The escalating threat of antimicrobial resistance has intensified the need for alternative strategies to combat pathogenic bacteria. Among promising candidates are antimicrobial peptides (AMPs), which represent a natural defense mechanism across diverse organisms. Human cathelicidin-derived LL-37 stands out as one of the most extensively studied AMPs due to its potent antimicrobial activity, despite an incomplete understanding of its precise mode of action. This study investigates the interaction between LL-37 and 1-Palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (POPG) vesicles—used as a model for bacterial membranes owing to the prevalence of POPG in bacterial lipid bilayers. A multidisciplinary approach combining small-angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), and coarse-grained molecular dynamics (CG MD) simulations was employed to elucidate the structural and mechanistic details of this interaction.
Experimental results reveal that increasing concentrations of LL-37 induce a progressive transformation from multilamellar vesicles to cylindrical micelles. SAXS data show a shift from a q⁻³ power-law decay characteristic of lamellar structures to a q⁻¹ dependence indicative of elongated cylindrical morphologies at high peptide-to-lipid ratios. This transition is further confirmed by DLS, which demonstrates a significant reduction in hydrodynamic diameter—from approximately 130 nm in pure POPG vesicles to around 20 nm at a POPG/LL-37 ratio of 1:2. Cryo-TEM imaging visualizes the morphological evolution, showing the disappearance of large vesicular structures and the emergence of smaller rod-like and branched nanoscale assemblies.
Complementing these observations, CG MD simulations provide atomic-level insights into the underlying mechanisms.1809249-37-3 Formula The simulations confirm that LL-37 preferentially localizes at the lipid-water interface, where it interacts electrostatically with the negatively charged phosphatidylglycerol head groups.CD300F Antibody supplier This interaction increases the effective head group area, thereby reducing the critical packing parameter (Cpp) and promoting curvature-driven self-assembly into flat or cylindrical micelles.PMID:34874114 Notably, no stable pore formation is observed; instead, the membrane undergoes a spontaneous reorganization into bicelle-like structures under high peptide concentrations, where POPG molecules form a planar polar surface stabilized by LL-37 distributed along the equatorial edge.
These findings collectively challenge the classical pore-forming hypothesis for LL-37 and instead support a mechanism centered on membrane curvature modulation and phase transformation. The ability of LL-37 to destabilize bacterial membrane mimics through such colloidal reorganization underscores its potential as a template for designing next-generation antimicrobial agents. By leveraging both experimental and computational tools, this work advances our fundamental understanding of AMP-membrane interactions and paves the way for rational design of peptide-based therapeutics capable of overcoming antibiotic resistance.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com