Structure, Dynamics, and Antimicrobial Function of LL37

The primary goal of this project is to understand the molecular basis of membrane disruption and antimicrobial activity of LL37, an important peptide in the human body's first line of defense against infection. LL37 is the only human antimicrobial peptide in the cathelicidin family. It is widely expressed in both neutrophils and epithelial tissues, and the propeptide form (hCAP18) is present in very high concentrations (1.18 µg/ml) in plasma. Infection and inflammation of epithelial tissues due to a variety of causes have been shown to induce a marked increase in expression. Although LL37 is an amphipathic peptide, preliminary results suggest that its salt-resistant antimicrobial activity, significant resistance to proteolytic degradation, aggregation state, structural stability, and predicted N-terminal structure differ from the well-studied archetypal antimicrobial peptides of this class. These differences affect features critical to the proposed pore model of antimicrobial activity by amphipathic a-helical peptides, isolated from invertebrates or vertebrates, and suggest a unique mechanism for LL37. Therefore, understanding of membrane disruption by LL37 may shed light on its in vivo activities and assist in the development of antimicrobial agents mimicking those of the human immune system for the treatment of bacterial infection in normal and immunocompromised persons and individuals with cystic fibrosis. In addition, it will provide insight into the activity of the broader class of a-helical antimicrobial peptides since these peptides are thought to form pores through transient aggregates which are difficult to study, while LL37 forms more stable aggregates whose structure and lipid interactions will be examined directly.