The discodermolide hairpin structure flows from conformationally stable modular motifs

Area of Science:

• Marine natural products chemistry
• Structural biology
• Computational chemistry

Background:

• (+)-Discodermolide (DDM) is a potent microtubule assembly promoter isolated from a marine sponge.
• Previous studies reported DDM conformations in solid-state, solution, and protein-bound states.
• A common hairpin conformational motif was observed across these diverse microenvironments.

Purpose of the Study:

• To investigate the conformational stability of (+)-Discodermolide (DDM) in different environments.
• To compare DDM conformers using computational and experimental methods.
• To elucidate the binding mode of DDM within beta-tubulin.

Main Methods:

• Force-field conformational searches were employed to explore DDM conformers.
• Nuclear Magnetic Resonance (NMR) deconvolution in various solvents was used for experimental validation.
• Docking protocols were utilized to predict DDM binding poses in beta-tubulin.

Main Results:

• The hairpin conformational motif of DDM was found to dominate across various environments, including solution and solid-state.
• The stability of the hairpin conformation is primarily attributed to steric factors within DDM's modular segments.
• Two potential binding poses (Pose-1 and Pose-2) for DDM in beta-tubulin were identified, with Pose-2 better accommodating Structure-Activity Relationship (SAR) data.

Conclusions:

• (+)-Discodermolide exhibits remarkable conformational constancy, primarily adopting a stable hairpin motif.
• Steric interactions within DDM's structure are crucial for maintaining this stable conformation.
• SAR data supports Pose-2 as a more biologically relevant binding mode for DDM in beta-tubulin, offering insights for drug design.