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202 Cell-Penetrating Peptides: Processes and Applications
and hydrophilicity values at all the grid nodes was calculated. The hydrophobic and
hydrophilic MHP surfaces were then drawn by joining the isopotential values.
9.3 RESULTS
9.3.1 EFFICIENCY OF MONTE CARLO METHOD APPLIED TO SHORT PEPTIDES
AND MEMBRANE PROTEINS
9.3.1.1 Hydrophobic Peptides
Different peptides have already been studied in order to evaluate the Monte Carlo
method by comparison with known experimental data. Different amphipathic,
transmembrane 31 and tilted peptides 55 have been analyzed in this goal.
18A is a synthetic amphipathic peptide shown to be α-helical and adsorbed at
the water–lipid interface. 56 In Figure 9.5, the restraint envelope is a function of the
peptide mass center penetration and axis tilt with respect to the membrane surface.
In its energy minimum position, the peptide is at the surface of the model bilayer.
For the 18A peptide, the energy minimum is reached when the peptide is in membrane
at about 16 Å of the bilayer center with a tilt of 10°, the position varies between
14-18 Å and 0-20° of angle of insertion, demonstrating that the peptide finds its
local minimum in a position parallel to the interface, which corresponds to a perfectly
amphipathic structure.
The M2δ peptide is a transmembrane α-helix present in the acetylcholine receptor
that can induce the lysis of red blood cells. 57 The peptide is biamphipathic and,
in the presence of a bilayer, it stands almost perpendicularly (around 70°) to the
plane in a transmembrane configuration. 31
The fusion peptide SIV (simian immunodeficiency virus) was among the first
tilted peptides described by molecular modeling (Figure 9.5.C). Tilted peptides have
10 to 20 residues and a peculiar hydrophobicity profile. When analyzed in a helix
FIGURE 9.5 (opposite) The different plots correspond to the peptides 18A (A), M2δ (B),
and SIV (C). IMPALA simulations are shown as 3D plots of the restraint energy vs. the
penetration of the peptide mass center and vs. the angle of insertion of a reference vector.
The reference vector is defined by 2 atoms of a helix or a strand, and the angle of this vector
with the XY plane is the index of the peptide orientation in the bilayer. The protein mass
center penetration in angstroms is plotted on the X axis (0 is the bilayer center); the Y axis
is the angle in degrees of the reference vector. The restraint values are plotted along the Z
axis. The energy minimum zones (light gray) locate the most favorable positions of the
peptides. The 3D envelopes are calculated as follows: a 2D grid using as X axis the position
of the molecule mass center between –15 and 15 Å, by steps of 0.5 Å, and along the Y axis,
the angle of the helix with respect to the plane of the bilayer by steps of 3°. Next, for each
grid knot, the minimal energy restraint is plotted. Data are extracted from the Pex2dstat files.
The ribbon picture of the most stable conformation of each peptide is shown in the model
membrane of IMPALA. The dotted line is the center of the bilayer (Z = 0 Å) and the black
line defines where the polar heads of lipids start (z = ±13.5 Å). The gray line is the water–lipid
interface (z = ±18 Å).