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

Abstract

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.

Measurement of Residual Dipolar Couplings of Organic Molecules in Multiple Solvent Systems Using a Liquid‐Crystalline‐Based Medium

“…We hypothesize that the main reason for the very weak background influence is attributed to the robust self-assembly of OPA, leading to broadened resonances beyond the NMR detection limit. [28] Furthermore,w ep erformed RDC measurements of oridonin (5)and estrone (6)inthe OPA/[D 6 ]DMSO medium. The[ 1 H, 13 C] JSB-HSQC spectra of 5 are shown in Figure 7.…”

“…[1] In this respect, residual dipolar coupling (RDC) belongs to one of the most commonly employed anisotropic NMR parameters,asit provides valuable global orientational restraints and reflects the spatial information of remote chiral centers. [2] Thea pplication of RDC has remarkably accelerated the structural determination process of novel natural products and organic molecules, [3] which, in turn, promoted the recent development of new computational approaches such as computer-assisted 3D structure elucidation (CASE-3D protocol), [4] distance geometry calculation, [5] moleculardynamics simulation using orientational constraints, [6] and molecular-alignment simulation. [7] Fort he acquisition of RDCs,an umber of stretched and compressed polymeric gels [8] and lyotropic liquid crystalline (LLC) phases [9] have been developed in the past for weakly aligning organic molecules dissolved in different organic solvents.Strikingly,c ross-linked poly(ethylene oxide) (PEO) shows unique capacity as an alignment medium to be compatible with very different types of solvents.…”

Determination of Configuration and Conformation of a Reserpine Derivative with Seven Stereogenic Centers Using Molecular Dynamics with RDC‐Derived Tensorial Constraints**

“…Several implementations have been reported based on an approximated alignment tensor as initial input [25] . An alignment tensor for a flexible molecule, however, is per se ill‐defined and the recently published MDOC approach seems far more appropriate in this case [6c, 7a] …”

Conformational Investigations in Flexible Molecules Using Orientational NMR Constraints in Combination with 3J-Couplings and NOE Distances

“…It would be interesting to evaluate the diastereomeric discrimination potential of MDOC for flexible molecules. MDOC was already introduced for this task in relatively rigid and slightly flexible molecules [32,33], but in the present case, it is expected that orientation pseudo-forces may arrive more easily at false positives (e.g., structures with quality criterion >1) especially if the molecule’s topology allows for large geometrical fluctuations due to increased number of degrees of freedom. On the other hand, the pseudo-forces from short-range NOEs and J- couplings may play an important role in hindering unrealistic ensembles.…”

“…Molecular Dynamics with Orientational Constraints (MDOC) simulations provide an alternative approach which uses tensorial NMR parameters as constraints [30,31] and which requires no alignment or order tensors. This approach was recently introduced and thoroughly investigated towards conformation and configuration determination on small molecules, from relatively rigid ring-systems to system with some level of internal flexibility, using only RDCs [32,33]. The MDOC method exhibits several important distinctions from the aforementioned MD methods [23,28,29].…”