Hoogsteen–Watson–Crick 9‑Methyladenine:1-Methylthymine Complex: Charge Density Study in the Context of Crystal Engineering and Nucleic Acid Base Pairing

This study provides a detailed charge density distribution analysis supported by comprehensive energetic investigations. The nature of the intermolecular interactions existing in the 9-methyladenine:1-methylthymine cocrystal structure with respect to those specific for the corresponding monocomponent crystals is explored. Charge density topological investigations lead to reliable hydrogen-bond interaction energies consistent with the results of the DFT approach with Grimme dispersion correction applied. The cocrystal structure cohesive energy corresponds with the average stability of its components’ crystals. This is in agreement with the experimental observations. Thus, formation of the particularly strong 9-methyladenine:1-methylthymine motif (interaction energy around −70 kJ·mol–1, DFT(B3LYP)/pVTZ, BSSE and dispersive corrections applied) may constitute the driving force for cocrystal growth. All three systems form molecular layers governed by hydrogen-bond interactions whereas interacting mostly dispersively with each other. The interlayer contacts are found to be significant. Formation of particularly short H···H contacts is a distinctive feature of the cocrystal lattice. Also, creation of the cis-Hoogsteen–Watson–Crick (cHW) adenine-thymine base pair motif (Leontis and Westhof classification), instead of creating the most frequently appearing DNA Watson–Crick base pair (cWW), is remarkable. It occurs that this A:U/T orientation is slightly more stable than the analogous cWW one. Nevertheless, in RNA chains, being more flexible than DNA molecules, the cHW A:U base pairing remains rather rarely encountered, which is probably the effect of the rigidity of nucleic acid chain backbones. In general, the purine-pyrimidine interaction strength is most sensitive to the directionality of the formed hydrogen bonds.