ (4.7 × 10⁶ M⁻¹). Binding of two TMPyP3 molecules to d(TTAGGG)₄ decreases the thermostability of G-quadruplex (ΔT_m = −8°C). Circular dichroism spectra of the TMPyP3 complexes with d(TTAGGG)₄ suggest that the ligand partially unfolds the G-quadruplex structure. Structural destabilization of the telomeric G-quadruplex by TMPyP3 can explain the relatively low activity of this ligand as a telomerase inhibitor and a low cytotoxicity for cultured tumor cells.     

Molecular surface electrostatic potentials and anesthetic activity

General anesthetics apparently act through weak, noncovalent and reversible interactions with certain sites in appropriate brain proteins. As a means of gaining insight into the factors underlying anesthetic potency, we have analyzed the computed electrostatic potentials V _S(r) on the surfaces of 20 molecules with activities that vary between zero and high. Our results are fully consistent with, and help to interpret, what has been observed experimentally. We find that an intermediate level of internal charge separation is required; this is measured by Π, the average absolute deviation of V _S(r), and the approximate window is 7 < Π < 13 kcal mol⁻¹. This fits in well with the fact that anesthetics need to be lipid soluble, but also to have some degree of hydrophilicity. We further show that polyhalogenated alkanes and ethers, which include the most powerful known anesthetics, have strong positive potentials, V _S,max, associated with their hydrogens, chlorines and bromines (but not fluorines). These positive sites may impede the functioning of key brain proteins, for example by disrupting their normal hydrogen-bond patterns. It has indeed been recognized for some time that the most active polyhalogenated alkanes and ethers contain hydrogens usually in combination with chlorines and/or bromines. Figure The computed HF/6-31G* electrostatic potential, in kcal mol⁻¹, on the 0.001 electrons/bohr³ surface of halothane, CF₃CHBrCl. The color ranges are: red, more positive than 25; yellow, between 15 and 25; green between 0 and 15; blue, between −10 and 0. The strongly positive (red) potential is due to the hydrogen; the yellow and green positive regions at the right are on the bromine surface Proceedings of “Modeling Interactions in Biomolecules II”, Prague, September 5th–9th, 2005.     

Preload-induced changes in isometric tension and [Ca<Superscript>2+</Superscript>]<Subscript>i</Subscript> in rat myocardium

Preload-induced changes of active tension and [Ca²⁺]i are “dissociated” in mammalian myocardium. This study aimed to describe the distinct effects of preload at low and physiological [Ca²⁺]_o. Rat RV papillary muscles were studied in isometric conditions at 25‡C and 0.33 Hz at 1 mM (hypo-Ca group) and 2.5 mM [Ca²⁺]_o (normal-Ca group). [Ca²⁺]_i was monitored with fura-2/AM. Increase of preload caused a rise of active tension in hypo-Ca and normal-Ca groups whereas peak fluorescence rose significantly only at low [Ca²⁺]_o. End-diastolic tension, end-diastolic level of fluorescence, time-to-peak tension, but not time-to-peak of Ca²⁺ transient, progressively increased with preload. Mechanical relaxation decelerated with preload while Ca²⁺ transient decay time decreased in the initial phase and increased in the late phase, resulting in a prominent “bump” configuration. The “bump” was assessed as a ratio of its area to the fluorescence trace area. It was a new finding that the preload-induced rise of this ratio was twice as large in hypo-Ca. Our results indicate that preload-induced changes in active tension and [Ca²⁺]_i are “dissociated” in rat myocardium, with relatively higher expression at low [Ca²⁺]_o. Ca-dependence of Ca-TnC association/dissociation kinetics is thought to be a main contributor to these preload-induced effects.     

Probing the nature of hydrogen bonds in DNA base pairs

Energy decomposition analyses based on the block-localized wave-function (BLW-ED) method are conducted to explore the nature of the hydrogen bonds in DNA base pairs in terms of deformation, Heitler–London, polarization, electron-transfer and dispersion-energy terms, where the Heitler–London energy term is composed of electrostatic and Pauli-exchange interactions. A modest electron-transfer effect is found in the Watson–Crick adenine–thymine (AT), guanine–cytosine (GC) and Hoogsteen adenine-thymine (H-AT) pairs, confirming the weak covalence in the hydrogen bonds. The electrostatic attraction and polarization effects account for most of the binding energies, particularly in the GC pair. Both theoretical and experimental data show that the GC pair has a binding energy (−25.4 kcal mol⁻¹ at the MP2/6-31G** level) twice that of the AT (−12.4 kcal mol⁻¹) and H-AT (−12.8 kcal mol⁻¹) pairs, compared with three conventional N-H···O(N) hydrogen bonds in the GC pair and two in the AT or H-AT pair. Although the remarkably strong binding between the guanine and cytosine bases benefits from the opposite orientations of the dipole moments in these two bases assisted by the π-electron delocalization from the amine groups to the carbonyl groups, model calculations demonstrate that π-resonance has very limited influence on the covalence of the hydrogen bonds. Thus, the often adopted terminology “resonance-assisted hydrogen bonding (RHAB)” may be replaced with “resonance-assisted binding” which highlights the electrostatic rather than electron-transfer nature of the enhanced stabilization, as hydrogen bonds are usually regarded as weak covalent bonds. Figure Electron density difference (EDD) maps for the GC pair: a shows the polarization effect (isodensity 1.2×10⁻³ a.u.); b shows the charge transfer effect (isodensity 2×10⁻⁴ a.u.) Dedicated to Professor Paul von Ragué Schleyer on the occasion of his 75th birthday     

