Conformational Energies of DNA Sugar−Phosphate Backbone: Reference QM Calculations and a Comparison with Density Functional Theory and Molecular Mechanics

The study investigates electronic structure and gas-phase energetics of the DNA sugar−phosphate backbone via advanced quantum chemical (QM) methods. The analysis has been carried out on biologically relevant backbone conformations composed of 11 canonical BI-DNA structures, 8 pathological structures with α/γ torsion angles in the g+/t region, and 3 real noncanonical γ-trans structures occurring in the loop region of guanine quadruplex DNA. The influence of backbone conformation on the intrinsic energetics was primarily studied using a model system consisting of two sugar moieties linked together via a phosphodiester bond (SPSOM model). To get the conformation of the studied system fully under control, for each calculation we have frozen majority of the dihedral angles to their target values. CCSD(T) energies extrapolated to the complete basis set were utilized as reference values. However, the calculations show that inclusion of higher-order electron correlation effects for this system is not crucial and complete basis set second-order perturbation calculations are sufficiently accurate. The reference QM data are used to assess performance of 10 contemporary density functionals with the best performance delivered by the PBE-D/TZVPP combination along with the Grimme’s dispersion correction, and by the TPSS-D/6-311++G(3df,3pd) augmented by Jurečka’s dispersion term. In addition, the QM calculations are compared to molecular mechanics (MM) model based on the Cornell et al. force field. The destabilization of the pathological g+/t conformers with respect to the reference canonical structure and the network of intramolecular CH···O interactions were investigated by means of natural bond orbital analysis (NBO) and atoms-in-molecules (AIM) Bader analysis. Finally, four additional model systems of different sizes were assessed by comparing their energetics to that of the SPSOM system. Energetics of smaller MOSPM model consisting of a sugar moiety linked to a phosphate group and capped with methyl and methoxy group on the 5′- and 3′-ends, respectively, is fairly similar to that of SPSOM, while the role of undesired intramolecular interactions is diminished.