Conformations of laulimalide in DMSO-d6

Area of Science:

• Natural Products Chemistry
• Computational Chemistry
• Molecular Biology

Background:

• Laulimalide is a novel macrolide exhibiting microtubule-stabilizing properties akin to Taxol.
• Its structural flexibility, characterized by 18 rotatable bonds, leads to a vast conformational landscape.

Purpose of the Study:

• To investigate the conformational energy surface of laulimalide.
• To identify and classify the distinct conformations adopted by laulimalide.

Main Methods:

• Utilized NAMFIS deconvolution analysis in DMSO-d6 to study laulimalide's conformations.
• Performed post-NAMFIS energy analysis using the Becke3LYP/6-31G level of theory.
• Examined the interplay between internal hydrogen bonding and syn-pentane interactions.

Main Results:

• Identified 15 stable conformations of laulimalide.
• Classified these conformations into five distinct families: Supine, Convex, Cobra, Stretch, and Concave.
• Revealed the significant influence of hydrogen bonding and steric interactions on laulimalide's conformational preferences.

Conclusions:

• The conformational flexibility of laulimalide is substantial, with identified conformations offering a detailed view of its structural diversity.
• Understanding these conformations is crucial for elucidating its mechanism of action as a microtubule stabilizer.
• The identified conformational families provide a framework for future structure-activity relationship studies of laulimalide and related compounds.