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.