Traditionally, the determination of three-dimensional structures of biological macromolecules by NMR has employed distance and torsion angle constraints. Despite its enormous successes, the strictly local nature of the experimental constraints can pose undesirable limitations to the attainable accuracy, especially with respect to the relative orientation of individual structural elements.
Recently, NMR methodology has been developed that exploits weak alignment of molecules in the magnetic field and allows the determination of orientational constraints from residual dipolar couplings (RDC). Incorporation of these qualitative different constraints into NMR based structure calculations results in remarkable improvements of the resulting structures, both locally and globally. A particular powerful application of RDC-based strategies concerns the validation of proteins folds, derived by modeling or low resolution data. Exploitation of such strategies allow for a direct and important contribution of NMR to fold determination/verification in Structural Genomics.