Abstract
Residual dipolar couplings (RDCs) and other residual anisotropic NMR parameters provide valuable structural information of high quality and quantity, bringing detailed structural models of flexible molecules in solution in reach. The corresponding data interpretation so far is directly or indirectly based on the concept of a molecular alignment tensor, which, however, is ill-defined for flexible molecules. The concept is typically applied to a single or a small set of lowest energy structures, ignoring the effect of vibrational averaging. Here, we introduce an entirely different approach based on time averaged molecular dynamics with dipolar couplings as tensorial orientational restraints that can be used to solve structural problems in molecules of any size without the need of introducing an explicit molecular alignment tensor into the computation. RDC restraints are represented by their full 3D interaction tensor in the laboratory frame, for which pseudo forces are calculated using a secular dipolar Hamiltonian as the target. The resulting rotational averaging of each individual tensorial restraint leads to structural ensembles that best fulfil the experimental data. Using one-bond RDCs, the approach has been implemented in the force field procedures of the program COSMOS and extensively tested. A concise theoretical introduction, including the special treatment of force fields for stable and fast MD simulations, as well as applications regarding configurational analyses of small to medium-sized organic molecules with different degrees of flexibility, is given. The observed results are discussed in detail.
Highlights
While it is widely recognized that residual anisotropic NMR parameters are suited for the determination of dynamics in biomolecules,[23,24] they are amenable to the structure elucidation of small molecules with inherent exibility
In the current work we have evaluated the performance and capabilities of molecular dynamics with orientational constraints (MDOC) simulations as implemented in COSMOS 6.0 to assign the relative con guration of stereogenic and prochiral centres in small organic molecules
In contrast to classical alignment tensor based methods, MDOC is entirely calculated in the laboratory frame, avoiding issues with the treatment of exibility where a common frame of reference for the alignment tensor is usually not accurately de ned
Summary
Residual dipolar couplings (RDCs) are an efficient tool for the determination of the relative con guration of small organic molecules.[1,2,3,4,5] The use of RDCs has been boosted by the availability of weak aligning media compatible with standard organic solvents such as CDCl3 6–10 or DMSO-d6,11–18 and most other common NMR solvents.[19,20,21,22] While it is widely recognized that residual anisotropic NMR parameters are suited for the determination of dynamics in biomolecules,[23,24] they are amenable to the structure elucidation of small molecules with inherent exibility. Physically sound data interpretation is difficult, especially in the case of small to medium sized molecules in which typically only a single alignment medium is employed and, in principle a multitude of internuclear couplings exists, the amount of practically accessible RDCs is limited. Rigid molecules simple harmonic modes can be obtained from DFT calculations and have been successfully applied,[25] but for most cases the corresponding contributions are either neglected or treated using considerable approximations. Instead, we introduce molecular dynamics with RDC-based orientational tensorial constraints applied in the laboratory frame as a physically sound method for the determination of relative con gurations of molecules with inherent exibility
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