Mesoscopic simulation study on a weakly charged block polyelectrolyte in aqueous solution

In this paper, we use density functional theory to study the effect of the charge of solvophilic beads and concentration on the mesoscale structures of polyelectrolyte solution. The polyelectrolyte A₆B₁₂A₆ was selected as the triblock polymer, and the solvophobic B blocks have no charges, while the solvophilic A blocks are charged. The simulation results showed: at higher concentration (above 50% systems), relatively small charges on the solvophilic block do not alter the bicontinuous phase inherent to uncharged solution, but at moderate concentrations (50% system), even though the charge per solvophilic bead is very small, the order lamellar structures become disturbed. Figure The density slice of A block in A₆B₁₂A₆ solution at dimensionless time τ=5,000. 2D cut through the middle of the box shown in Fig. 2a for a (z orientation) and b (y orientation); in Fig. 2g for c (z orientation) and d (y orientation); and for 80% system with the charge of z _A =0.5 for e (z orientation) and d (y orientation)     

Boron nitride cages from B12N12 to B36N36: square–hexagon alternants vs boron nitride tubes

The structures and stabilities of square–hexagon alternant boron nitrides (B _x N _x , x=12–36) vs their tube isomers containing octagons, decagons and dodecagons have been computed at the B3LYP density functional level of theory with the correlation-consistent cc-pVDZ basis set of Dunning. It is found that octagonal B₂₀N₂₀ and B₂₄N₂₄ tube structures are more stable than their square–hexagon alternants by 18.6 and 2.4 kcal mol⁻¹, respectively, while the square–hexagon alternants of other cages are more stable. Trends in stability as a function of cluster size are discussed.Figure The octagonal B₂₀N₂₀ and B₂₄N₂₄ tube structures are more stable than their square-hexagon alternant cagesDedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday     

3D pharmacophore models for thromboxane A2 receptor antagonists

Thromboxane A₂ (TXA₂) is an endogenous arachidonic acid derivative closely correlated to thrombosis and other cardiovascular diseases. The action of TXA₂ can be effectively inhibited with TXA₂ receptor antagonists (TXRAs). Previous studies have attempted to describe the interactions between the TXA₂ receptor and its ligands, but their conclusions are still controversial. In this study, ligand-based computational drug design is used as a new and effective way to investigate the structure-activity relationship of TXRAs. Three-dimensional pharmacophore models of TXRAs were built with HypoGenRefine and HipHop modules in CATALYST software. The optimal HypoGenRefine model was developed on the basis of 25 TXRAs. It consists of two hydrophobic groups, one aromatic ring, one hydrogen-bond acceptor and four excluded volumes. The optimal HipHop model contains two hydrophobic groups and two hydrogen-bond acceptors. These models describe the key structure-activity relationship of TXRAs, can predict their activities, and can thus be used to design novel antagonists. Figure Optimal three-dimensional pharmacophore models of TXA₂ receptor antagonists (TXRAs) built with HypoGenRefine (a) and HipHop (b) modules. a Hypo-1 model mapped with compounds 11 (purple), and 20 (green). b Hypo-2 model mapped with compounds 31 (green) and 64 (yellow). Spheres: Green Hydrogen bond acceptors (HBA), cyanhydrophobic (H), orange aromatic rings (RA), black excluded volumes (EV) Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Mechanistic study of palladium-catalyzed telomerization of 1,3-butadiene with methanol

The Pd-catalyzed telomerization in the presence of phosphine and carbene ligands has been computed. It is shown that the C–C coupling of the less stable complex A with one trans- and one cis-butadiene in syn orientation forms the most stable intermediate B and is favorable both kinetically and thermodynamically. Protonation of B leads to equilibrium of the two most stable isomers of intermediate C. The overall regioselectivity is favored thermodynamically.      

