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.
Highlights
Tensorial NMR observables, such as chemical shift anisotropy, dipole-dipole couplings or nuclear quadrupolar splittings, give access to structurally-relevant local orientation at nuclear sites relative to the external magnetic field
24, 4417 bond CH residual”dipolar couplings (RDCs) (1A:14, 1B:14) and long-range HH RDCs (1A:8, 1B:10)), nuclear Overhauser enhancements (NOEs) (1A: 7, 1B:5), 3Jcouplings (1A: 5, 1B:5), each translated into a pseudo-force term for the molecular dynamic simulation with orientation constraints (MDOC) simulations
In good accord with the entire corresponding measured datasets, which include four categories of Figure 3 shows that the running ensembles of the MDOC simulation for both 1-SS and 1-SR are NMR parameter types
Summary
Tensorial NMR observables, such as chemical shift anisotropy, dipole-dipole couplings or nuclear quadrupolar splittings, give access to structurally-relevant local orientation at nuclear sites relative to the external magnetic field. 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 molecular mechanic force-field includes the elaborate bond polarization theory (BPT) which calculates electrostatic energy along the trajectory, and is extendable with other accessible NMR parameters, such as chemical shifts, J-couplings and NOEs which can be applied as time-averaged constraints With its attributes, this light-weight yet rich MD platform, available within the COSMOS package, allows the bypass of explicit solvent or aligned media, since their influence is embodied within the reorienting pseudo-forces. Molecules 2019, 24, x FOR PEER REVIEW structural ensemble and show encouraging potential towards guiding the correct configuration assignment
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