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ACS Chem Biol. 2017 Aug 18;12(8):2157-2163. doi: 10.1021/acschembio.7b00281. Epub 2017 Jul 12.

Progressive Stereo Locking (PSL): A Residual Dipolar Coupling Based Force Field Method for Determining the Relative Configuration of Natural Products and Other Small Molecules.

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Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
Biological Chemistry and Molecular Pharmacology Department, Harvard Medical School , Boston, Massachusetts 02115, United States.
Department of Chemistry, Carnegie Mellon University , Pittsburgh, Pennsylvania 15213, United States.
Center for Information Technology, National Institutes of Health , Bethesda, Maryland 20892-5624, United States.


Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to allow free sampling of both R and S configurations of the stereocenters of interest. The algorithm uses a floating alignment tensor in a simulated annealing protocol to identify the conformations and configurations that best fit experimental RDC and distance restraints (from NOE and J-coupling data). A unique configuration (for rigid molecules) or a very small number of configurations (for less rigid molecules) of the structural models having the lowest chiral angle energies and reasonable magnitudes of the alignment tensor are provided as the best predictions of the unknown configuration. For highly flexible molecules, the progressive locking of their stereocenters into their statistically dominant R or S state dramatically reduces the number of possible relative configurations. The result is verified by checking that the same configuration is obtained by initiating the locking from different regions of the molecule. For all molecules tested having known configurations (with conformations ranging from mostly rigid to highly flexible), the method accurately determined the correct configuration.

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