The simulation of NMR data of flexible molecules: sagittamide A as an example for MD simulations with orientational constraints.

The recently developed MDOC (Molecular Dynamics with Orientational Constraints) simulation is applied for the first time to a fully flexible molecule. MDOC simulations aim to single out the naturally existing configuration of molecules and to elucidate conformer populations. The performance of the method was first demonstrated on a well-studied test case, the five-membered ring lactone (α-methylene-γ-butyrolactone). In the case of sagittamide A, one-bond 1H-13C residual dipolar couplings (RDC) are used as orientational constraints that reorient the molecule or parts of it. In addition, NOE distances and 3J scalar couplings are used as constraints. Five possible configurations of sagittamide A (labelled a to e) are considered. One experimental RDC value per flexible unit was available and this was not sufficient to single out one valid configuration. The problem could be solved by including NOE distances as well as 3J couplings as complementary constraints into the MDOC simulations. In accordance with former investigations, we confirmed the configuration a for the natural product. A detailed analysis of conformers of the central chain of 6 chiral carbon atoms could be given by inspecting the MDOC trajectory. The relative abundance of these conformers is crucial in fulfilling all three sets of constraints.