The antimicrobial activity of human cathelicidin LL-37 is increasingly recognized as stemming from its ability to dynamically reorganize lipid membrane architectures. This study presents a detailed mechanistic analysis of how LL-37 induces structural disassembly in bacterial membrane mimics composed of 1-Palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (POPG) vesicles, integrating high-resolution experimental data with atomistic-level molecular dynamics simulations.
Small-angle X-ray scattering (SAXS) reveals a concentration-dependent transformation from multilamellar vesicles to cylindrical micelles. At low LL-37 concentrations, the scattering profile exhibits a q⁻³ decay characteristic of lamellar ordering, with distinct Bragg peaks indicating regular bilayer stacking. As the peptide-to-lipid ratio increases—particularly at 1:1 and 1:2 mass ratios—the Bragg reflections diminish, and the scattering intensity shifts toward a q⁻¹ dependence, signaling the emergence of elongated, cylindrical nanostructures. The absence of long-range order confirms the loss of vesicular integrity and the formation of small, disordered aggregates.
Dynamic light scattering (DLS) quantifies this morphological transition, showing a dramatic reduction in hydrodynamic diameter—from ~130 nm for pure POPG vesicles to ~20 nm upon exposure to high LL-37 levels. Concurrent zeta potential measurements indicate a shift from highly negative surface charge (−45 mV) to near-neutral values, suggesting electrostatic screening by cationic LL-37 and the disruption of interparticle repulsion, which may initially promote aggregation before final disassembly.
Cryogenic transmission electron microscopy (cryo-TEM) provides direct visual evidence. Images of untreated POPG systems display intact unilamellar and multilamellar vesicles. With increasing LL-37, vesicles fragment into smaller discoidal and rod-like structures, some exhibiting branched morphologies.CD56 Antibody supplier These features are consistent with the onset of non-lamellar phases driven by curvature stress.PLK1 Antibody web
Coarse-grained molecular dynamics (CG MD) simulations reveal the molecular basis of these transformations.PMID:34610467 In all systems, LL-37 rapidly adsorbs to the lipid-water interface, adopting a lateral orientation parallel to the membrane plane. Its positively charged face engages strongly with anionic POPG head groups, while the hydrophobic face remains minimally inserted. This interaction leads to a localized expansion of the effective head group area, reducing the critical packing parameter (Cpp) and promoting negative curvature. Over time, this results in spontaneous bilayer flattening and the formation of stable flat micelles or bicelles—structures that persist under simulation conditions.
Importantly, no evidence of transmembrane pore formation is observed. Instead, the primary mechanism involves curvature-driven phase inversion, where the membrane transitions from a closed vesicle to open, extended micellar assemblies. This process is energetically favorable due to the enhanced solvation of polar head groups and the release of strain induced by peptide binding.
In summary, this work demonstrates that LL-37 disrupts POPG vesicles not through pore formation but via a curvature-mediated disassembly pathway. By altering the thermodynamic balance of lipid self-assembly, LL-37 triggers a cascade of colloidal transformations that compromise membrane continuity. These findings provide a robust foundation for designing next-generation AMP-based therapeutics that exploit membrane remodeling rather than permeabilization, offering a promising strategy to circumvent resistance mechanisms in pathogenic bacteria.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