Ligation of Aza bases to the AgF<Subscript>2</Subscript> molecule: a theoretical study

We have analyzed the electronic structure and chemical bonding for molecular adducts of the Ag(II)F₂ molecule with various aza Lewis bases including ammonia, nitriles, secondary amines, and their derivatives exhibiting various degrees of fluorination. Density functional theory calculations indicate that a progressive shift occurs of the spin density from the Ag center towards the coordinating nitrogen atoms of aza ligands, as the ligation energy increases. Chemistry of Ag(II) might be extended with little effort beyond the known aza connections, to include nitriles, perfluorinated nitriles and perfluorinated amines. Figure Properties of a variety of novel adducts of the AgF₂ molecule with two aza bases (L), possible precursors of the AgF₂L₂ extended solids, were assessed by the DFT calculations Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. This work is dedicated to memory of Wojciech Ochmański, unforgettable person, good-hearted man, whose craftsmanship in work was second-to-none.     

Aromatic C20F20 cage and its endohedral complexes X@C20F20 (X = H-, F-, Cl-, Br-, H, He)

The structure and stability of endohedral X@C₂₀F₂₀ complexes (X = H⁻, F⁻, Cl⁻, Br⁻, H, He) have been computed at the B3LYP level of theory. All complexes in I _h symmetry were found to be energy minimum structures. H⁻@C₂₀F₂₀ and F⁻@C₂₀F₂₀ complexes have negative inclusion energies, while other complexes have positive inclusion energies. Similarity between C₂₀F₂₀ and C₂₀H₂₀ has been found for X = H and He. On the basis of the computed nucleus independent chemical shift values at the cage center, both C₂₀F₂₀ and C₂₀F₂₀ are aromatic. Figure Endohedral X@C₂₀F₂₀ complexes     

Microbial transformation of ginsenoside Rb<Subscript>1</Subscript> by <Emphasis Type="Italic">Acremonium strictum</Emphasis>

Preparative-scale fermentation of ginsenoside Rb₁ (1) with Acremonium strictum AS 3.2058 gave three new compounds, 12β-hydroxydammar-3-one-20 (S)-O-β-d-glucopyranoside (7), 12β, 25-dihydroxydammar-(E)-20(22)-ene-3-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside (8), and 12β, 20 (R), 25-trihydroxydammar-3-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside (9), along with five known compounds, ginsenoside Rd (2), gypenoside XVII (3), ginsenoside Rg₃ (4), ginsenoside F₂ (5), and compound K (6). The structural elucidation of these metabolites was based primarily on one- and two-dimensional nuclear magnetic resonance and high-resolution electron spray ionization mass spectra analyses. Among these compounds, 2–6 are also the metabolites of ginsenoside Rb₁ in mammals. This result demonstrated that microbial culture parallels mammalian metabolism; therefore, A. strictum might be a useful tool for generating mammalian metabolites of related analogs of ginsenosides for complete structural identification and for further use in pharmaceutical research in this series of compounds. In addition, the biotransformation kinetics was also investigated.     

Abundance and Diversity of CO<Subscript>2</Subscript>-fixing Bacteria in Grassland Soils Close to Natural Carbon Dioxide Springs

Gaseous conditions at natural CO₂ springs (mofettes) affect many processes in these unique ecosystems. While the response of plants to extreme and fluctuating CO₂ concentrations ([CO₂]) is relatively well documented, little is known on microbial life in mofette soil. Therefore, it was the aim of this study to investigate the abundance and diversity of CO₂-fixing bacteria in grassland soils in different distances to a natural carbon dioxide spring. Samples of the same soil type were collected from the Stavešinci mofette, a natural CO₂ spring which is known for very pure CO₂ emissions, at different distances from the CO₂ releasing vents, at locations that clearly differed in soil CO₂ efflux (from 12.5 to over 200 μmol CO₂ m⁻² s⁻¹ yearly average). Bulk and rhizospheric soil samples were included into analyses. The microbial response was followed by a molecular analysis of cbbL genes, encoding for the large subunit of RubisCO, a carboxylase which is of crucial importance for C assimilation in chemolitoautotrophic microbes. In all samples analyzed, the “red-like” type of cbbL genes could be detected. In contrast, the “green-like” type of cbbL could not be measured by the applied technique. Surprisingly, a reduction of “red-like” cbbL genes copies was observed in bulk soil and rhizosphere samples from the sites with the highest CO₂ concentrations. Furthermore, the diversity pattern of “red-like” cbbL genes changed depending on the CO₂ regime. This indicates that only a part of the autotrophic CO₂-fixing microbes could adapt to the very high CO₂ concentrations and adverse life conditions that are governed by mofette gaseous regime. Urška Videmšek, Alexandra Hagn, Michael Schloter, and Dominik Vodnik contributed equally to this study.