The study shows that the natural way LL‑37 peptides stick together (oligomerize) changes how well they kill microbes and how they affect human cells. Different dimer shapes (parallel vs antiparallel) can make the peptide more or less potent and more or less toxic. Researchers also created a special version of LL‑37 that can be “locked” together with UV light to see how it groups in solution and membranes.

LL-37 is a multifunctional component of innate immunity, with a membrane-directed antimicrobial activity and receptor-mediated pleiotropic effects on host cells. Sequence variations in its primate orthologues suggest that two types of functional features have evolved; human LL-37-like peptides form amphipathic helical structures and self-assemble under physiological conditions, whereas rhesus RL-37-like peptides only adopt this structure in the presence of bacterial membranes. The first type of peptide has a lower and more medium-sensitive antimicrobial activity than the second type, but an increased capacity to stimulate host cells. Oligomerization strongly affects the mode of interaction with biological membranes and, consequently, both cytotoxicity and receptor-mediated activities. In the present study we explored the effects of LL-37 self-association by using obligate disulfide-linked dimers with either parallel or antiparallel orientations. These had an increased propensity to form stacked helices in bulk solution and when in contact with either anionic or neutral model membranes. The antimicrobial activity against Gram-positive or Gram-negative bacteria, as well as the cytotoxic effects on host cells, strongly depended on the type of dimerization. To investigate the extent of native oligomerization we replaced Phe5 with the photoactive residue Bpa (p-benzoyl-L-phenylalanine), which, upon UV irradiation, enabled covalent cross-linking and allowed us to assess the extent of oligomerization in both physiological solution and in model membranes.