Molecular interaction modes of host-defense peptide cathelicidin LL-37 and its mutants dictate the diverse antimicrobial activities

Abstract

The host-defense peptide cathelicidin LL-37 is an innate immune defense peptide with broad-spectrum antimicrobial effects. Experiments showed that the antimicrobial activity of LL37(17-29), the active core of LL37, was associated with the peptide aggregation and fibrillization. While the wild-type (WT) LL37(17-29) aggregated into densely packed fibrils with strong antimicrobial activity, the F17S mutation exhibited a weaker antimicrobial effect and I24K totally abolished the antimicrobial activity with no fibrils formed. To uncover the mechanisms of the distinct antimicrobial activities, we explored the structures and aggregation dynamics of LL37(17-29) and mutants using discrete molecular dynamics (DMD) simulations, an efficient molecular dynamics algorithm with accurate predictions. Results showed that LL37(17-29) peptides formed helix-helix contacts driven by hydrophobic interactions, which further aggregated into fibrils of densely packed helices. The F17S peptides, with monomeric structure similar to WT peptides, were more flexible and formed weak interpeptide contacts between short helices and ultimately inhibited the aggregation. In comparison, although the helix structure of the monomeric I24K peptide was promoted compared to the WT peptide, the helix-helix contacts between I24K peptides were diminished due to the reduced hydrophobic interaction and enhanced electrostatic repulsion, resulting in suppressed aggregation and antimicrobial activity. Together, our results elucidated molecular mechanisms of the diverse aggregation and antimicrobial activities of the LL37(17-29) WT and mutants, offering valuable insights for the rational design of novel antibacterial agents.