Use of quantum mechanics/molecular mechanics-based FEP method for calculating relative binding affinities of FBPase inhibitors for type-2 diabetes

A quantum mechanics (QM)/molecular mechanics (MM)-based free energy perturbation (FEP) method, developed recently, provides most accurate estimation of binding affinities. The validity of the method was evaluated for a large set of diverse inhibitors for fructose 1,6-bisphosphatase (FBPase), a target enzyme for type-II diabetes mellitus. The validation set comprises of 22 important structurally different mutations. The calculated relative binding free energies using the QM/MM-based FEP method reproduce the experimental values with exceptional precision of less than ±0.5 kcal/mol. The CPU requirements for QM/MM-based FEP are about fivefold greater than conventional FEP methods, but it is superior in accuracy of predictions. In addition, the QM/MM-based FEP method eliminates the need for time-consuming development of MM force field parameters, which are frequently required for novel inhibitors described by MM. Future automation of the method and parallelization of the code for 128/256/512 cluster computers is expected to enhance the speed and increase its use for drug design and lead optimization. The present application of QM/MM-based FEP method for structurally diverse set of analogs serves to enhance the scope of FEP method and demonstrate the utility of QM/MM-based FEP method for its potential in drug discovery.     

New Application of Chemically Modified Multiwalled Carbon Nanotubes with Thiosemicarbazide as a Sorbent for Separation and Preconcentration of Trace Amounts of Co(II), Cd(II), Cu(II), and Zn(II) in Environmental and Biological Samples Prior to Determination by Flame Atomic Absorption Spectrometry

The present article reports the application of Thiosemicarbazide‐modified multiwalled carbon nanotubes (MWCNTs‐TSC) as a new, easily prepared selective and stable solid sorbent for the preconcentration of trace Co(II), Cd(II), Cu(II) and Zn(II) ions in aqueous solution prior to the determination by flame atomic absorption spectrometry. The studied metal ions can be adsorbed quantitatively on MMWNTs at pH 5.0 and then eluted completely with HNO₃ (1.5 mol L^?1) prior to their determination by flame atomic absorption spectrometry. The separation/preconcentration conditions of analytes were investigated, including the pH, the sample flow rate and volume, the elution condition and the interfering ions. The maximum adsorption capacity of the adsorbent at optimum conditions were found to be 32.5, 27.3, 44.5 and 34.1 mg g^?1 for Co(II), Cd(II), Cu(II) and Zn(II), and the detection limits of the method were found to be 0.28, 0.13, 0.21 and 0.17 μg L^?1, respectively. The proposed method was successfully applied for extraction and determination of the analytes in well water, sea water, wastewater, soil, and blood samples.     

How silanization of silica particles affects the adsorption of PDMS chains on its surface

A series of six fumed silica types, with different surface areas in the 50–400 m²/g range, were modified by grafting with trimethylchlorosilane. The grafting reaction was controlled by elemental analyses, surface hydroxyl titration, and combustion techniques. The silica surface energy was determined as a function of silanization degree by inverse gas chromatography (IGC). Adsorption of a series of poly(dimethylsiloxane) elastomers with molecular weights ranging between 4 and 420 kg/mol on silica was followed using flow microcalorimeter (FMC). IGC results show that free adsorption energies of two series of alkanes and siloxanes as well as the dispersive component of the surface energy were found to decrease monotonously with surface silanization and so does the polymer molar heat of adsorption. FMC results indicate, however, that the conformation of the macromolecules on silica depends on the silica surface area but remains unaffected by the surface treatments. A given polymer chain was found to remain adsorbed on the surface preserving its same conformation until its molar heat of adsorption falls bellow a critical value. These findings offer a better monitoring of surface–polymer interactions as it defined a comprehensive relationship between the degree of modifications of the filler surface and polymer adsorption conditions. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2010     

Relative solvation free energies calculated using an ab initio QM/MM-based free energy perturbation method: dependence of results on simulation length

Molecular dynamics (MD) simulations in conjunction with thermodynamic perturbation approach was used to calculate relative solvation free energies of five pairs of small molecules, namely; (1) methanol to ethane, (2) acetone to acetamide, (3) phenol to benzene, (4) 1,1,1 trichloroethane to ethane, and (5) phenylalanine to isoleucine. Two studies were performed to evaluate the dependence of the convergence of these calculations on MD simulation length and starting configuration. In the first study, each transformation started from the same well-equilibrated configuration and the simulation length was varied from 230 to 2,540 ps. The results indicated that for transformations involving small structural changes, a simulation length of 860 ps is sufficient to obtain satisfactory convergence. In contrast, transformations involving relatively large structural changes, such as phenylalanine to isoleucine, require a significantly longer simulation length (>2,540 ps) to obtain satisfactory convergence. In the second study, the transformation was completed starting from three different configurations and using in each case 860 ps of MD simulation. The results from this study suggest that performing one long simulation may be better than averaging results from three different simulations using a shorter simulation length and three different starting configurations.     

