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Biophys. J. BioFAST: First Published July 21, 2006. doi:10.1529/biophysj.106.084046
© 2006 by the Biophysical Society.

A more recent version of this article appeared on October 15, 2006.
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BIOPHYSICAL THEORY AND MODELING

Interaction of Protegrin-1 (PG-1) with Lipid Bilayers: Membrane Thinning Effect

Hyunbum Jang 1, Buyong Ma 2*, Thomas Woolf 3 and Ruth Nussinov 4

1 NCI-Frederich
2 NCI-frederick, NIH
3 John Hopkins Univ. Sch. of Medicine
4 SAIC Frederick, Inc

* To whom correspondence should be addressed. E-mail: mab{at}ncifcrf.gov.

Submitted on February 24, 2006
Revised on April 18, 2006
Accepted on 12 July 2006


  Abstract
Protegrins are important in defending host tissues, preventing infection via an attack on the membrane surface of invading microorganisms. Protegrins have powerful antibiotic abilities but the molecular-level mechanisms underlying the interactions of their {beta}-sheet motifs with the membrane are not known. Protegrin-1 (PG-1) is composed of 18 amino-acids with a high content of basic residues and two disulfide bonds. Here we focused on the stability of PG-1 at the amphipathic interface in lipid bilayers and on the details of the peptide-membrane interactions. We simulated all-atom models of the PG-1 monomer with explicit water and lipid bilayers composed of both homogeneous POPC lipids and a mixture of POPC:POPG (4:1) lipids. We observed that local thinning of the lipid bilayers mediated by the peptide is enhanced in the lipid bilayer containing POPG, consistent with experimental results of selective membrane targeting. The {beta}-hairpin motif of PG-1 is conserved in both lipid settings, while it is highly bent in aqueous solution. The conformational dynamics of PG-1, especially the highly charged {beta}-hairpin turn region are found to be mostly responsible for disturbing the membrane. Even though the eventual membrane disruption requires PG-1 oligomers, our simulations clearly show the first step of the monomeric effects. The thinning effects in the bilayer should relate to pore/channel formation in lipid bilayer and thus responsible for further defects in the membrane caused by oligomer.

Key Words: antibiotic, dimerization, membrane disruption, molecular dynamics simulation, peptide, protegrin




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Copyright © 2006 by the Biophysical Society.