Enhancing the accuracy of virtual screening: molecular dynamics with quantum-refined force fields

Summary A methodology aimed at improving the accuracy of current docking–scoring procedures is proposed, and validated through detailed tests of its performance in predicting the activity of HIV-1 protease inhibitors. This methodology is based on molecular dynamics simulations using a force field whose effective charges are refined by means of a novel procedure that relies on quantum-mechanical calculations and preserves the internal consistency of the parameterization scheme.     

Inorganic Elements in Mytilus galloprovincialis Shells: Geographic Traceability by Multivariate Analysis of ICP-MS Data

The international seafood trade is based on food safety, quality, sustainability, and traceability. Mussels are bio-accumulative sessile organisms that need regular control to guarantee their safe consumption. However, no well-established and validated methods exist to trace mussel origin, even if several attempts have been made over the years. Recently, an inorganic multi-elemental fingerprint coupled to multivariate statistics has increasingly been applied in food quality control. The mussel shell can be an excellent reservoir of foreign inorganic chemical species, allowing recording long-term environmental changes. The present work investigates the multi-elemental composition of mussel shells, including Al, Cu, Cr, Zn, Mn, Cd, Co, U, Ba, Ni, Pb, Mg, Sr, and Ca, determined by inductively-coupled plasma mass-spectrometry in Mytilus galloprovincialis collected along the Central Adriatic Coast (Marche Region, Italy) at 25 different sampling sites (18 farms and 7 natural banks) located in seven areas. The experimental data, coupled with chemometric approaches (principal components analysis and linear discriminant analysis), were used to create a statistical model able to discriminate samples as a function of their production site. The LDA model is suitable for achieving a correct assignment of >90% of individuals sampled to their respective harvesting locations and for being applied to counteract fraud.     

Azobioisosteres of Curcumin with Pronounced Activity against Amyloid Aggregation,Intracellular Oxidative Stress,and Neuroinflammation

Many (poly-)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid-β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril-like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate-induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV-2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μm (83 % cell survival), whereas curcumin only showed very low protection at 10 μm (21 % cell survival).     

Modulating the Enantiodiscrimination Features of Inherently Chiral Selectors by Molecular Design: A HPLC and Voltammetry Study Case with Atropisomeric 2,2’-Biindole-Based Monomers and Oligomer Films

A family of inherently chiral electroactive selectors based on the 2,2’-biindole atropisomeric scaffold, of easy synthesis and modulable functional properties, is studied in cascade in two enantioselection contexts. They are at first investigated as probes in enantioselective HPLC, studying molecular structure and temperature effects, and achieving very efficient semipreparative enantioseparation. The enantiomers thus obtained, of remarkable chiroptical features (optical rotation as well as circular dichroism), are successfully applied as selectors in chiral voltammetry in different media for discrimination of the enantiomers of chiral electroactive probes, either by conversion into enantiopure electroactive electrode surfaces by electrooligomerization on glassy carbon substrate (the two monomers with shorter alkyl chains), or as chiral additive in achiral ionic liquid (the monomer with longest alkyl chains). Discrimination is conveniently and reproducibly achieved in terms of significant potential differences for the two enantiomers, specularly inverting either probe or selector configuration. In one case successful discrimination is also observed with the two probe enantiomers concurrently present, either as racemate or with enantiomeric excesses, neatly accounted for by the peak current ratios.     

Affinity capillary electrophoresis study of the linkage existing between proton and zinc ion binding to bacitracin A1

Measurements by capillary electrophoresis (CE) of bacitracin A(1) effective mobility at different pH values permitted to estimate the five acidic dissociation constants and the Stokes radii at different protonation stages of the macrocyclic dodecapeptide. The pK(a) values were 3.6 and 4.4 for the two carboxylic groups of the lateral chains of D-Asp-11 and D-Glu-4, respectively, 6.4 for the aza-atom of the imidazole ring of His-10, 7.6 for the amino group of N-terminal Ile-1 and 9.7 for the delta-amino group of D-Orn-7, very close to the values obtained by other researchers by titration experiments. In agreement with a rigid macrocyclic structure the Stokes radii of different protonated forms ranged only between 14.3 and 14.8 A. Best fitting procedures performed on experimental mobility measured at two different pH values (5.50 and 6.72) in the presence of increasing Zn(+2) concentration allowed confirming the model that assumes the binding of Zn(+2) to P(0) peptide form with a 1.5 x 10(3) M(-1) intrinsic association constant. Following to Zn(+2) binding, the pK(a) of the amino group of N-terminal Ile-1 is shifted from 7.6 to 5.9 and the Stokes radius is reduced of about 3 A. The mean charge of the bacitracin A(1)-Zn(+2) complex resulted +1.67 and +1.12 at pH 5.50 and 6.72, respectively. These results suggest that the amino group of N-terminal Ile-1 is not essential for Zn(+2) binding.     

