The innate immunity of multicellular organisms relies in large part on the action of antimicrobial peptides (AMPs) to resist microbial invasion. Crafted by evolution into an extremely diversifi ed array of sequences and folds, AMPs do share a common amphiphilic 3-D arrangement. This feature is directly linked with a common mechanism of action that predominantly (although not exclusively) develops upon interaction of peptides with cell membranes of target cells. It is generally agreed that AMPs are essentially unstructured in the aqueous phase and fold upon contact with the membrane, adopting an amphiphilic fold. This favours absorption of peptides onto lipid bilayer and their subsequent integration into the membrane with expansion of the outer leafl et, which in turn leads to membrane thinning and permeabilization. However, recent observation suggest that things might be more complicated than previously believed. Indeed, MD simulations coupled to CD spectroscopy, studies with model membranes, and antimicrobial assays, have shown that, at least for some peptides, a signifi cant correlation exists between the conformation adopted by the peptide in solution, i.e. before the interaction with membranes, and its antimicrobial activity. The linear peptides we have studied following this approach include two members of the frog skin-derived temporin family, namely temporin A and temporin L, and two members of amphibian bombinins H, i.e. bombinins H2 and H4. We observed that the presence of a partially folded structure in water solution may facilitate, both thermodynamically and kinetically, the peptide folding in the microbial membrane, and thus favour biological activity. Looking for such built-in conformational characteristics could well help to rationalize the different spectrum and level of activity recorded for cationic alpha-helical AMPs on membraneenveloped targets, and assist the design of improved analogs and biomimetic synthetic peptides with antibiotic properties.
Folding propensity and biological activity of selected antimicrobial peptides
RINALDI, ANDREA
2008-01-01
Abstract
The innate immunity of multicellular organisms relies in large part on the action of antimicrobial peptides (AMPs) to resist microbial invasion. Crafted by evolution into an extremely diversifi ed array of sequences and folds, AMPs do share a common amphiphilic 3-D arrangement. This feature is directly linked with a common mechanism of action that predominantly (although not exclusively) develops upon interaction of peptides with cell membranes of target cells. It is generally agreed that AMPs are essentially unstructured in the aqueous phase and fold upon contact with the membrane, adopting an amphiphilic fold. This favours absorption of peptides onto lipid bilayer and their subsequent integration into the membrane with expansion of the outer leafl et, which in turn leads to membrane thinning and permeabilization. However, recent observation suggest that things might be more complicated than previously believed. Indeed, MD simulations coupled to CD spectroscopy, studies with model membranes, and antimicrobial assays, have shown that, at least for some peptides, a signifi cant correlation exists between the conformation adopted by the peptide in solution, i.e. before the interaction with membranes, and its antimicrobial activity. The linear peptides we have studied following this approach include two members of the frog skin-derived temporin family, namely temporin A and temporin L, and two members of amphibian bombinins H, i.e. bombinins H2 and H4. We observed that the presence of a partially folded structure in water solution may facilitate, both thermodynamically and kinetically, the peptide folding in the microbial membrane, and thus favour biological activity. Looking for such built-in conformational characteristics could well help to rationalize the different spectrum and level of activity recorded for cationic alpha-helical AMPs on membraneenveloped targets, and assist the design of improved analogs and biomimetic synthetic peptides with antibiotic properties.
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