Numerical Simulation of the Kinetics of Radical Decay in Single-Pulse High-Energy Electron-Irradiated Polymer Aqueous Solutions.

A new method for the numerical simulation of the radiation chemistry of aqueous polymer solutions is introduced. The method makes use of a deterministic approach combining the conventional homogeneous radiation chemistry of water with the chemistry of polymer radicals and other macromolecular species. The method is applied on single-pulse irradiations of aqueous polymer solutions. The speciation of macromolecular species accounts for the variations in the number of alkyl radicals per chain, molecular weight, and number of internal loops (as a consequence of an intramolecular radical-radical combination). In the simulations, the initial polymer molecular weight, polymer concentration, and dose per pulse (function of pulse length and dose rate during the pulse) were systematically varied. In total, 54 different conditions were simulated. The results are well in line with the available experimental data for similar systems. At a low polymer concentration and a high dose per pulse, the kinetics of radical decay is quite complex for the competition between intra- and intermolecular radical-radical reactions, whereas at a low dose per pulse the kinetics is purely second-order. The simulations demonstrate the limitations of the polymer in scavenging all the radicals generated by water radiolysis when irradiated at a low polymer concentration and a high dose per pulse. They also show that the radical decay of lower-molecular-weight chains is faster and to a larger extent dominated by intermolecular radical-radical reactions, thus explaining the mechanism behind the experimentally observed narrowing of molecular weight distributions.

Quantitative Interpretation of Intracellular Drug Binding and Kinetics Using the Cellular Thermal Shift Assay.

Evidence of physical interaction with the target protein is essential in the development of chemical probes and drugs. The cellular thermal shift assay (CETSA) allows evaluation of drug binding in live cells but lacks a framework to support quantitative interpretations and comparisons with functional data. We outline an experimental platform for such analysis using human kinase p38α. Systematic variations to the assay's characteristic heat challenge demonstrate an apparent loss of compound potency with an increase in duration or temperature, in line with expectations from the literature for thermal shift assays. Importantly, data for five structurally diverse inhibitors can be quantitatively explained using a simple model of linked equilibria and published binding parameters. The platform further distinguishes between ligand mechanisms and allows for quantitative comparisons of drug binding affinities and kinetics in live cells and lysates. We believe this work has broad implications in the appropriate use of the CETSA for target and compound validation.

Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study.

A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

Calculation of Derivative Thermodynamic Hydration and Aqueous Partial Molar Properties of Ions Based on Atomistic Simulations.

The raw ionic solvation free energies calculated on the basis of atomistic (explicit-solvent) simulations are extremely sensitive to the boundary conditions and treatment of electrostatic interactions used during these simulations. However, as shown recently [Kastenholz, M. A.; Hünenberger, P. H. J. Chem. Phys.2006, 124, 224501 and Reif, M. M.; Hünenberger, P. H. J. Chem. Phys.2011, 134, 144104], the application of an appropriate correction scheme allows for a conversion of the methodology-dependent raw data into methodology-independent results. In this work, methodology-independent derivative thermodynamic hydration and aqueous partial molar properties are calculated for the Na(+) and Cl(-) ions at P° = 1 bar and T(-) = 298.15 K, based on the SPC water model and on ion-solvent Lennard-Jones interaction coefficients previously reoptimized against experimental hydration free energies. The hydration parameters considered are the hydration free energy and enthalpy. The aqueous partial molar parameters considered are the partial molar entropy, volume, heat capacity, volume-compressibility, and volume-expansivity. Two alternative calculation methods are employed to access these properties. Method I relies on the difference in average volume and energy between two aqueous systems involving the same number of water molecules, either in the absence or in the presence of the ion, along with variations of these differences corresponding to finite pressure or/and temperature changes. Method II relies on the calculation of the hydration free energy of the ion, along with variations of this free energy corresponding to finite pressure or/and temperature changes. Both methods are used considering two distinct variants in the application of the correction scheme. In variant A, the raw values from the simulations are corrected after the application of finite difference in pressure or/and temperature, based on correction terms specifically designed for derivative parameters at P° and T(-). In variant B, these raw values are corrected prior to differentiation, based on corresponding correction terms appropriate for the different simulation pressures P and temperatures T. The results corresponding to the different calculation schemes show that, except for the hydration free energy itself, accurate methodological independence and quantitative agreement with even the most reliable experimental parameters (ion-pair properties) are not yet reached. Nevertheless, approximate internal consistency and qualitative agreement with experimental results can be achieved, but only when an appropriate correction scheme is applied, along with a careful consideration of standard-state issues. In this sense, the main merit of the present study is to set a clear framework for these types of calculations and to point toward directions for future improvements, with the ultimate goal of reaching a consistent and quantitative description of single-ion hydration thermodynamics in molecular dynamics simulations.