The anionic sugar-phosphate backbone of nucleic acids substantially contributes to their structural flexibility. To model nucleic acid structure and dynamics correctly, the potentially sampled substates of the sugar-phosphate backbone must be properly described. However, because of the complexity of the electronic distribution in the nucleic acid backbone, its representation by classical force fields is very challenging. In this work, the three-dimensional potential energy surfaces with two independent variables corresponding to rotations around the alpha and gamma backbone torsions are studied by means of high-level ab initio methods (B3LYP/6-31+G*, MP2/6-31+G*, and MP2 complete basis set limit levels). The ability of the AMBER ff99 [Wang, J. M.; Cieplak, P.; Kollman, P. A. J. Comput. Chem. 2000, 21, 1049-1074] and parmbsc0 [Perez, A.; Marchan, I.; Svozil, D.; Sponer, J.; Cheatham, T. E.; Laughten, C. A.; Orozco, M. Biophys. J. 2007, 92, 3817-3829] force fields to describe the various alpha/gamma conformations of the DNA backbone accurately is assessed by comparing the results with those of ab initio quantum chemical calculations. Two model systems differing in structural complexity were used to describe the alpha/gamma energetics. The simpler one, SPM, consisting of a sugar and methyl group linked through a phosphodiester bond was used to determine higher-order correlation effects covered by the CCSD(T) method. The second, more complex model system, SPSOM, includes two deoxyribose residues (without the bases) connected via a phosphodiester bond. It has been shown by means of a natural bond orbital analysis that the SPSOM model provides a more realistic representation of the hyperconjugation network along the C5'-O5'-P-O3'-C3' linkage. However, we have also shown that quantum mechanical investigations of this model system are nontrivial because of the complexity of the SPSOM conformational space. A comparison of the ab initio data with the ff99 potential energy surface clearly reveals an incorrect ff99 force-field description in the regions where the gamma torsion is in the trans conformation. An explanation is proposed for why the alpha/gamma flips are eliminated so successfully when the parmbsc0 force-field modification is used.
Base-stacking energies in ten unique B-DNA base-pair steps and some other arrangements were evaluated by the second-order Moller-Plesset (MP2) method, complete basis set (CBS) extrapolation, and correction for triple (T) electron-correlation contributions. The CBS(T) calculations were compared with decade-old MP2/6-31G*(0.25) reference data and AMBER force field. The new calculations show modest increases in stacking stabilization compared to the MP2/6-31G*(0.25) data and surprisingly large sequence-dependent variation of stacking energies. The absolute force-field values are in better agreement with the new reference data, while relative discrepancies between quantum-chemical (QM) and force-field values increase modestly. Nevertheless, the force field provides good qualitative description of stacking, and there is no need to introduce additional pair-additive electrostatic terms, such as distributed multipoles or out-of-plane charges. There is a rather surprising difference of about 0.1 A between the vertical separation of base pairs predicted by quantum chemistry and derived from crystal structures. Evaluations of different local arrangements of the 5'-CG-3' step indicate a sensitivity of the relative stacking energies to the level of calculation. Thus, describing quantitative relations between local DNA geometrical variations and stacking may be more complicated than usually assumed. The reference calculations are complemented by continuum-solvent assessment of solvent-screening effects.
