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

Abstract

The downscaling of NMR tensorial interactions, such as dipolar couplings, from tens of kilohertz to a few hertz in low-order media is the result of dynamics spanning several orders of magnitudes, including vibrational modes (~ns-fs), whole-molecule reorientation (~ns) and higher barrier internal conformational exchange (<ms). In this work, we propose to employ these dynamically averaged interactions to drive an “alignment-tensor-free” molecular dynamic simulation with orientation constraints (MDOC) in order to efficiently access the conformational space sampled by flexible small molecules such as natural products. Key to this approach is the application of tensorial pseudo-force restraints which simultaneously guide the overall reorientation and conformational fluctuations based on defined memory function over the running trajectory. With the molecular mechanics force-field, which includes bond polarization theory (BPT), and complemented with other available NMR parameters such as NOEs and scalar J-couplings, MDOC efficiently arrives at dynamic ensembles that reproduce the entire NMR dataset with exquisite accuracy and theoretically reveal the systems conformational space and equilibrium. The method as well as its potential towards configurational elucidation is presented on diastereomeric pairs of flexible molecules: a small 1,4-diketone 1 with a single rotatable bond as well as a 24-ring macrolide related to the natural product mandelalide A 2.

Statistical evaluation of simulated NMR data of flexible molecules

“…Using all NMR data (RDC, NOE distances and 3 J -couplings) provided by Schuetz et al 34 as constraints, an MDOC simulation was performed by Sternberg et al 44 Since only data from the central part of the molecule were available, no conclusions could be drawn on conformers or motion of the two chains R1 and R2 (see Fig. 5).…”

Hydrocarbon Macrocycle Conformer Ensembles and 13C‐NMR Spectra

“…Before presenting our computational approach, we briefly discuss previous works in the field of conformational analysis focusing on macrocyclic compounds in solution. From an experimental viewpoint NMR data like nuclear Overhauser effect (NOE) crosspeak volumes, 3 J scalar couplings constants and residual dipolar couplings (RDCs) [15–17] are used to analyse structural motifs. This data provides information on interatomic distances, dihedral angles and relative orientational restraints from which a molecular structure can be derived.…”

TITANIA: Model-Free Interpretation of Residual Dipolar Couplings in the Context of Organic Compounds

“…In 2018, Immel et al used a floating chirality restrained distance geometry and distance-bound driven dynamics (fc-rDG/DDD) protocol to generate structural models and optimize them according to RDC restraints in configurational and conformational architect (ConArch + ) . Furthermore, tensorial restraints are employed in the MD protocol published as computer simulation of molecular structures (COSMOS) by Sternberg and Luy. − These algorithms have in common that the optimization of the structures is performed on the difference of user-defined experimental NMR observables and the back-calculated values to define or extend a (pseudo) force field. In addition, multiple alignment media are treated as individual sources of information for the refinement of structures and not globally as is proposed here.…”