NMR-Based Configurational Assignments of Natural Products: Gibbs Sampling and Bayesian Inference Using Floating Chirality Distance Geometry Calculations.

Floating chirality restrained distance geometry (fc-rDG) calculations are used to directly evolve structures from NMR data such as NOE-derived intramolecular distances or anisotropic residual dipolar couplings (RDCs). In contrast to evaluating pre-calculated structures against NMR restraints, multiple configurations (diastereomers) and conformations are generated automatically within the experimental limits. In this report, we show that the "unphysical" rDG pseudo energies defined from NMR violations bear statistical significance, which allows assigning probabilities to configurational assignments made that are fully compatible with the method of Bayesian inference. These "diastereomeric differentiabilities" then even become almost independent of the actual values of the force constants used to model the restraints originating from NOE or RDC data.

Configurational analysis by residual dipolar couplings: A critical assessment of diastereomeric differentiabilities.

Two independent statistical models for evaluating the certainties of configurational assignments of compounds based on nuclear magnetic resonance (NMR) data are evaluated and compared. Both methods yield weights or probabilities with which two or more structure models (constitutional or configurational isomers or even conformers) could be differentiated based on experimental parameters. Although this paper focusses on the use of residual dipolar couplings (RDCs) for the differentiation of diastereomers, the concept can be expanded to any set of experimental NMR-derived parameters. It is demonstrated that highly reliable configurational assignments crucially must depend on thorough statistical analysis, which is frequently neglected in the literature.