Unveiling the inhibition mechanism of host-defense peptide cathelicidin LL-37 on the amyloid aggregation of the human islet amyloid polypeptide.

The aberrant aggregation of the human islet amyloid polypeptide (hIAPP) is a hallmark of type II diabetes. LL37, the only cathelicidin host-defense peptide in humans, plays essential roles in antimicrobial and immunomodulatory activities. Mounting evidence indicates that LL37 can inhibit the amyloid aggregation of hIAPP, suggesting possible interplays between infections and amyloid diseases while the mechanism remains unclear. In this paper, we explored the molecular interactions between hIAPP and LL37 using all-atom discrete molecular dynamics (DMD), a novel and predictive molecular dynamics engine with improved sampling efficiencies. We found that the LL37 peptides can effectively interact with hIAPP in monomer, oligomer, and fibril states driven by hydrophobic associations and pi-pi interactions. Specifically, the hydrophobic residues in the N- and C-termini of LL37 peptides can firmly bind with the monomeric and oligomeric hIAPP, especially in the amyloidogenic regions, to prevent the self-interactions of amyloidogenic regions and thus hinder the formation of amyloid fibrils. Furthermore, LL37 can bind to the elongation surfaces of the hIAPP fibril seeds with geometric incompatibility for monomer addition to block the fibril growth. Together, we identified the crucial residues and key driving forces for the interactions between LL37 and hIAPP peptides and revealed the related dynamics and conformational changes. The uncovered mechanism can contribute to a better understanding of the pathological links between microbial infections and amyloid diseases and guide the designs of novel therapies combining antimicrobial and anti-amyloid functions.