The carcinogenesis of urethane (ethyl carbamate), a by-product of fermentation that is consistently found in various food products, was investigated with a combination of kinetic experiments and quantum chemical calculations. The main objective of the study was to find ΔG‡, the activation free energy for the rate-limiting step of the SN2 reaction between the ultimate carcinogen of urethane, vinyl carbamate epoxide (VCE), and different nucleobases of the DNA. In the experimental part, the second-order reaction rate constants for the formation of the main 7-(2-oxoethyl)guanine adduct in aqueous solution of deoxyguanosine and in DNA were determined. A series of ab initio, density functional theory (DFT) and semiempirical molecular orbital (MO) calculations was then performed to determine the activation barriers for the reaction between VCE and nucleobases methylguanine, methyladenine, and methylcytosine. Effects of hydration were incorporated with the use of the solvent reaction field method of Tomasi and co-workers and the Langevine dipoles model of Florian and Warshel. The computational results for the main adduct were found to be in good agreement with the experiment, thus presenting a strong evidence for the validity of the proposed SN2 mechanism. This allowed us to predict the activation barriers of reactions leading to side products for which kinetic experiments have not yet been performed. Our calculations have shown that the main 7-(2-oxoethyl)deoxyguanosine adduct indeed forms preferentially because the emergence of other adducts either proceeds across a significantly higher activation barrier or the geometry of the reaction requires the Watson–Crick pairs of the DNA to be broken. The computational study also considered the questions of stereoselectivity, the ease of the elimination of the leaving group, and the relative contributions of the two possible reaction paths for the formation of the 1,N2-ethenoguanosine adduct.
Monte Carlo simulation and theory were used to study the potential of mean force (PMF) between a pair of big colloidal (solute) particles suspended in a sea of smaller particles (solvent) interacting via Baxter's sticky hard sphere (SHS) potential. Simulation results were obtained by applying a special simulation technique developed for sampling the hard sphere collision force, while the theoretical predictions were calculated from the analytic solution of the Percus-Yevick/Ornstein-Zernike integral equation for spatial correlations in a two-component mixture at vanishing solute concentration. Both theory and simulation revealed oscillations of the solute-solute PMF with a period equal to the diameter of the solvent molecules. Further, the attractive PMF between solute particles in the SHS fluid decays slower than in a hard sphere solvent. Upon increasing the strength of attraction (stickiness) between the molecules of solvent, these oscillations gradually disappear, the PMF becoming long ranged and attractive at all separations.
The structure of simple linear alkanals from propanal to nonanal was studied utilizing configurational bias Monte Carlo (MC) simulations of the aldehydes modeled according to the transferable potential for phase equilibria-united atom force field (TraPPE-UA) and was compared to experimental small-angle X-ray scattering (SAXS) results. This was done by exploiting a recently developed approach for calculating the scattering intensities from theoretically obtained MC data by utilizing the Debye equation (Tomsic et al. J. Phys. Chem. B 2007, 111, 1738). Similar calculations were also performed utilizing a well-established approach based on the reciprocal lattice. Comparison of the calculated scattering data with the experimental SAXS results in the first instance revealed information on the molecular organization in simple aldehydes and in addition also served as a good structural test of the TraPPE-UA force field used to model the aldehydes studied. However, it turned out that such a structural test is a rather strict test for the model which otherwise showed good agreement with the experimental data from the thermodynamic point of view.
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