Penetratin-membrane association: W48/R52/W56 shield the peptide from the aqueous phase.

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 headgroups 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.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Lensink MF,Christiaens B,Vandekerckhove J,Prochiantz A,Rosseneu M

doi

10.1529/biophysj.104.052787

subject

Has Abstract

pub_date

2005-02-01 00:00:00

pages

939-52

issue

2

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(05)73166-0

journal_volume

88

pub_type

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