DFTB method
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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.
A new database of nucleic acid base trimers has been developed that includes 141 geometries and stabilization energies obtained at the RI-MP2 level of theory with the TZVPP basis set. Compared to previously compiled biologically oriented databases, this new construct includes considerably more complicated structures; the various intermolecular interactions in the trimers are quite heterogeneous and in particular include simultaneous hydrogen bonding and stacking interactions, which is similar to the situation in actual biopolymers. Validation against these benchmark data is therefore a more demanding task for approximate models, since correct descriptions of all energy terms are unlikely to be accomplished by fortuitous cancellations of systematic errors. The density functionals TPSS (both with and without an empirical dispersion term), PWB6K, M05-2X, and BH&H, and the self-consistent charge density functional tight binding method augmented with an empirical dispersion term (SCC-DFTB-D) were assessed for their abilities accurately to compute structures and energies. The best reproduction of the BSSE corrected RI-MP2 stabilization energies was achieved by the TPSS functional (TZVPP basis set) combined with empirical dispersion; removal of the dispersion correction leads to significantly degraded performance. The M05-2X and PWB6K functionals performed very well in reproducing the RI-MP2 geometries, but showed a systematic moderate underestimation of the magnitude of base stacking interactions. The SCC-DFTB-D method predicts geometries in fair agreement with RI-MP2; given its computational efficiency it represents a good option for initial scanning of analogous biopolymeric potential energy surfaces. BH&H gives geometries of comparable quality to the other functionals but significantly overestimates interaction energies other than stacking.