[Re5(μ-H)4(CO)20]− and [Re5(μ-H)5(CO)20], Two Isolobal Analogues of Cyclopentane

The first five-membered rings of metal atoms connected by M–M or M-H-M bonds only have been obtained by a Re₂+Re₃ condensation in which a polyhydride acts as a bridging bidentate ligand toward a coordinatively unsaturated fragment (see scheme below). In spite of the octahedral coordination of the Re centers, the Re₅ rings display conformations (twisted and envelope) comparable with those observed for organic five-membered rings of tetrahedral carbon atoms.     

Two‐dimensional non‐close‐packed arrays of nanoparticles via core‐shell nanospheres and reactive ion etching

Nanosized PTFE/polystyrene core‐shell particles were prepared by seed emulsion polymerization technique starting from PTFE seeds of 20 nm. At the end of the reaction, no residual PTFE nor secondary nucleation was observed and by appropriately choosing the ratio between the monomer and the PTFE seed it was possible to obtain particles, with predetermined size in the range 60–100 nm, featuring an extremely narrow size distribution. These particles were successfully employed as building blocks for the preparation of large scale nanosized monolayers through the floating technique. Reactive ion etching was further applied to modulate the size characteristics of the resulting 2D ordered nanostructure. Although for relatively short RIE times a peculiar continuous morphology was observed in which the particles are interconnected through thin arms, on further increasing the RIE time a well‐organized 2D arrangement of particles with size of about 30 nm was obtained. Considering the shell as an expendable ordering and spacing tool, the use of core‐shell nanospheres allows a wide variety of controlled morphologies to be designed and prepared thus opening new perspectives for nanostructure fabrication processes through nanosphere lithography (NSL). Copyright © 2011 John Wiley & Sons, Ltd.     

Surface reactions kinetics between nanocrystalline magnetite and uranyl

Magnetite is the most important end member of iron corrosion products under reducing environment, which is the condition expected in a deep geological high level radioactive waste disposal. Nanocrystalline magnetite was synthesized in the laboratory and its physicochemical properties were analyzed in detail. The kinetics of the adsorption of U(VI) and the kinetics of the actinide reduction to a lower oxidation state, in presence of the oxide, were studied by means of batch sorption techniques and X-ray photoelectron spectroscopy (XPS) analysis. The results showed that the uranium sorption and reduction processes on the magnetite surface have very fast kinetics (hours), the reduction process being triggered by sorption. XPS measurements showed that the speciation of uranium at the surface does not show significant changes with time (from 1 day to 3 months), as well as the quantity of uranium detected at the surface. The surface speciation depended on the initial pH of the contact solution. Considering that the Eh of equilibrium between magnetite and the solution, under our experimental conditions, is slightly positive (50-100 mV), the uranium reduction would also be thermodynamically possible within the liquid phase. However, the kinetics of reduction in the liquid occur at a much slower rate which, in turn, has to depend on the attainment of the magnetite/solution equilibrium. The decrease of uranium in solution, observed after the uranyl adsorption stage, and particularly at acidic pH, is most probably due to the precipitation of U(IV) formed in the solution.     

Interaction of Cu(+) and Cu(2+) ions with alpha-alanine. A density functional study

The Cu(+) and Cu(2+) preferred binding sites on alpha-alanine and their affinity values for this amino acid were determined at the density functional level using three different hybrid exchange correlation potentials and the 6-311++G** basis set. The results demonstrated that the two ions both give stable complexes with alpha-alanine but the stability order of the metalated species and the coordination sites are different depending on the nature of the cation. In particular, the Cu(+)-alpha-alanine ground-state structure is characterized by an eta(2)-N,O coordination with the nitrogen and oxygen atoms belonging to the amino and carbonyl groups, respectively. In contrast, the most stable complex of the Cu(2+)-alpha-alanine system has an eta(2)-O,O coordination with the cation bonded to the -CO(2) (-) moiety of the zwitterionic form of the amino acid. Comparison with the Cu(+) and Cu(2+) affinity values for glycine, computed at the same levels of theory, demonstrated that the relative values do not change significantly as different hybrid functionals are used, although the absolute affinities are strongly influenced by the choice of the hybrid potential.