Using molecular strain and aromaticity to create ultraweak C-H bonds and stabilized carbon-centered radicals

An approach based on relief of molecular strain in the parent hydrocarbon, extended conjugation in the radical, and the driving force toward aromaticity is used to d

Computational modeling of substituent effects on phenol toxicity

Standard computational models of cytotoxicity of substituted phenols relate the toxicity to a set of qualitative structure-activity relationship (QSAR) descriptors such as log P, pKa, OH bond dissociation enthalpy (BDE), etc. I

Understanding the toxicity of phenols: Using quantitative structure-activity relationship and enthalpy changes to discriminate between possible mechanisms

Experimental studies of the "extended toxicity" of substituted phenols are mainly of two types: the toxicity due to phenoxyl radical formation and the toxicity cause

Interaction force diagrams: New insight into ligand-receptor binding

A method is described to calculate and visualize the interaction forces of ligand-receptor complexes. Starting from an X-ray crystallographic structure, a 'thawing' procedure results in a force-field energy-minimized geometry which is close to the crystallographic starting point. By subtracting non-bonded interactions of the ligand with each amino acid residue and using the resulting force vectors to describe the slope of the remaining potential, two types of interaction force diagrams are created; the first shows the direction of the force vectors in 3D and the second shows the magnitude of the force vectors. The latter representation leads to definition of an 'Interaction Force Fingerprint' (IFFP) which is characteristic of the ligand-receptor binding. IFFPs are used to discuss ligand binding in the human estrogen receptors ERα and ERβ, and provide new insight into ligand selectivity between receptor isoforms

Stability of carbon-centered radicals: Effect of functional groups on the energetics of addition of molecular oxygen

In this paper we examine a series of hydrocarbons with structural features which cause a weakening of the C-H bond. We use theoretical calculations to explore whether the carbon-centered radicals R* which are created after breaking the bond can be stabilized enough so that they resist the addition of molecular oxygen, i.e. where the reaction R* + O 2 → ROO* becomes energetically unfavorable. Calculations using a B3LYP-based method provide accurate bond dissociation enthalpies (BDEs) for R-H and R-00* bonds, as well as Gibbs free energy changes for the addition reaction. The data show strong correlations between R-00* and R-H BDEs for a wide variety of structures. They also show an equally strong correlation between the R-00* BDE and the unpaired spin density at the site of addition. Using these data we examine the major functional group categories proposed in several experimental studies, and assess their relative importance. Finally, we combine effects to try to optimize resistance to the addition of molecular oxygen, an important factor in designing carbon-based antioxidants

Experimental and theoretical thermodynamic studies of the adsorption of polyhalogenated organic compounds from aqueous solution by chemically modified multi-walled carbon nanotubes

Multi-walled carbon nanotubes (MWCNTs) were chemically modified with octadecyl amine or polyethyleneglycol and then used as solid phase adsorbents for the adsorption from aqueous solution of different polyhalogenated organic pollutants: pentachlorophenol, 2,4,5-trichlorophenol, 3,3′,4,4′- tetrachlorobiphenyl and 2,2′,5,5′-tetrabromobiphenyl from model aqueous solutions. The effects of temperature were measured and thus the Gibbs energy, enthalpy, and entropy of adsorption were calculated. In general, the Gibbs energy of adsorption was negative for the target analytes, indicating that adsorption was spontaneous at all temperatures. On the other hand, the values of the enthalpy and entropy of adsorption were significantly dependent on the type of modified MWCNTs as well as the analytes used. Computer modeling was used to simulate the adsorption process and calculate the Gibbs energies of adsorption. The results showed moderate agreement with the experimentally determined values

Investigation of residues Lys112, Glu136, His138, Gly247, Tyr248, and Asp249 in the active site of yeast cystathionine β-synthase

Cystathionine β-synthase (CBS), the first enzyme of the reverse transsulfuration pathway, catalyzes the pyridoxal 5′-phosphate-dependent condensation of L-serine and L-homocysteine to form L-cystathionine (L-Cth). A model of the L-Cth complex of the truncated form of yeast CBS (ytCBS), comprising the catalytic core, was constructed to identify residues involved in the binding of L-homocysteine and the distal portion of L-Cth. Residue K112 was selected for site-directed mutagenesis based on the results of the in silico docking of L-Cth to the modeled structure of ytCBS. Residues E136, H138, Y248, and D249 of ytCBS were also targeted as they correspond to identical polar residues lining the mouth of the active site in the structure of human CBS. A series of 8 site-directed mutants was constructed, and their order of impact on the ability of ytCBS to catalyze the β-replacement reaction is G247S ≈ K112Q > K112L ≈ K112R ≫ Y248F > D249A ≈ H138F > E136A. The β-replacement activity of G247S, which corresponds to the homocystinuria-associated G307S mutant of human CBS, is undetectable. The Km L-Ser of the K112L and K112R mutants is increased by 50- and 90-fold, respectively, while Km L-Hcys increases by only 2- and 4-fold, respectively. The Km L-Hcys of H138F and Y248F is increased by 8- and 18-fold, respectively. These results indicate that, while the targeted residues are not direct determinants of L-Hcys binding, G307, Y248, and K112 play essential roles in the maintenance of appropriate active-site conformation

Experimental versus predicted affinities for ligand binding to estrogen receptor: Iterative selection and rescoring of docked

The computational determination of binding modes for a ligand into a protein receptor is much more successful than the prediction of relative binding affinities (RBAs) for a set of ligands. Here we consider the binding of a set of 26 synthetic A-CD ligands into the estrogen receptor ERα. We show that the MOE default scoring function (London dG) used to rank the docked poses leads to a negligible correlation with experimental RBAs. However, switching to an energy-based scoring function, using a multiple linear regression to fit experimental RBAs, selecting top-ranked poses and then iteratively repeating this process leads to exponential convergence in 4-7 iterations and a very strong correlation. The method is robust, as shown by various validation tests. This approach may be of general use in improving the quality of predicted binding affinities