Pattern recognition based on color-coded quantum mechanical surfaces for molecular alignment

A pattern recognition algorithm for the alignment of drug-like molecules has been implemented. The method is based on the calculation of quantum mechanical derived local properties defined on a molecular surface. This approach has been shown to be very useful in attempting to derive generalized, non-atom based representations of molecular structure. The visualization of these surfaces is described together with details of the methodology developed for their use in molecular overlay and similarity calculations. In addition, this paper also introduces an additional local property, the local curvature (C _L), which can be used together with the quantum mechanical properties to describe the local shape. The method is exemplified using some problems representing common tasks encountered in molecular similarity. Figure Molecular surfaces for Lorazepam (left) and Diazepam (right)     

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

Study of a ligand complexed with Cdk2/Cdk4 by computer simulation

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K _i =6 nM) but a low affinity with cyclin-dependent kinase 4 (K _i =1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4. Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by LIGPLOT.      

Conformation and tautomerizm of the 2-methyl-4-pyridin-2′-yl-1,5-benzodiazepine molecule. An ab initio study

The protomeric tautomerizm and conformation of the 2-methyl-4-pyridin-2′-yl-1,5-benzodiazepine molecule were investigated, and its three neutral tautomers (B₁,B₂,B₃) and their rotamers (C₁,C₂,C₃) were considered. Full geometry optimizations were carried out at the HF/6-31G* and B3LYP/6-31G* levels in gas phase and in water. The tautomerization processes in water (ɛ = 78.54) were studied by using self-consistent reaction field theory. The calculation showed that the boat conformation is dominant for the seven-membered diazepine ring in all of the structures, even with different double bond positions. The calculated relative free energies (ΔG) showed that the tautomer C₁ was the most stable structure, and its conformer B₁ was the second most stable in the gas phase and in water. Figure 2-Methyl-4-pyridin-2′-yl-1,5-benzodiazepine     

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     

An experimental and theoretical study of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amides

The mechanism of the enantioselective deprotonation of cyclohexene oxide with isopinocampheyl-based chiral lithium amide was studied by quantum chemical calculations. The transition states of eight molecules were fully optimized at the ab initio HF/3-21G and density functional B3LYP/3-21G levels with Gaussian 98. The activation energies were calculated at the B3LYP/6-31+G(3df,2p)//B3LYP/3-21G level. We found the theoretical evaluation to be consistent with the experimental data. At the best case, an enantiomeric excess of up to 95% for (R)-2-scyclohexen-1-ol was achieved with (−)-N, N-diisopinocampheyl lithium amide. Enantioselective deprotonation of cyclohexene oxide Electronic Supplementary Material Supplementary material is available for this article at Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday.     

Molecular models of protein kinase 6 from Plasmodium falciparum

Cyclin-dependent kinases (CDKs) have been identified as potential targets for development of drugs, mainly against cancer. These studies generated a vast library of chemical inhibitors of CDKs, and some of these molecules can also inhibit kinases identified in the Plasmodium falciparum genome. Here we describe structural models for Protein Kinase 6 from P. falciparum (PfPK6) complexed with Roscovitine and Olomoucine. These models show clear structural evidence for differences observed in the inhibition, and may help designing inhibitors for PfPK6 generating new potential drugs against malaria. Figure Ribbon diagram of PfPK6 complexed with a roscovitine and b olomoucine     

Umpolung catalysts: comparative assessments on reactivities

Umpolung catalysis is studied by a sequence of model reactions (CPCM in THF, B3LYP/6-31G*) with different aldehydes and catalysts. We involved addition of the catalyst to the aldehyde and 1,2-H-migration to form a carbanionic d¹-species, which is the crucial intermediate according to the Lapworth- and Breslow-mechanisms. Cyanide, N-methylthiazol-2-ylidene, and a glycol-based phosphite perform as umpolung catalysts, formaldehyde, acetaldehyde, benzaldehyde, and acrolein are substrates in this study. In these aldehyde substrates, alkyl-substitution disfavors but π-conjugation favors formation of the carbanionic d¹-intermediate. The nucleophilic carbene, N-methylthiazol-2-ylidene, is the strongest umpolung catalyst, while the phosphite is about as active as cyanide. Figure Transitions structure for the umpolung of formaldehyde with a glycol phosphinite catalyst Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday     

