Relative stability of different DNA guanine quadruplex stem topologies derived using large-scale quantum-chemical computations

Abstract

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.

Figure 1

2-quartet G-DNA stem in the 5′-anti-anti-3′ (AA) arrangement.

Figure 2

Two orientations of the glycosidic torsion angle χ: anti (left) and syn (center and right). χ torsion angle is defined as O4′-C1′-N9-C4 and O4′-C1′-N1-C2 for purines and pyrimidines, respectively. The O5′H…N3(G) hydrogen bond typical for 5′-terminal syn guanosines in the G-DNA is depicted right.

Figure 3

Two-quartet G-DNA stems used in our computations. From left to right: AA, AS, 3AA+1SS, SA-aabb, SA-abab, SA-aaab and SA-aaaa structures. Each stem consists of four 5′-GG-3′ dinucleotide steps (strands); S and A stand for syn and anti guanines. The notation ‘a’ and ‘b’ is used to distinguish SA stems with different relative 5’-3’ orientation of the adjacent strands around the structure; a is used for strands oriented upward in our Figure while b for strands oriented downward; c.f., the names of the structures with the relative orientation of the arrows showing the 5’-3’ directionality of the strands. White rectangle marks syn and grey anti nucleosides. The channel cation (K⁺) is not shown. The first six arrangements were considered in the preceding MD simulation study, the seventh arrangement has been added in the course of this study.

Figure 4

QM_opt (green) and X-ray (red) AA structures.

Figure 5

Detailed view on the non-native N2(G) … O4′(G+1) H-bonds in the QM_opt structure of the AA model.

Figure 6

Explicit water molecules prevent non-native N2(G)…O4′(G+1) H-bonds in the QM_opt AA structure. Left - the X-ray water position (red ball, only oxygen is visible), which is essentially identical in all observed instances. Center - example of the water position after the QM optimization; note that the water molecule has somewhat relocated. Right - the non-native H-bond in absence of the explicit water molecule.