Comparative evaluation of MMPBSA and XSCORE to compute binding free energy in XIAP-peptide complexes

Evaluation of binding free energy in receptor-ligand complexes is one of the most important challenges in theoretical drug design. Free energy is directly correlated to the thermodynamic affinity constant, and, as a first step in druglikeness, a lead compound must have this constant in the range of micro- to nanomolar activity. Many efforts have been made to calculate it by rigorous computational approaches, such as free energy perturbation or linear response approximation. However, these methods are still computationally expensive. We focus our work on XIAP, an antiapoptotic protein whose inhibition can lead to new drugs against cancer disease. We report here a comparative evaluation of two completely different methodologies to estimate binding free energy, MMPBSA (a force field based function) and XSCORE (an empirical scoring function), in seven XIAP-peptide complexes using a representative set of structures generated by previous molecular dynamics simulations. Both methods are able to predict the experimental binding free energy with acceptable errors, but if one needs to identify slight differences upon binding, MMPBSA performs better, although XSCORE is not a bad choice taking into account the low computational cost of this method.     

Experimental and theoretical evidence of the first Au(i)...Bi(iii) interaction

Complex [Au(C6F5)2][Bi(C6H4CH2NMe(2)-2)2] displays the first example of an interaction between Au(I) and Bi(III), the nature of which is shown to be consistent with the presence of a high ionic contribution (79%) and a dispersion type (van der Waals) interaction (21%).     

Live-cell-permeant thiophene fluorophores and cell-mediated formation of fluorescent fibrils

In our search for thiophene fluorophores that can overcome the limits of currently available organic dyes in live-cell staining, we synthesized biocompatible dithienothiophene-S,S-dioxide derivatives (DTTOs) that were spontaneously taken up by live mouse embryonic fibroblasts and HeLa cells. Upon treatment with DTTOs, the cells secreted nanostructured fluorescent fibrils, while cell viability remained unaltered. Comparison with the behavior of other cell-permeant, newly synthesized thiophene fluorophores showed that the formation of fluorescent fibrils was peculiar to DTTO dyes. Laser scanning confocal microscopy of the fluorescent fibrils showed that most of them were characterized by helical supramolecular organization. Electrophoretic analysis and theoretical calculations suggested that the DTTOs were selectively recognized by the HyPro component of procollagen polypeptide chains and incorporated through the formation of multiple H-bondings.     

A multiscale simulation system for the prediction of drug-induced cardiotoxicity

The preclinical assessment of drug-induced ventricular arrhythmia, a major concern for regulators, is typically based on experimental or computational models focused on the potassium channel hERG (human ether-a-go-go-related gene, K(v)11.1). Even if the role of this ion channel in the ventricular repolarization is of critical importance, the complexity of the events involved make the cardiac safety assessment based only on hERG has a high risk of producing either false positive or negative results. We introduce a multiscale simulation system aiming to produce a better cardiotoxicity assessment. At the molecular scale, the proposed system uses a combination of docking simulations on two potassium channels, hERG and KCNQ1, plus three-dimensional quantitative structure-activity relationship modeling for predicting how the tested compound will block the potassium currents IK(r) and IK(s). The obtained results have been introduced in electrophysiological models of the cardiomyocytes and the ventricular tissue, allowing the direct prediction of the drug effects on electrocardiogram simulations. The usefulness of the whole method is illustrated by predicting the cardiotoxic effect of several compounds, including some examples in which classic hERG-based models produce false positive or negative results, yielding correct predictions for all of them. These results can be considered a proof of concept, suggesting that multiscale prediction systems can be suitable for being used for preliminary screening in lead discovery, before the compound is physically available, or in early preclinical development when they can be fed with experimentally obtained data.     

Application of ATR-far-infrared spectroscopy to the analysis of natural resins

This study proposes FTIR spectroscopy in the far-infrared region (FarIR) as an alternative method for the characterisation of natural resins. To this purpose, standards of natural resins belonging to four different categories (sesquiterpenic, i.e. elemi, shellac; diterpenic, i.e. colophony, Venice turpentine; diterpenic with polymerised components, i.e. copal, sandarac; triterpenic, i.e. mastic and dammar) used as paint varnishes have been analysed by FarIR spectroscopy in ATR mode. Discrimination between spectral data and repeatability of measurements have been magnified and verified using principal component analysis, in order to verify the effectiveness of the method in distinguishing the four resin categories. The same samples were analysed in the MidIR range, but the spectral differences between the different categories were not evident. Moreover, the method has been tested on historical samples from the painting “La Battaglia di Cialdiran” (sixteenth century) and from a gilded leather (seventeenth century). In the first case, FarIR spectroscopy allowed confirmation of the results obtained by analytical pyrolysis. In the latter, FarIR spectroscopy proved successfully, effective in the identification of the superficial resin layer that could not be detected with the bulk chromatographic analyses.     

