Computationally Assisted Assignment of Kahalalide Y Configuration Using an NMR-Constrained Conformational Search

Abstract

Assignment of the absolute configuration of cyclic peptides frequently yields challenges, leaving one or more stereogenic centers unassigned due to small quantities of sample and the limited utility of Marfey’s or other methods for assigning amino or hydroxy acids. Here, we report isolation of kahalalide Y (1) from Bryopsis pennata for the first time; in addition, the application of a combination of molecular modeling and NOE distance constraint calculations was utilized to determine the conformation of 1 and the absolute configuration of the final stereogenic center of 1. Using the Schrödinger suite, the structure of 1 was sketched in Maestro and minimized using the OPLS2005 force field in Macromodel. A conformational search was performed separately for structures having R or S configuration at C-3 of the beta-hydroxy fatty acid subunit that completes the cyclic scaffold of 1, after which multiple minimizations for all generated conformers were carried out. The lowest energy conformers of R and S stereoisomers were then subjected to B3LYP geometry optimizations including solvent effects. The S stereoisomer was shown to be in excellent agreement with the NOE-derived distance constraints and hydrogen bonding stability studies.

Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy

“…41,42 Furthermore, interproton distances can be deduced from NOE or ROE correlation intensities and correlate with the interproton distances measured on the calculated structure. 35,43 This last approach was used efficiently for rigid or flexible molecules. 44,45 These pluridisciplinary approaches have never been undertaken for the structural elucidation of macrocyclic diterpene esters, despite the complex stereostructure of the latter compounds.…”

Marine natural products

“…Using constrained NOESY NMR data, a conformational search has helped assign the conguration (3S) in the 9-methyl-3decanol subunit of kahalalide Y (Elysia rufescens): 898 unfortunately the study made use of the enantiomer of the NP and so the conguration should in fact be (3R). 899,900 Investigation of the mechanism of cytotoxic action of aplyronine A (Aplysia kurodai) 901 using photoaffinity biotinylated derivatives has identied aplyronine A to synergistically bind to tubulin in association with actin in a 1 : 1 : 1 ratio, leading to inhibition of tubulin polymerisation, and ultimately prevention of spindle formation and mitosis. 902 Similar experiments using aplyronine C 902 (lacks the trimethylserine sidechain of aplyronine A; 903 three orders of magnitude less cytotoxic) showed it to bind to actin, as previously reported, but it did not bind to tubulin in this present study.…”

Pagoamide A, a Cyclic Depsipeptide Isolated from a Cultured Marine Chlorophyte, Derbesia sp., Using MS/MS-Based Molecular Networking

“…Interestingly, a number of these are of a peptide constitution, such as the depsipeptide kahalalide F, first reported in 1993 from a Hawaiian Bryopsis species . Subsequently a series of articles clarified stereochemical features of this molecule as well as reported on a number of related compounds, kahalalides A–Z2. − Most cyclic kahalalides possess unique structural features composed of a macrocyclic region that forms from an ester bond between the C-terminus and the β-hydroxy group of a threonine residue. Further, they possess a terminal polyketide moiety or a branched acyclic peptide.…”