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Biophys. J. BioFAST: First Published November 12, 2004. doi:10.1529/biophysj.104.052787
© 2004 by the Biophysical Society.

A more recent version of this article appeared on February 1, 2005.
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BIOPHYSICAL THEORY AND MODELING

Penetratin-Membrane Association: W48/R52/W56 Shield the Peptide from the Aqueous Phase

Marc F. Lensink 1*, Bart Christiaens 1, Joel Vandekerckhove 2, Alain Prochiantz 3 and Maryvonne Rosseneu 1

1 University of Ghent
2 Flanders Interuniversity Institute for Biotechnology
3 Ecole Normale Superieure de Paris

* To whom correspondence should be addressed. E-mail: lensink{at}scmbb.ulb.ac.be.

Submitted on September 14, 2004
Revised on October 7, 2004
Accepted on 2 November 2004


  Abstract
Using molecular dynamics simulations, we studied the mode of association of the cell-penetrating peptide penetratin with both a neutral and a charged bilayer. The results show that the initial peptide-lipid association is a fast process driven by electrostatic interactions. The homogeneous distribution of positively charged residues along the axis of the helical peptide, and especially residues K46, R53 and K57, contribute to the association of the peptide with lipids. The bilayer enhances the stability of the penetratin helix. Oriented parallel to the lipid-water interface, the subsequent insertion of the peptide through the bilayer head groups is significantly slower. The presence of negatively charged lipids considerably enhances peptide binding. Lateral side-chain motion creates an opening for the helix into the hydrophobic core of the membrane. The peptide aromatic residues form a {pi}-stacking cluster through W48/R52/W56 and F49/R53, protecting the peptide from the water phase. Interaction with the penetratin peptide has only limited effect on the overall membrane structure, as it affects mainly the conformation of the lipids which interact directly with the peptide. Charge matching locally increases the concentration of negatively charged lipids, lateral lipid diffusion locally decreases. Lipid disorder increases, through decreased order parameters of the lipids interacting with the penetratin side chains. Penetratin molecules at the membrane surface do not seem to aggregate.

Key Words: Bilayer, Cation/{pi}, Cell-Penetrating, Homeodomain, Molecular Dynamics, Translocation




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Copyright © 2004 by the Biophysical Society.