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.

Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?

“…As roxithromycin can be expected to exist as a dynamic ensemble of interconverting conformations in solution, we analyzed it in water and chloroform solutions using the NAMFIS algorithm that has previously been successfully applied for the description of the solution ensemble of various flexible macrocycles. − Experimental population-averaged distances were determined by the acquisition of nuclear Overhauser enhancement (NOE) buildups at 900 MHz and by conversion of the initial buildup rates into interproton distances (Tables S6 and S7, Supporting Information). A theoretical ensemble covering the entire available conformational space was generated using an unrestrained Monte Carlo conformational search using water and chloroform solvation models.…”

Conformational Control of Macrocycles by Remote Structural Modification

“…117 In some cases, NAMFIS indicates conformations that are not identified using restrained conformational searches. 118 There is no standardized method to determine the solution structures of a macrocycle, and authors often use different force fields, search algorithms, and simulation times. Sometimes intramolecular hydrogen bonds determined using the spectroscopic methods mentioned above are also utilized as restraints during force field based conformational searches.…”

“…Since NAMFIS does not rely on energy calculations, inaccurate evaluation of conformer populations due to long-range interactions or inappropriate force-fields is avoided . In some cases, NAMFIS indicates conformations that are not identified using restrained conformational searches . There is no standardized method to determine the solution structures of a macrocycle, and authors often use different force fields, search algorithms, and simulation times.…”