Enantiomer Differentiation by Interaction-Specific Prediction of Residual Dipolar Couplings in Spherical-like Molecules

Residual Dipolar Couplings (RDCs) are averaged dipolar couplings between nuclear spins of atoms in a molecule that can be measured by nuclear magnetic resonance (NMR) spectroscopy upon partial alignment by a chiral alignment medium. The estimation of differences in alignment of enantiomers may, in principle, enable the determination of absolute configuration. Here, we use molecular dynamics (MD) simulations to mimic the alignment of chiral molecules (i.e., isopinocampheol, quinuclidin-3-ol, borneol, and camphor) to the chiral poly-γ-benzyl-L-glutamate (PBLG) polymer to predict RDCs <i>in silico</i> and compare calculated and experimentally measured residual dipolar couplings for the four enantiomeric pairs. The aim is to validate the computational scheme for the prediction of RDCs in chiral molecules and understand the interaction leading to the alignment in more detail. We determine the indispensable importance of hydrogen bonds between a chiral molecule and the alignment medium on the overall quality of the simulated alignment and interaction poses toward high agreement with experiments. A good correlation with experimental data is found for camphor and isopinocampheol, while the correlation for quinuclidin-3-ol and borneol is lower. We attribute this observation to the high difficulty of the RDC prediction for rather almost spherical molecules. The study reveals that the prediction of alignment with small enantiomeric differences is possible with an MD-based approach; however, extended simulation times (e.g., 50-100 μs) are required to sufficiently reduce the statistical uncertainty. This may be further used for the determination of the relative, as well as absolute, configuration of chiral molecules.