Abstract
Antimicrobial peptides (AMPs) are ubiquitous weapons of all higher organisms to suppress antimicrobial growth. Despite intensive research, the killing mechanism of these peptides after interaction with the bacterial cell wall and cytoplasm is not well understood. To investigate this mechanism at a molecular level, we chose a well-studied AMP, Magainin-2 (Mag-2), for biophysical and structural studies. Circular dichroism experiments showed that the folding propensity of Mag-2 is strongly altered towards fully folded molecules in the presence of detergent. To study the pore-forming properties of Mag-2 in membranes, we crystallized the wild-type peptide in the presence of the membrane-mimicking dodecylphosphocholine detergent and obtained crystals diffracting to atomic resolution. Mag-2 structure shows an antiparallel arrangement of monomers, which is stabilised by a phenylalanine zipper motif spanning the hydrophobic interaction surface of this dimer. Trimerization of dimers leads to the formation of a hexameric peptide channel complex with a positively charged pore and a hydrophobic membrane-exposed belt. Using molecular dynamics simulations, a spontaneous flow of ions through this channel was observed, demonstrating anion-selectivity induced by the electrostatic potential characteristics of Mag-2. This first atomic-resolution structure of wild-type Mag-2 showing oligomerization will allow the rational design of improved Mag-2 peptide channels.