| Popis: |
Piscidin, an amphipathic cationic antimicrobial peptide (AMP) active against a broad range of pathogens including multidrug-resistant bacteria and HIV-1, belongs to a large family of vital host-defense peptides that interact, at least initially, with negatively-charged microbial membranes in order to perform their function. While two piscidin isoforms, piscidin 1 (p1) and piscidin 3 (p3), are highly homologous, they display unequal antimicrobial and hemolytic effects. As a way to identify factors optimizing specific molecular interactions directly related to their mode of membrane activity, we have investigated p1 and p3 bound to lipid membranes that mimic bacterial membranes.Previously, we used solid-state NMR on 15N-labeled peptides to demonstrate that membrane-bound p1 and p3 adopt an alpha-helical structure and lie in the plane of hydrated lipid bilayers where they experience fast dynamics. Our recent analysis of two-dimensional solid-state NMR data has lead to the first atomic resolution three-dimensional backbone structures of p1 and p3 bound to aligned lipid bilayers. Structural calculations based on the NMR data and molecular dynamics simulations have been performed to yield a refined structure and membrane location for each peptide.We will explain how our atomic-level investigation of the structure, dynamics, and bilayer location of piscidin provides new insights into its mode of action and therefore allows us better to understand how AMPs disrupt bacterial membranes and induce cell death. The long term goal is to derive common principles that could facilitate the design of pharmaceuticals with enhanced antibacterial activity and lower toxicity on mammalian cells. |
