In silico screening of mutational effects on enzyme-proteic inhibitor affinity: a docking-based approach

<p>Abstract</p> <p>Background</p> <p>Molecular recognition between enzymes and proteic inhibitors is crucial for normal functioning of many biological pathways. Mutations in either the enzyme or the inhibitor protein often lead to a modulation of the binding affinity with no major alterations in the 3D structure of the complex.</p> <p>Results</p> <p>In this study, a rigid body docking-based approach has been successfully probed in its ability to predict the effects of single and multiple point mutations on the binding energetics in three enzyme-proteic inhibitor systems. The only requirement of the approach is an accurate structural model of the complex between the wild type forms of the interacting proteins, with the assumption that the architecture of the mutated complexes is almost the same as that of the wild type and no major conformational changes occur upon binding. The method was applied to 23 variants of the ribonuclease inhibitor-angiogenin complex, to 15 variants of the barnase-barstar complex, and to 8 variants of the bovine pancreatic trypsin inhibitor-β Trypsin system, leading to thermodynamic and kinetic estimates consistent with in vitro data. Furthermore, simulations with and without explicit water molecules at the protein-protein interface suggested that they should be included in the simulations only when their positions are well defined both in the wild type and in the mutants and they result to be relevant for the modulation of mutational effects on the association process.</p> <p>Conclusion</p> <p>The correlative models built in this study allow for predictions of mutational effects on the thermodynamics and kinetics of association of three substantially different systems, and represent important extensions of our computational approach to cases in which it is not possible to estimate the absolute free energies. Moreover, this study is the first example in the literature of an extensive evaluation of the correlative weights of the single components of the ZDOCK score on the thermodynamics and kinetics of binding of protein mutants compared to the native state.</p> <p>Finally, the results of this study corroborate and extend a previously developed quantitative model for in silico predictions of absolute protein-protein binding affinities spanning a wide range of values, i.e. from -10 up to -21 kcal/mol.</p> <p>The computational approach is simple and fast and can be used for structure-based design of protein-protein complexes and for in silico screening of mutational effects on protein-protein recognition.</p

The cientificWorldJOURNAL Research Article Acid-Base Chemistry of White Wine: Analytical Characterisation and Chemical Modelling

A chemical model of the acid-base properties is optimized for each white wine under study, together with the calculation of their ionic strength, taking into account the contributions of all significant ionic species (strong electrolytes and weak one sensitive to the chemical equilibria). Coupling the HPLC-IEC and HPLC-RP methods, we are able to quantify up to 12 carboxylic acids, the most relevant substances responsible of the acid-base equilibria of wine. The analytical concentration of carboxylic acids and of other acid-base active substances was used as input, with the total acidity, for the chemical modelling step of the study based on the contemporary treatment of overlapped protonation equilibria. New protonation constants were refined (L-lactic and succinic acids) with respect to our previous investigation on red wines. Attention was paid for mixed solvent (ethanol-water mixture), ionic strength, and temperature to ensure a thermodynamic level to the study. Validation of the chemical model optimized is achieved by way of conductometric measurements and using a synthetic &quot;wine&quot; especially adapted for testing

“Evidence-Based Dentistry in Oral Surgery: Could We Do Better?”

Evidence-based Dentistry (EBD), like Evidence-based Medicine (EBM), was born in order to seek the “best available research evidence” in the field of dentistry both in research and clinical routine

Extreme events representation in CMCC-CM2 standard and high-resolution general circulation models

The recent advancements in climate modeling partially build on the improvement of horizontal resolution in different components of the simulating system. A higher resolution is expected to provide a better representation of the climate variability, and in this work we are particularly interested in the potential improvements in representing extreme events of high temperature and precipitation. The two versions of the Centro Euro-Mediterraneo sui Cambiamenti Climatici (CMCC-CM2) model used here adopt the highest horizontal resolutions available within the last family of the global coupled climate models developed at CMCC to participate in the Coupled Model Intercomparison Projects, Phase 6 (CMIP6) effort. The main aim of this study is to document the ability of the CMCC-CM2 models to represent the spatial distribution of extreme events of temperature and precipitation, under the historical period, comparing model results to observations, the European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis (ERA5), multi-source weighted-ensemble precipitation (MSWEP) and Climate Hazards Group infrared precipitation with station data (CHIRPS) observations. For a more detailed evaluation we use both 6-hourly and daily time series, to compute indices representative of intense and extreme conditions. In terms of mean climate, the two models are able to realistically reproduce the main patterns of temperature and precipitation. The high resolution version ( ∘ horizontal resolution) of the atmospheric model provides better results than the standard resolution one (1°), not only in terms of means but also in terms of intense and extreme events of temperature defined at daily and 6-hourly frequencies. This is also the case of average and intense precipitation. On the other hand the extreme precipitation is not improved by the adoption of a higher horizontal resolution

The Accuracy of Computer-Assisted Implant Surgery Performed Using Fully Guided Templates versus Pilot-Drill Guided Templates

Purpose. Computer-assisted stereolithographically guided surgery allows an ideal implant placement for prosthetic restoration. Two types of stereolithographic templates are currently available: a fully guided template and a pilot-drill guided template. The purpose of this study was (i) to evaluate the accuracy of implant insertion using these types of surgical templates and (ii) to define parameters influencing accuracy. Materials and Methods. 20 patients were enrolled and divided into 2 study groups: in group A, implants were placed using CAD-CAM templates with fully guided sleeves; in group B, implants were placed with a template with only pilot-drill guided sleeves. Pre- and postoperative computed tomographies were used to measure differences between final positions of implants and virtually planned positions. Three linear discrepancies (coronal, apical, and depth) and two angular ones (buccolingual and mesiodistal) were measured. Correlations between accuracy and jaws of interest, implant length and diameters, and type of edentulism were also analysed. Results. A total of 50 implants were inserted in 15 patients using CAD-CAM templates: 23 implants in group A and 27 in group B. The mean coronal deviations were 1.16 and 1.11 mm (P = 0.35), respectively; the mean apical deviations were 1.65 and 1.71 mm (P = 0.22); the mean depth deviations were 0.95 and −0.68 mm (P = 0.032); the mean buccolingual angular deviations were 4.16° and 6.72° (P = 0.042); and the mean mesiodistal ones were 2.81° and 5.61° (P = 0.029). In addition, the accuracy was statistically influenced only by implant diameter for coronal discrepancy (P = 0.035) and by jaw of interest for mesiodistal angulation (P = 0.045). Conclusion. Fully guided implant surgery was more accurate than pilot-drill guided surgery for different parameters. For both types of surgery, a safety margin of at least 2mm should be preserved during implant planning to prevent damage to nearby anatomical structures