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.