Adsorption of Unstructured Protein β-Casein to Hydrophobic and Charged Surfaces

In this Monte Carlo simulation study we use mesoscopic modeling to show that β-casein, an unstructured milk protein, adsorbs to surfaces not only due to direct electrostatic and hydrophobic interactions but also due to structural rearrangement and charge regulation due to proton uptake and release. β-casein acts as an amphiphilic chameleon, changing properties according to the chemical environment, and binding is observed to both positively and negatively charged surfaces. The binding mechanisms, however, are fundamentally different. A detailed, per-residue-level analysis shows that the adsorption process is controlled by a few very specific regions of the protein and that these change dramatically with pH. Caseins, being the most abundant proteins in milk, are crucial for the properties of fermented dairy products, such as nutrition, texture, and viscosity, but may also influence adhesion to packaging materials. The latter leads to product losses of about 10%, leading to economical and environmental problems.     

On the design of experiments for determining ternary mixture free energies from static light scattering data using a nonlinear partial differential equation

We mathematically design sets of static light scattering experiments to provide for model-independent measurements of ternary liquid mixing free energies to a desired level of accuracy. A parabolic partial differential equation (PDE), linearized from the full nonlinear PDE [D. Ross, G. Thurston, and C. Lutzer, J. Chem. Phys. 129, 064106 (2008)], describes how data noise affects the free energies to be inferred. The linearized PDE creates a net of spacelike characteristic curves and orthogonal, timelike curves in the composition triangle, and this net governs diffusion of information coming from light scattering measurements to the free energy. Free energy perturbations induced by a light scattering perturbation diffuse along the characteristic curves and towards their concave sides, with a diffusivity that is proportional to the local characteristic curvature radius. Consequently, static light scattering can determine mixing free energies in regions with convex characteristic curve boundaries, given suitable boundary data. The dielectric coefficient is a Lyapunov function for the dynamical system whose trajectories are PDE characteristics. Information diffusion is heterogeneous and system-dependent in the composition triangle, since the characteristics depend on molecular interactions and are tangent to liquid-liquid phase separation coexistence loci at critical points. We find scaling relations that link free energy accuracy, total measurement time, the number of samples, and the interpolation method, and identify the key quantitative tradeoffs between devoting time to measuring more samples, or fewer samples more accurately. For each total measurement time there are optimal sample numbers beyond which more will not improve free energy accuracy. We estimate the degree to which many-point interpolation and optimized measurement concentrations can improve accuracy and save time. For a modest light scattering setup, a sample calculation shows that less than two minutes of measurement time is, in principle, sufficient to determine the dimensionless mixing free energy of a non-associating ternary mixture to within an integrated error norm of 0.003. These findings establish a quantitative framework for designing light scattering experiments to determine the Gibbs free energy of ternary liquid mixtures.     

Crystal structure of ammonia dihydrate II

We have used density-functional-theory (DFT) methods together with a structure searching algorithm to make an experimentally constrained prediction of the structure of ammonia dihydrate II (ADH-II). The DFT structure is in good agreement with neutron diffraction data and verifies the prediction. The structure consists of the same basic structural elements as ADH-I, with a modest alteration to the packing, but a considerable reduction in volume. The phase diagram of the known ADH and ammonia monohydrate + water-ice structures is calculated with the Perdew-Burke-Ernzerhof density functional, and the effects of a semi-empirical dispersion corrected functional are investigated. The results of our DFT calculations of the finite-pressure elastic constants of ADH-II are compared with the available experimental data for the elastic strain coefficients.     

Water-soluble ionic benzoporphyrins

Novel ionic water-soluble tetrabenzoporphyrins have been successfully synthesized via a cascade reaction based on the Heck reaction. The UV-Vis spectra of these porphyrins displayed red-shifted and broadened Soret bands, and significantly enhanced Q bands. These porphyrins are highly water soluble.     

Ab initio parametrized polarizable force field for rutile-type SnO<Subscript>2</Subscript>

We report a new, polarizable classical force field for the rutile-type phase of SnO₂, casserite. This force field has been parametrized using results from ab initio (density functional theory) calculations as a basis for fitting. The force field was found to provide structural, dynamical and thermodynamic properties of tin oxide that compare well with both ab initio and experimental results at ambient and high pressures.     

Application of Fragment Screening and Merging to the Discovery of Inhibitors of the Mycobacterium tuberculosis Cytochrome P450 CYP121

Pieces of the puzzle: The first fragment-based approach was used to target cytochrome?P450 enzymes (CYPs) for drug development. The experiments provide new insights into the binding site of the essential Mycobacterium tuberculosis CYP121 enzyme, and resulted in a promising novel lead compound based on fragment merging.     

High-throughput interrogation of ligand binding mode using a fluorescence-based assay

Probing the pocket: A high-throughput fluorescence-based thermal shift (FTS) assay utilized different forms of a protein (in gray) to establish the binding mode of a ligand (see picture). The assay serves in the rapid evaluation of structure-activity binding-mode relationships for a series of ligands of Plk1, an important target of anticancer therapy.     

Switching pathways: room-temperature neutral solvolysis and substitution of amides

Stick or twist: By introducing steric hindrance at the nitrogen atom, stable linear amides bearing an electron-withdrawing α-substituent (Z = Ar, PhSO(2), P(O)(OR)(2), CN, or CO(2)R) can be induced to undergo solvolysis and substitution reactions through an elimination-addition mechanism (see picture). Key to this process is a low barrier to rotation around the amide bond and the α-substituent?Z.     

Complementary α-alkylation approaches for a sterically hindered spiro[pyrazolopyranpiperidine]ketone

Complementary α-alkylation methods are used to derivatize a sterically hindered spiro[pyrazolopyranpiperidine]ketone. More specifically, enolate alkylations in the presence of DMPU and aldol condensations are employed to deliver these compounds.