Higher-Level Structural Classification of Pseudomonas Cyclic Lipopeptides through Their Bioactive Conformation

Area of Science:

• Biochemistry
• Structural Biology
• Microbiology

Background:

• Cyclic lipodepsipeptides (CLiPs) are Pseudomonas-derived metabolites with antimicrobial properties.
• Understanding CLiP structure-function relationships is crucial for applications in plant biocontrol and medicine.
• Limited 3D structural data hinders comprehensive analysis of CLiP diversity.

Purpose of the Study:

• To determine the solution conformations of eight distinct Pseudomonas CLiPs.
• To establish a new structural classification for Pseudomonas CLiPs.
• To provide a foundation for future molecular design and functional studies.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy.
• Molecular dynamics simulations in dodecylphosphocholine micelles.
• Synthesis and structural analysis of a modified orfamide A analogue.

Main Results:

• All studied CLiPs adopt left-handed α-helical conformations.
• Two distinct helical motifs, 'stapled' and 'catch-pole', were identified based on macrocycle size.
• These motifs define two superfamilies encompassing most known Pseudomonas CLiPs.
• Structural classification correlates with the organization of CLiP biosynthetic gene clusters.

Conclusions:

• A novel, coherent structural classification framework for Pseudomonas CLiPs has been established.
• The identified structural dichotomy provides insights into CLiP function and evolution.
• Findings facilitate homology modeling and rational design of CLiPs for targeted applications.