The geometries of a 13 mer of a DNA double helix (5'-GCGTACACATGCG-3') were determined by molecular dynamics simulations using a Cornell et al. empirical force field. The bases in the central base pair (shown in bold) were replaced (one or both) by a series of hydrophobic base analogues (phenyl, biphenyl, phenylnaphathalene, phenylanthracene and phenylphenanthrene). Due to the large fluctuations of the systems, an average geometry could not be determined. The interaction energies of the Model A, which consisted of three central steps of a duplex without a sugar phosphate backbone, taken from molecular dynamics simulations (geometry sampled every 1 ps), were calculated by the self-consistent charge density functional based tight-binding (SCC-DFTB-D) method and were subsequently averaged. The higher the stability of the systems the higher the aromaticity of the base analogues. To estimate the desolvation energy of the duplex, the COSMO continuum solvent model was used and the calculations were provided on a larger model, Model B (the three central steps of the duplex with a sugar phosphate backbone neutralised by H atoms), taken from molecular dynamics simulations (geometry sampled every 200 ps) and subsequently averaged. The selectivity of the base analogue pairs was ascertained (Model B) by including the desolvation energy and the interaction energy of both strands, as determined by the SCC-DFTB-D method. The highest selectivity was found for a phenylphenanthrene. Replacing the nucleic acid bases with a base analogue leads to structural changes of the central pair. Only with the smallest base analogues (phenyl) does the central base pair stay planar. When passing to larger base analogues the central base pair is usually stacked.
The dynamic structure and potential energy surface of adenine...thymine and guanine...cytosine base pairs and their methylated analogues interacting with a small number (from 1 to 16 molecules) of organic solvents (methanol, dimethylsulfoxide, and chloroform) were investigated by various theoretical approaches starting from simple empirical methods employing the Cornell et al. force field to highly accurate ab initio quantum chemical calculations (MP2 and particularly CCSD(T) methods). After the simple molecular dynamics simulation, the molecular dynamics in combination with quenching technique was also used. The molecular dynamics simulations presented here have confirmed previous experimental and theoretical results from the bulk solvents showing that, whereas in chloroform the base pairs create hydrogen-bonded structures, in methanol, stacked structures are preferred. While methanol (like water) can stabilize the stacked structures of the base pairs by a higher number of hydrogen bonds than is possible in hydrogen-bonded pairs, the chloroform molecule lacks such a property, and the hydrogen-bonded structures are preferred in this solvent. The large volume of the dimethylsulfoxide molecule is an obstacle for the creation of very stable hydrogen-bonded and stacked systems, and a preference for T-shaped structures, especially for complexes of methylated adenine...thymine base pairs, was observed. These results provide clear evidence that the preference of either the stacked or the hydrogen-bonded structures of the base pairs in the solvent is not determined only by bulk properties or the solvent polarity but rather by specific interactions of the base pair with a small number of the solvent molecules. These conclusions obtained at the empirical level were verified also by high-level ab initio correlated calculations.
- MeSH
- chloroform chemie MeSH
- dimethylsulfoxid chemie MeSH
- financování organizované MeSH
- konformace nukleové kyseliny MeSH
- methanol chemie MeSH
- metylace DNA MeSH
- molekulární modely MeSH
- nukleotidy chemie MeSH
- párování bází MeSH
- počítačová simulace MeSH
- voda chemie MeSH
- vodíková vazba MeSH
- zastoupení bazí MeSH
