Molecular Dynamics with Orientational Tensorial Constraints: A New Approach to Probe the Torsional Angle Distributions of Small Rotationally Flexible Molecules

The potential of residual dipolar couplings (RDCs) in conformational studies of small molecules is now widely recognized, but current theoretical approaches for their interpretation have several limitations and there is still the need for a general method to probe the torsional angle distributions applicable to any rotationally flexible molecule. Molecular dynamics simulations with RDC-based orientational tensorial constraints (MDOC), implemented in the software COSMOS, are presented here as a conceptually new strategy. For the cases of the fluorinated anti-inflammatory drug diflunisal and the disaccharide cellobiose, we demonstrate that MDOC simulations with one-bond RDCs as tensorial constraints unveil torsion distributions and allow the determination of relative configuration in the presence of rotational flexibility. The independence of the initial structure or any a priori assumption as well as the possibility to combine different experimental constraints represent features, which make the COSMOS software a promising tool for the investigation of torsional angle distributions of flexible molecules, regardless of their size and degree of freedom.