Carcinogenesis of urethane: simulation versus experiment.

The carcinogenesis of urethane (ethyl carbamate), a byproduct 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 among 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 solutions 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 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,N(2)-ethenodeoxyguanosine adduct.

Structural study of simple organic acids by small-angle x-ray scattering and monte carlo simulations.

This study represents an extension of our previous research on the structural properties of simple organic liquids to the systems of organic acids. A set of simple acids from ethanoic to octanoic was modelled with the TraPPE-UA force field and configurational bias Monte Carlo (CBMC) simulations were used to obtain a number of configurations of each system. These data were subsequently used as a basis for the calculation of X-ray scattering intensities, partial radial distribution functions and statistical analysis of molecular aggregation in liquid organic acids. The comparison of simulated X-ray scattering curves with the results of SAXS measurements has shown the agreement to be overall somewhat poorer than in our previous studies on alcohols and aldehydes, although it did improve with increasing molecular length. Hydrogen bonds between the hydroxylhydrogen atom and the carbonyl oxygen have been found to have a profound effect on the structure of the liquid acids. However, the model-based results showed that the formation of intermolecular hydrogen bonds involving the hydroxyl oxygen was disproportionately scarce in these systems. Statistical evaluation of the model configurations has shown that only about 4% of acid molecules form such a type of hydrogen bonds, in contrast to 68% of molecules that form the hydrogen bond with the carbonyl oxygen. This suggests that the force field might be underestimating the hydrogen bonding via hydroxyl oxygen. The statistical analysis has also shown that the simulated molecules preferred to assemble into small molecular aggregates, particularly into double-bonded molecule pairs.

The complemented system approach: a novel method for calculating the x-ray scattering from computer simulations.

In this paper, we review the main problem concerning the calculation of x-ray scattering of simulated model systems, namely, their finite size. A novel method based on the Rayleigh-Debye-Gans approximation was derived, which allows sidestepping this issue by complementing the missing surroundings of each particle with an average image of the system. The method was designed to operate directly on particle configurations without an intermediate step (e.g., calculation of pair distribution functions): in this way, all information contained in the configurations was preserved. A comparison of the results against those of other known methods showed that the new method combined several favorable properties: an arbitrary q-scale, scattering curves free of truncation artifacts, and good behavior down to the theoretical lower limit of the q-scale. A test of computational efficiency was also performed to establish a relative scale between the speeds of all known methods: the reciprocal lattice approach, the brute force method, the Fourier transform approach, and the newly presented complemented system approach.

Exploring the structural properties of simple aldehydes: a Monte Carlo and small-angle X-ray scattering study.

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.