AMBER modelling of intercalated PAHTC-DNA complexes

The equilibrium conformations of physical complexes of selected PAHTC s with a dinucleotide fragment of B-DNA have been calculated by the all-atom AMBER empirical force field method [112]. The B-DNA has been represented by the dG2.dC2 dinucleotide fragment. No phosphate groups were placed at the ends of the strands, which instead carried terminal 03 and 05 hydroxyl groups. 

The B-DNA structure given by Amott and Hukins [171] is taken as initial conformation for the DNA fragment as this structure is close to the native DNA at physiological conditions. According to electric linear dichroism measurements [154], there are several possibilities for the mutual geometrical arrangement of the components of the physical complex. Hence, different initial orientations and conformations of PAH metabolites were considered with the aim to find the most stable structure of the intercalated complex. 

The equilibrium geometry of the carbon skeleton of TC s does not change much upon complexation, while the hydroxyl groups alter substuf t/ally their conformations and are involved in specific intermolecular interactions. The AMBER structures of the physical complexes of the dinucleotide with TC s are characterised by the following common features  

Thus two hydrogen-bonds between TC s and the DNA fragment determine their mutual orientation and stabilise the complex. In addition, these H-bonds are stereospecific and caused by the stereochemical compatibility of the N(3) atoms in successive guanine residues and the axial hydroxyl groups in PAHTC s. 

The most interesting examples for PAH metabolite-DNA steric incompatibility are the enantiomers 19 and 20 of the carcinogenic metabolites 8 and 9 of benzo[a]pyrene, respectively. All of these four structures are electronically highly stabilised [16] and form stable complexes with the DNA fragment, but with 19 and 20 the fragment 

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