Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37

Area of Science:

• Biophysics
• Biochemistry
• Membrane Biology

Background:

• LL-37 is a key human antimicrobial peptide with a known amphipathic alpha-helical structure.
• Understanding LL-37's mechanism of action against bacterial membranes is crucial for developing new antimicrobial therapies.

Purpose of the Study:

• To elucidate the precise orientation and mechanism of lipid bilayer disruption by the antimicrobial peptide LL-37.
• To investigate LL-37's interaction with lipid bilayers using biophysical techniques.

Main Methods:

• Site-specific (15)N labeling of LL-37 for NMR spectroscopy.
• (15)N chemical shift and dipolar-shift spectroscopy in oriented lipid bilayers.
• (31)P NMR spectroscopy to assess lipid perturbation.
• Differential scanning calorimetry to determine phase transition temperatures.

Main Results:

• LL-37 adopts a surface-parallel orientation in both anionic and zwitterionic lipid bilayers, independent of temperature and concentration.
• Electrostatic factors, lipid type, and cholesterol influence LL-37's perturbation of lipid bilayers.
• LL-37 increases the lamellar to inverted hexagonal phase transition temperature, indicating induced positive curvature strain.
• NMR data exclude barrel-stave and detergent-like mechanisms for LL-37-induced membrane disruption.

Conclusions:

• LL-37's surface-parallel orientation and induction of positive curvature strain support a toroidal pore model for antimicrobial activity.
• The findings provide critical insights into the biophysical mechanisms underlying LL-37's membrane-disrupting capabilities.
• This study refines our understanding of how antimicrobial peptides interact with and permeabilize target membranes.