The study used computer simulations to watch how the human antimicrobial peptide LL‑37 behaves when it meets two types of cell membranes: a negatively charged one that mimics bacteria (POPG) and a neutral one that mimics human cells (POPC). LL‑37 quickly sticks to the bacterial‑like membrane, stays helical, lies flat, and bends the membrane, while it interacts more slowly with the human‑like membrane, loses its shape, and barely penetrates it.

Cathelicidins are a large family of cationic antimicrobial peptides (AMPs) found in mammals with broad spectrum antimicrobial activity. LL-37 is the sole amphipathic &#x3b1;-helical AMP from human Cathelicidins family. In addition to its bactericidal capability, LL-37 has antiviral, anti-tumor, and immunoregulatory activity. Despite many experimental studies, its molecular mechanism of action is not yet fully understood. Here, we performed three independent molecular dynamics simulations (600 ns or more) of a LL-37 peptide in the presence of 256 lipid bilayers with 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphoglycerol (POPG) mimicking bacterial and 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine (POPC) mimicking mammalian membranes. We found that LL-37 can be quickly absorbed onto the POPG bilayer without loss of its helical conformation in the core region and with the helix lying in parallel to the bilayer. The POPG bilayer was deformed. In contrast, LL-37 is slower in reaching the POPC surface and loss much of its helical conformation during the interaction with the bilayer. LL-37 only partially entered the POPC bilayer without significant deformation of the membrane. The observed difference for different bilayers is largely due to the fact that LL-37 is positively charged, POPG is negatively charged, and POPC is neutral. Our simulation results demonstrated the initial stage of disruption of the bacterial membrane by LL-37 in atomic details. Comparison to experimental results on LL-37 and simulation studies in other systems was made.