Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

Abstract

The stevastelins are depsipeptide natural products that show valuable immunomodulatory and phosphatase inhibitory activity. A previous report described the synthesis, conformational analysis, and biological activity of modified diastereomeric C3 analogs (1) of these molecules and deduced a single dominant conformational scaffold for each of the six benzylated stevastelin diastereomers in solution. In this study, we report a combined computational and experimental approach (NAMFIS) of these analogs based on geometric variables from the NMR data and extensive conformational searching that suggests a more subtle and complex distribution of conformations in solution. Although the results indicate some conformations to be similar to those previously proposed, they include novel motifs not observed earlier such as gamma turns. In addition, the NAMFIS analysis confirms dramatic changes in conformations accompanying a chirality change at the C3 center and also establishes the conformational homogeneity of the D-serine diastereomers. The NAMFIS analysis thus suggests the use of D-serine as a possible constraining element in peptide design and derives a set of experimental solution conformers that could shed light on the bioactive conformation of the stevastelins. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 968-976, 2010.