Interactions of Cationic-Hydrophobic Peptides with Lipid Bilayers: A Monte Carlo Simulation Method

¹ Tel-Aviv University
² Bogazici University
³ Tel Aviv University

^* To whom correspondence should be addressed. E-mail: bental{at}ashtoret.tau.ac.il.

Submitted on December 31, 2006
Revised on March 10, 2007
Accepted on 19 March 2007

	Abstract

We present a computational model of the interaction between hydrophobic cations, such as the antimicrobial peptides Magainin2, and membranes that include anionic lipids. The peptide's amino acids were represented as two interaction sites: one corresponds to the backbone -carbon and the other to the side-chain. The membrane was represented as a hydrophobic profile, and its anionic nature was represented by a surface of smeared charges. Thus, the Coulombic interactions between the peptide and the membrane were calculated using the Gouy-Chapman theory that describes the electrostatic potential in the aqueous phase near the membrane. Peptide conformations and locations near the membrane, and changes in the membrane width, were sampled at random using the Metropolis criterion, taking into account the underlying energetics. Simulations of the interactions of heptalysine and the hydrophobic-cationic peptide, Magainin2, with acidic membranes were used to calibrate the model. The calibrated model reproduced structural data and the membrane-association free energies that were measured also for other basic and hydrophobic-cationic peptides. Interestingly, amphipathic peptides, such as Magainin2, were found to adopt two main membrane-associated states. In the first, the peptide resided mostly outside the polar headgoups region. In the second, which was energetically more favorable, the peptide assumed an amphipathic-helix conformation, where its hydrophobic face was immersed in the hydrocarbon region of the membrane and the charged residues were in contact with the surface of smeared charges. This dual behavior provides a molecular interpretation of the available experimental data.

Key Words: Gouy-Chapman theory, Metropolis Monte Carlo, Peptide-membrane interactions, anti-microbial peptide