Reynolds Number Effects on the Coherent Dynamics of the Turbulent Horseshoe Vortex System

The adverse pressure gradient induced by a surface-mounted obstacle in a turbulent boundary layer causes the approaching flow to separate and form a dynamically rich horseshoe vortex system (HSV) in the junction of the obstacle with the wall. The Reynolds number of the flow (Re) is one of the important parameters that control the rich coherent dynamics of the vortex, which are known to give rise to low-frequency, bimodal fluctuations of the velocity field (Devenport and Simpson, J Fluid Mech 210:23–55, 1990; Paik et al., Phys Fluids 19:045107, 2007). We carry out detached eddy simulations (DES) of the flow past a circular cylinder mounted on a rectangular channel for Re = 2.0 × 10⁴ and 3.9 × 10⁴ (Dargahi, Exp Fluids 8:1–12, 1989) in order to systematically investigate the effect of the Reynolds number on the HSV dynamics. The computed results are compared with each other and with previous experimental and computational results for a related junction flow at a much higher Reynolds number (Re = 1.15 × 10⁵) (Devenport and Simpson, J Fluid Mech 210:23–55, 1990; Paik et al., Phys Fluids 19:045107, 2007). The computed results reveal significant variations with Re in terms of the mean-flow quantities, turbulence statistics, and the coherent dynamics of the turbulent HSV. For Re = 2.0 × 10⁴ the HSV system consists of a large number of necklace-type vortices that are shed periodically at higher frequencies than those observed in the Re = 3.9 × 10⁴ case. For this latter case the number of large-scale vortical structures that comprise the instantaneous HSV system is reduced significantly and the flow dynamics becomes quasi-periodic. For both cases, we show that the instantaneous flowfields are dominated by eruptions of wall-generated vorticity associated with the growth of hairpin vortices that wrap around and disorganize the primary HSV system. The intensity and frequency of these eruptions, however, appears to diminish rapidly with decreasing Re. In the high Re case the HSV system consists of a single, highly energetic, large-scale necklace vortex that is aperiodically disorganized by the growth of the hairpin mode. Regardless of the Re, we find pockets in the junction region within which the histograms of velocity fluctuations are bimodal as has also been observed in several previous experimental studies.     

Surface versus volume effects in luminescent ceria nanocrystals synthesized by an oil-in-water microemulsion method

Pure and europium (Eu(3+)) doped cerium dioxide (CeO(2)) nanocrystals have been synthesized by a novel oil-in-water microemulsion reaction method under soft conditions. In-situ X-ray diffraction and RAMAN spectroscopy, high-resolution transmission electron microscopy, UV/Vis diffuse-reflectance and Fourier transform infrared spectroscopy as well as time-resolved photoluminescence spectroscopy were used to characterize the nanaocrystals. The as-synthesized powders are nanocrystalline and have a narrow size distribution centered on 3 nm and high surface area of ~250 m(2) g(-1). Only a small fraction of the europium ions substitutes for the bulk, cubic Ce(4+) sites in the europium-doped ceria nanocrystals. Upon calcination up to 1000 °C, a remarkable high surface area of ~120 m(2) g(-1) is preserved whereas an enrichment of the surface Ce(4+) relative to Ce(3+) ions and relative strong europium emission with a lifetime of ~1.8 ms and FWHM as narrow as 10 cm(-1) are measured. Under excitation into the UV and visible spectral range, the europium doped ceria nanocrystals display a variable emission spanning the orange-red wavelengths. The tunable emission is explained by the heterogeneous distribution of the europium dopants within the ceria nanocrystals coupled with the progressive diffusion of the europium ions from the surface to the inner ceria sites and the selective participation of the ceria host to the emission sensitization. Effects of the bulk-doping and impregnation with europium on the ceria host structure and optical properties are also discussed.     

Multiple solutions for Neumann and periodic problems with singular ?-Laplacian

We use the critical point theory for convex, lower semicontinuous perturbations of C¹-functionals to establish existence of multiple radial solutions for some one parameter Neumann problems involving the operator . Similar results for periodic problems are also provided.     

On the Birch and Swinnerton-Dyer conjecture for abelian varieties attached to Hilbert modular forms

In this paper we prove that if the Birch and Swinnerton-Dyer conjecture holds for abelian varieties attached to Hilbert newforms of parallel weight 2 with trivial central character, then the Birch and Swinnerton-Dyer conjecture holds for abelian varieties attached to Hilbert newforms of parallel weight 2 with trivial central character regarded over arbitrary totally real number fields.