- Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure.
- NMRFAM developed a protocol for structural analysis of complex natural products to include Residual Dipolar Couplings (RDCs) in addition to NOE and the J-based analysis. For complex compounds (e.g. natural products), the use of only later two leads to hundreds of possible configurations and corresponding structures, and this ambiguity can be lifted if RDCs are added to the analysis. Unlike all published methods that use RDCs to elucidate a molecule’s configuration, our method does not require any DFT model. In fact, we highlight the shortcomings of using DFT models in conjunction with RDCs measured in solution: sometimes DFT models with different configurations fit poorly or equally well the experimental RDCs or, for more dynamic molecules, no DFT model would fit the experimental RDCs within their experimental errors
- We adapted a force field structure calculation methodology to allow free sampling ofboth 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).
- The novelty of our method does not reside in simply using RDCs for determining the structure and configuration of small molecules, but in the unique and simple way of doing it, in contrast with the time consuming (e.g. for Ecteinamycin, with 14 chiral centers, generating up to 213 DFT models is also computationally intensive), and sometimes complex ways this has been done in all published studies to date, particularly in the cases of molecules with flexible parts and/or with conformational heterogeneity (that required computing exhaustive DFT models, MD simulations, computing conformational models, establishing conformer populations, filtering conformers based on experimental data, etc.). For the all literature cases analyzed we proved that our method matched the accuracy of the published methods using a vastly simpler approach.
Cornilescu G, Ramos Alvarenga RF, Wyche TP, Bugni TS, Gil RR, Cornilescu CC, Westler WM, Markley JL, Schwieters CD
- Progressive Stereo Locking (PSL): A Residual Dipolar Coupling Based Force Field Method for Determining the Relative Configuration of Natural Products and Other Small Molecules, ACS Chem Biol [Epub ahead of print], 2017
Wyche TP, Alvarenga RFR, Piotrowski JS, Duster MN, Warrack SR, Cornilescu G, De Wolfe TJ, Hou Y, Braun DR, Ellis GA, Simpkins SW, Nelson J, Myers CL, Steele J, Mori H, Safdar N, Markley JL, Rajski SR, Bugni TS
- Chemical Genomics, Structure Elucidation, and in Vivo Studies of the Marine-Derived Anticlostridial Ecteinamycin, ACS Chem Biol [Epub ahead of print], 2017