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214 Cell-Penetrating Peptides: Processes and Applications
E
(top)
(bottom)
Total Restraints (kJ/mol Å 2 )
FIGURE 9.9 (continued)
pAntp (inner leaflet charge: -0.02)
Mass Center Penetration (Å)
core of the bilayer. The lipid perturbation restraint is similar to that calculated for
the first helix and for the full-length homeodomain.
Finally, our simulations predict that, with such a charge distribution, the penetratin
peptide may cross the bilayer due to the influence of membrane charges. This
restraint is indeed greatly favorable during the bilayer crossing simulation. Furthermore,
the evolution of the hydrophobic restraint suggests that the helix hydrophobic
properties would not allow crossing the bilayer hydrophobic core in the absence of
the superficial charge density located at the internal leaflet. However, although the
charge restraint becomes unfavorable from –10 Å, the hydrophobic restraint, in turn,
becomes favorable, and allows the mass center of the third helix to stabilize at –13 Å,
forming a 3° angle with the bilayer plan. The discontinuous course during crossing
(indicated by dots, Figure 9.9E, top) suggests that the crossing is very rapid. Lipid
perturbation restraint stays at the same level as for the previous simulations (8
kJ/mol.Å 2 ), indicating that the crossing has no major destabilizing effects on the
Angle(°)