Thermal and solvent effects on NMR indirect spin-spin coupling constants of a prototypical Chagas disease drug

NMR J-couplings across hydrogen bonds reflect the static and dynamic character of hydrogen bonding. They are affected by thermal and solvent effects and can therefore be used to probe such effects. We have applied density functional theory (DFT) to compute the NMR (n)J(N,H) scalar couplings of a prototypical Chagas disease drug (metronidazole). The calculations were done for the molecule in vacuo, in microsolvated cluster models with one or few water molecules, in snapshots obtained from molecular dynamics simulations with explicit water solvent, and in a polarizable dielectric continuum. Hyperconjugative and electrostatic effects on spin-spin coupling constants were assessed through DFT calculations using natural bond orbital (NBO) analysis and atoms in molecules (AIM) theory. In the calculations with explicit solvent molecules, special attention was given to the nature of the hydrogen bonds formed with the solvent molecules. The results highlight the importance of properly incorporating thermal and solvent effects into NMR calculations in the condensed phase.