Folded
Structure and Insertion Depth of the Frog-Skin
Antimicrobial Peptide Esculentin-1b(1–18) in the Presence of
Differently Charged Membrane-Mimicking Micelles
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Abstract
Antimicrobial peptides (AMPs) are
effectors of the innate immunity
of most organisms. Their role in the defense against pathogen attack
and their high selectivity for bacterial cells make them attractive
for the development of a new class of antimicrobial drugs. The N-terminal
fragment of the frog-skin peptide esculentin-1b (Esc(1–18))
has shown broad-spectrum antimicrobial activity. Similarly to most
cationic AMPs, it is supposed to act by binding to and damaging the
negatively charged plasma membrane of bacteria. Differently from many
other AMPs, Esc(1–18) activity is preserved in biological fluids
such as serum. In this work, a structural investigation was performed
through NMR spectroscopy. The 3D structure was obtained in the presence
of either zwitterionic or negatively charged micelles as membrane
models for eukaryotic and prokaryotic membranes, respectively. Esc(1–18)
showed a higher affinity for and deeper insertion into the latter
and adopted an amphipathic helical structure characterized by a kink
at the residue G8. These findings were confirmed by measuring penetration
into lipid monolayers. The presence of negatively charged lipids in
the bilayer appears to be necessary for Esc(1–18) to bind,
to fold in the right three-dimensional structure, and, ultimately,
to exert its biological role as an AMP