Relative Stability of Different DNA Guanine Quadruplex Stem Topologies Derived Using Large-Scale Quantum-Chemical Computations

We
provide theoretical predictions of the intrinsic stability of
different arrangements of guanine quadruplex (G-DNA) stems. Most computational
studies of nucleic acids have applied Molecular Mechanics (MM) approaches
using simple pairwise-additive force fields. The principle limitation
of such calculations is the highly approximate nature of the force
fields. In this study, we for the first time apply accurate QM computations
(DFT-D3 with large atomic orbital basis sets) to essentially complete
DNA building blocks, seven different folds of the cation-stabilized
two-quartet G-DNA stem, each having more than 250 atoms. The solvent
effects are approximated by COSMO continuum solvent. We reveal sizable
differences between MM and QM descriptions of relative energies of
different G-DNA stems, which apparently reflect approximations of
the DNA force field. Using the QM energy data, we propose correction
to earlier free energy estimates of relative stabilities of different
parallel, hybrid, and antiparallel G-stem folds based on classical
simulations. The new energy ranking visibly improves the agreement
between theory and experiment. We predict the 5′-anti-anti-3′ GpG dinucleotide step to be the most stable one, closely
followed by the 5′-syn-anti-3′ step.
The results are in good agreement with known experimental structures
of 2-, 3-, and 4-quartet G-DNA stems. Besides providing specific results
for G-DNA, our study highlights basic limitations of force field modeling
of nucleic acids. Although QM computations have their own limitations,
mainly the lack of conformational sampling and the approximate description
of the solvent, they can substantially improve the quality of calculations
currently relying exclusively on force fields.