Docking studies suggest ligand-specific δ-opioid receptor conformations

An automated docking procedure was used to study binding of a series of δ-selective ligands to three models of the δ-opioid receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement with point mutation studies and suggest that different ligands—agonists and antagonists—may bind to the same binding site under different receptor conformations. Docking to different receptor models (conformations) also suggests that by changing to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands. Figure  Ligands 5 (green) and 6 (orange) in bindingpocket BP1 of the R1 δ-opioid receptor model     

Electronic analysis of vanadium and iron complexes containing distorted aromatic rings

Aromatic rings can suffer severe distortions upon substituting transition metal centers with certain kinds of organometallic compounds. This property is very interesting because aromaticity can remain despite the deformation. Theoretical calculations at the density functional theory level were carried out on two such structures containing vanadium and iron centres [(C₅H₅-V-H)₂C₆H₆ and (CpFe)₂C₆(CH₃)₆] in order to analyze the nature of the bonds as well as the magnitude of the prevalent aromaticity and how this depends on the electronic characteristics around each metal atom. The analysis of aromaticity was carried out on the basis of known methods, such as HOMA and FLU, with consistent results. The results also show features that suggest a possible catalytic behavior of the species under study. Figure Molecules under study     

DFT investigation of the 1-octene metathesis reaction mechanism with the Phobcat precatalyst

The productive self-metathesis reaction of 1-octene in the presence of the Phobcat precatalyst [RuCl₂(Phoban-Cy)₂(=CHPh)] using density functional theory was investigated and compared to the Grubbs 1 precatalyst [RuCl₂(PCy₃)₂(=CHPh)]. At the GGA-PW91/DNP level, the geometry optimization of all the participating species and the PES scans of the various activation and catalytic cycles in the dissociative mechanism were performed. The formation of the catalytically active heptylidene species is kinetically and thermodynamically favored, while the formation of trans-tetradecene is thermodynamically favored.      

Why are dimethyl sulfoxide and dimethyl sulfone such good solvents?

We have carried out B3PW91 and MP2-FC computational studies of dimethyl sulfoxide, (CH₃)₂SO, and dimethyl sulfone, (CH₃)₂SO₂. The objective was to establish quantitatively the basis for their high polarities and boiling points, and their strong solvent powers for a variety of solutes. Natural bond order analyses show that the sulfur–oxygen linkages are not double bonds, as widely believed, but rather are coordinate covalent single S⁺→O⁻ bonds. The calculated electrostatic potentials on the molecular surfaces reveal several strongly positive and negative sites (the former including σ-holes on the sulfurs) through which a variety of simultaneous intermolecular electrostatic interactions can occur. A series of examples is given. In terms of these features the striking properties of dimethyl sulfoxide and dimethyl sulfone, their large dipole moments and dielectric constants, their high boiling points and why they are such good solvents, can readily be understood. Figure Dimers of dimethyl sulfoxide (DMSO; left) and dimethyl sulfone (DMSO2; right) showing O S—O -hole bonding and C H—O hydrogen bonding. Sulfur atoms are yellow, oxygens are red, carbons are gray and hydrogens are white     

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     

G2, G3, and complete basis set calculations on the thermodynamic properties of triazane

As a follow-up study to our study on tetrazane (N₄H₆), we present computed thermodynamic properties of triazane (N₃H₅). Calculated properties include optimized geometries, infrared vibrations, enthalpy of formation, enthalpy of combustion, and proton affinities. We have also mapped the potential energy surface as the molecule is rotated about the N-N bond. We have predicted a specific enthalpy of combustion for triazane of about -20 kJ g⁻¹. Figure Schematic diagram of the dielectric barrier discharge (left) and typical temporal profiles of voltage and current, as obtained from the simulations (right)