Investigations of Stacked DNA Base-Pair Steps: Highly Accurate Stacking Interaction Energies, Energy Decomposition, and Many-Body Stacking Effects

The stacking energies of 10 unique B-DNA base-pair steps were calculated with highly accurate quantum chemistry and used as reference values in a thorough benchmark of (dispersion-corrected) DFT, wave function methods, tight-binding methods, and different force fields, including charge variants thereof. The reference values were computed using a focal-point energy function based on extrapolated explicitly correlated MP2-F12 and conventional CCSD­(T) data at the triple-ζ level. A collection of 29 different density functionals, sometimes with multiple dispersion corrections (D3­(BJ), D3M­(BJ), and VV10) were evaluated, including recent functionals like B97M-V, ωB97M-V, and SCAN-D3­(BJ), which perform excellently. The double-hybrid DSD-BLYP-NL was found to be the best DFT method. Common wave function methods (MP2, SCS-MP2, and MP2.5) and the SNS-MP2 protocol were tested as well, where only the latter and DLPNO-CCSD­(T)/CBS were competitive with DFT. The tight-binding methods DFTB3-D3 and GFN-xTB revealed a comparatively low accuracy. The AMBER force field outperformed CHARMM and GROMOS but still showed systematic gas-phase overbinding, which could be traced back to the electrostatic term, as revealed by comparison of different sets of point charges. High-order SAPT, e.g., SAPT2 + 3δ­(MP2), was not only benchmarked but also used to study the nature of the stacking interactions to high accuracy. The δ­(MP2) term turned out to be crucially important to reach high accuracy. Finally, we investigated four-body stacking effects with DLPNO-CCSD­(T) and DFT, which were found to be significant and strongest for the CpC base-pair step where they reached almost 30% of the total stacking energy.