Density functional theory calculations of 1H and 13C chemical shifts have proven to be a useful tool in natural product identification and experimental organic chemistry, for example, to assign relative configurations or to confirm the identity of side products or reactive intermediates. Another useful application of these predicted chemical shifts can be found in the field of peptide chemistry, as conformations of cyclic peptides can dictate their properties and reactivity. We proposed an alternative approach, which we called CANDLE (Conformational Analysis from NMR and Density-functional prediction of Low-energy Ensembles) that employs iterative molecular dynamic (MD) simulations and DFT calculations of energy and 1H and 13C chemical shifts to solve for the low-energy conformational ensembles of cyclic peptides. In our case studies, MD simulations using CHARMM force field, were conducted at high temperature (2000 K) to explore various peptide backbone conformations, and then at room temperature (300 K) to refine sidechain orientations. DFT calculations with Gaussian09 were used for energy refinement, optimization and NMR calculations (specifically linear regression method to scale computed isotropic values to chemical shifts). CANDLE workflow provides a complementary approach to solving high-quality solutions for cyclic peptides with mean absolute deviations of less than 0.2 ppm for 1H and less than 2.0 ppm for 13C.

CANDLE: Complementary approach to solving cyclic peptide conformations using chemical shifts

256th National Meeting (2018)

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