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Biophys. J. BioFAST: First Published April 7, 2006. doi:10.1529/biophysj.105.073890
© 2006 by the Biophysical Society.

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MEMBRANES

Solid-State NMR Investigation of the Membrane-Disrupting Mechanism of Antimicrobial Peptides MSI-78 and MSI-594 Derived From Magainin 2 and Melittin

Sathiah Thennarasu 1, Dong Kuk Lee 2, Anmin Tan 2, Lee Maloy 3 and Ayyalusamy Ramamoorthy 4*

1 University of Michigan
2 University of Michigan,
3 Genaera Pharmaceuticals
4 The University of Michigan

* To whom correspondence should be addressed. E-mail: ramamoor{at}umich.edu.

Submitted on September 11, 2005
Revised on January 17, 2006
Accepted on 14 March 2006


  Abstract
The mechanism of membrane interaction of two amphipathic antimicrobial peptides, MSI-78 and MSI-594 derived from magainin-2 and melittin, is presented. Both the peptides show excellent antimicrobial activity. The 8-anilinonapthalene-1-sulfonic acid uptake experiment using E.coli cells suggests that the outer membrane permeabilization is mainly due to electrostatic interactions. The interaction of MSI-78 and MSI-594 with lipid membranes was studied using 31P and 2H solid-state NMR, circular dichroism, and differential scanning calorimetry techniques. The binding of MSI-78 and MSI-594 to the lipid membrane is associated with a random coil to {alpha}-helix structural transition. MSI-78 and MSI-594 also induce the release of entrapped dye from POPC/POPG (3:1) vesicles. Measurement of the phase transition temperature of peptide-DiPoPE dispersions shows that both MSI-78 and MSI-594 repress the lamellar-to-inverted hexagonal phase transition by inducing positive curvature strain. 15N NMR data suggest that both the peptides are oriented nearly perpendicular to the bilayer normal, which infers that the peptides most likely do not function via barrel-stave mechanism of membrane-disruption. Data obtained from 31P NMR measurements using peptide-incorporated POPC and POPG oriented lamellar bilayers, show a disorder in the orientation of lipids up to a peptide/lipid (P/L) ratio of 1:20, and the formation of non-bilayer structures at P/L ratio >1:8. 2H-NMR experiments with selectively deuterated lipids reveal peptide-induced disorder in the methylene units of the lipid acyl chains. These results are discussed in light of lipid-peptide interactions leading to the disruption of membrane via either a carpet or a toroidal-type mechanism.

Key Words: Antimicrobial Peptide, Lipid bilayers, magainin analog, membrane disruption, solid-state NMR






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Copyright © 2006 by the Biophysical Society.