Molecular motions in drug design: the coming age of the metadynamics method

Metadynamics is emerging as a useful free energy method in physics, chemistry and biology. Recently, it has been applied also to investigate ligand binding to biomolecules of pharmacological interest. Here, after introducing the basic idea of the method, we review applications to challenging targets for pharmaceutical intervention. We show that this methodology, especially when combined with a variety of other computational approaches such as molecular docking and/or molecular dynamics simulation, may be useful to predict structure and energetics of ligand/target complexes even when the targets lack a deep binding cavity, such as DNA and proteins undergoing fibrillation in neurodegenerative diseases. Furthermore, the method allows investigating the routes of molecular recognition and the associated binding energy profiles, providing a molecular interpretation to experimental data.     

Analysis of fluid-structure interaction in low pressure MEMS by Integral Equations

The evaluation of gas dissipation occurring in inertial polysilicon MEMS is addressed focusing the attention on the free–molecule flow. In this regime, which is very often of interest for industrial applications, collisions between molecules can be neglected and the momentum transfer to the moving shuttle can be easily computed. Since the surfaces of silicon MEMS are generally very rough, a complete diffusion model is adopted to describe the wall–molecule interaction. A Boundary Integral Equation approach is proposed and it is shown that the introduction of the key assumption of small perturbations is crucial in the development of a robust and fast numerical tool. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Sul moto d’un punto sollecitato verso una retta

Rendiconti del Circolo Matematico di Palermo Series 1 -     

Interacting localized solutions for the Zakharov–Kusnetsov equation

Analytical investigation of the Zakharov–Kusnetsov equation shows the existence of approximate interacting localized solutions. Using the asymptotic perturbation method, based on Fourier expansion and spatio-temporal rescaling, it is found that the amplitude slow modulation of Fourier modes is described by a C-integrable (solvable via an appropriate change of variables) system of non-linear evolution equations. It is demonstrated the existence of localized solutions (dromions, lumps, ring solitons and breathers) as well as of multiple instanton solutions. The interaction between the localized solutions are completely elastic, because they pass through each other and preserve their shape, the only change being a phase shift.     

Thermodynamic study of the vaporization of uracil

The vapour pressure of uracil was measured in the temperature range 452–587 K using different techniques and the pressure—temperature equation log P(kPa) = 12.13 ± 0.50 — (6823 ± 210)/T was derived. The thermodynamic functions of gaseous and solid uracil were also evaluated through spectroscopic and calorimetric measurements. The sublimation enthalpy of uracil, ΔH⁰₂₉₈ = 131 ± 5 kJ mole^?1, was derived from second and third law treatment of the vapour data.     

Kinetics and bioenergetics of Spirulina platensis cultivation by fed-batch addition of urea as nitrogen source

The cyanobacterium Spirulina platensis was cultivated in bench-scale miniponds on bicarbonate/carbonate solutions using urea as nitrogen source. To minimize limitation and inhibition phenomena, urea was supplied semicontinuously using exponentially increasing feeding rates. The average growth rates obtained alternately varying the total mass of urea added per unit reactor volume (275<m _T<725 mg/L) and the total feeding time (9<t _T<15 d) clearly evidenced nitrogen limitation for m _T<500 mg/L and excess nitrogen inhibition above this threshold. The time behavior of the specific growth rate at variable urea feeding patterns allowed estimation of the time-dependent Gibbsenergy dissipation for cell growth under the actual depletion conditions of fed-batch cultivations. Comparison of the yield of growth on Gibbs energy obtained using either urea or KNO₃ pointed to the preference of S. platensis for the former nitrogen source, likely owing to more favorable bioenergetic conditions.     

Surfing silica surfaces superciliously

The present mini-review summarizes the experience gathered by our group in developing different classes of novel quaternarized heterocyclic compounds able to modulate and reverse the electroendoosmotic flow (EOF) in a most peculiar manner. The first class comprises mono-salt compounds, with the determinant omega-iodoalkyl chains of different lengths (typically C4-C8), able to be adsorbed by silicas, at alkaline pH, and spontaneously alkylate ionised silanols, thus becoming covalently affixed to it. The second class is constituted by di-salt compounds, attached at the termini of an alkyl chain of variable lengths (here too, typically, C4-C8). This second class is unable to bind covalently silica surfaces, although, in thin-layer chromatography, it exhibits an extraordinary affinity for silica beads, contrary to the first one. On the basis of the strikingly different behaviour, structural rules are derived for the minimum requirements for general classes of amines to bind to silica walls and modify EOF. For compounds unable to bind covalently to the wall, the most important structural motif is two quaternary nitrogens spaced apart by a C4 chain: this seems to be the average distance (i.e., 0.8 nm) between two adjacent, ionized silanols for a snug fit. The other structural binding motif is the "hydrophobic decoration", i.e., the ratio of charged groups to alkyl residue in the various amines; amines with high levels of such alkane groups (i.e., with higher hydrophobicity), seem to bind more tenaciously to the wall, probably due to hydrophobic interaction not to the wall but among the amine derivatives themselves, when carpeting the silica.     

Prediction of wheat dough W and P/L inflation test parameters by capillary zone electrophoresis of a protein extract followed by multivariate regression

A procedure for the evaluation of the wheat flour hardness, based on capillary electrophoresis of a protein extract in an isoelectric acidic buffer, was developed. The 13 flour samples were extracted twice, and two injections of each extract were made. Separations were performed in a background electrolyte (BGE) containing 40 mM aspartic acid, 6 M urea, and 0.5% hydroxyethylcellulose at 60 degrees C. Using the normalized and corrected areas of 79 peaks and peak groups, a partial least squares regression (PLS1) model was able to predict the flour strength or dough deformation work (W) and the dough tenacity/extensibility ratio (P/L) (Alveograph parameters) with an average relative standard deviation in the predictions of +/- 3% and +/-8%, respectively. These values amounted to a +/- 6-8% and +/- 11% with multiple linear regression (MLR) and PLS1 models constructed by measuring only 12 peaks and peak group areas on the electropherograms.     

A new kinetic approach to the fermentation of multisubstrate complex media

Ethanol production from natural complex media has been studied in this work. A new kinetic approach is presented for two-substrate media, such as hardwood hemicellulose hydrolysate, which predominantly consists of a mixture of xylose and glucose. It has been founded on the supposition that the whole ethanol production and biomass growth can be subdivided into two separated components imputable to glucose and xylose consumptions, respectively. A model describing the continuous fermentation in CSTR byPachysolen tannophilus has been also presented, and experimentally verified; it takes into account the different substrate consumption rates of these sugars contained in both natural and synthetic complex media.