Mimicking both petal and lotus effects on a single silicon substrate by tuning the wettability of nanostructured surfaces

We describe a new method of fabricating large-area, highly scalable, "hybrid" superhydrophobic surfaces on silicon (Si) substrates with tunable, spatially selective adhesion behavior by controlling the morphologies of Si nanowire arrays. Gold (Au) nanoparticles were deposited on Si by glancing-angle deposition, followed by metal-assisted chemical etching of Si to form Si nanowire arrays. These surfaces were chemically modified and rendered hydrophobic by fluorosilane deposition. Au nanoparticles with different size distributions resulted in the synthesis of Si nanowires with very different morphologies (i.e., clumped and straight nanowire surfaces). The difference in nanowire morphology is attributed to capillary force-induced nanocohesion, which is due to the difference in nanowire porosity. The clumped nanowire surface demonstrated the lotus effect, and the straighter nanowires demonstrated the ability to pin water droplets while maintaining large contact angles (i.e., the petal effect). The high contact angles in both cases are explained by invoking the Cassie-Baxter wetting state. The high adhesion behavior of the straight nanowire surface may be explained by a combination of attractive van der Waals forces and capillary adhesion. We demonstrate the spatial patterning of both low- and high-adhesion superhydrophobicity on the same substrate by the simultaneous synthesis of clumped and straight silicon nanowires. The demonstration of hybrid superhydrophobic surfaces with spatially selective, tunable adhesion behavior on single substrates paves the way for future applications in microfluidic channels, substrates for biologically and chemically based analysis and detection where it is necessary to analyze a particular droplet in a defined location on a surface, and as a platform to study in situ chemical mixing and interfacial reactions of liquid pearls.     

Palladium-catalyzed selective alkoxycarbonylation of α,β-unsaturated amides: a novel approach toward new ω-amido esters and N-substituted cyclic succinimides

The alkoxycarbonylation of α,β-unsaturated amides proceeded efficiently and regioselectivity to give ω-amido esters with complete conversion in the presence of the catalyst system: Pd(PPh₃)₂Cl₂/MeOH/CO/H₂O. The reaction was successfully applied to the alkoxycarbonylation of bis-acrylamides yielding, selectively, the corresponding di-ω-amido esters. These mono and di-ω-amido esters have been used as precursors for the synthesis of N-substituted cyclic succinimides in moderate to high yields.     

Facile Access to Benzothiazole‐Containing Pyrrolo[1,2‐a]quinolines and Pyrrolo[2,1‐a]isoquinolines via Nitrogen Ylides

Quinoline and isoquinoline react with 2‐(bromoacetyl)benzothiazole ( 1 ) in dry benzene to give the corresponding quinolinium and isoquinolinium salts 2 and 10 which undergo base‐mediated [3+2] 1,3‐dipolar cycloaddition with some acetylene and ethylene derivatives to give the corresponding benzothiazole‐containing pyrrolo[1,2‐a]quinoline and pyrrolo[2,1‐a]isoquinoline derivatives.     

Photocatalytic Water Oxidation by a Mixed‐Valent MnIII3MnIVO3 Manganese Oxo Core that Mimics the Natural Oxygen‐Evolving Center

The functional core of oxygenic photosynthesis is in charge of catalytic water oxidation by a multi‐redox Mn^III/Mn^IV manifold that evolves through five electronic states (S_i , where i=0–4). The synthetic model system of this catalytic cycle and of its S₀→S₄ intermediates is the expected turning point for artificial photosynthesis. The tetramanganese‐substituted tungstosilicate [Mn^III₃Mn^IVO₃(CH₃COO)₃(A‐α‐SiW₉O₃₄)]^6? (Mn₄POM) offers an unprecedented mimicry of the natural system in its reduced S₀ state; it features a hybrid organic–inorganic coordination sphere and is anchored on a polyoxotungstate. Evidence for its photosynthetic properties when combined with [Ru(bpy)₃]²⁺ and S₂O₈^2? is obtained by nanosecond laser flash photolysis; its S₀→S₁ transition within milliseconds and multiple‐hole‐accumulating properties were studied. Photocatalytic oxygen evolution is achieved in a buffered medium (pH 5) with a quantum efficiency of 1.7 %.