Monte Carlo-Based Prediction of Residual Dipolar Couplings in Weakly Aligned Molecules

For the determination of the relative configuration in chiral molecules aligned by an alignment medium, the measurement and analysis of residual dipolar couplings (RDCs) is an established method. However, the agreement of in silico predicted RDCs, which are expected to also enable the determination of the absolute configuration, remains unsatisfactory for a range of chiral molecules. In this work, we use different intermolecular interaction models to determine the alignment of analyte molecules aligned by poly-γ-benzyl-l-glutamate (PBLG)/CDCl3 and predict RDCs by means of a Monte Carlo (MC) method for the sampling of analyte poses and structures. We compare the MC-calculated RDCs to experimentally measured values and to RDCs calculated using molecular dynamics (MD) simulations with explicit solvent. With this new approach, we find better agreement with the experimental RDCs than reported from MD for several molecules, with the best overall agreement using a pure Coulomb potential. The investigation of different interaction potentials (based on geometry and electrostatics, including the interaction potential of the P3D (“PALES 3D”) model and an implicit solvation model) and the importance of treating the molecules as nonrigid reveals new insights into the alignment mechanism and represents a potentially substantial improvement of the previously existing methodology with a more accurate prediction of the RDCs.