Prediction of Residual Dipolar Couplings in analyte molecules aligned by Poly-𝛾-benzyl-L-glutamate

Nuclear magnetic resonance (NMR) spectroscopy is an essential tool for the determination of molecular structures. However, due to the identical chemical environment of enantiomers and to a lesser extent diastereomers, the determination of relative and especially absolute configuration remains challenging. A promising method is the measurement of residual dipolar couplings (RDCs), which arise due to the partial alignment of analyte molecule orientations by an alignment medium. If the alignment of chiral analyte molecules is caused by a chiral alignment medium, the measured RDCs between the enantiomers differ. Previous studies showed that an approximate prediction of RDCs suitable for the determination of relative configuration is possible in some cases. In the case of the absolute configuration however, only tentative evidence exists that the assignment of enantiomers based on the prediction of RDCs is feasible.
In this thesis, I use atomistic approaches for the development of computational schemes to predict the RDCs in small analyte molecules aligned by the poly-𝛾-benzyl-L-glutamate (PBLG) alignment medium in (deuterated) chloroform. ... mehrThis includes the detailed description of the interactions between the analyte molecules and PBLG, which lead to partial alignment. One approach are Molecular Dynamics (MD) simulations with explicit solvent, which provide detailed insights into the alignment interactions and, most importantly, indeed succeed in the correct assignment of enantiomers for molecules with hydrogen bond donors by comparing the differences between RDCs. For these molecules, hydrogen bonds to PBLG are essential for the alignment and the enantiodiscrimination. However, there are molecules whose RDCs by themselves do not agree with experiment and the MD simulations are computationally expensive. For this reason, I study the binding free energies to PBLG and evaluate different interaction models, including implicit solvation models. Using them in Monte Carlo (MC) calculations showed a pure Coulomb potential between PBLG and the analyte molecule to result in the best agreement with experiment. For the analyte molecules with O–H hydrogen bond donor, the agreement is also significantly better than with the MD simulations, although the strength of the alignment is severely overestimated. The difference between enantiomers in the MC simulations is very small however, showing the full MD simulations to be necessary for the determination of the absolute configuration.
The methods developed in this thesis are thus a significant step for the prediction of RDCs, which in the future may be used for the design of new alignment media. Additionally, the demonstrated theoretical approach can be already applied for the distinction of enantiomers if the differences of the RDCs are large enough.