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FIGURE 9.8 The center of the figure represents evolution of the total restraint vs. the mass center penetration of all simulated compounds in an uncharged bilayer model. Figures 9.8A, B, C, D, and E represent the position and the orientation of AntHD–DNA complex, AntHD, 1st helix, 2nd helix, pAntp, respectively, at the energy minimum value. Structure Prediction of CPPs and Iterative Development of Novel CPPs 209
210 Cell-Penetrating Peptides: Processes and Applications translocation across the bilayer, we applied the Monte Carlo procedure to each helix separately. The energy restraint evolution as a function of the mass center penetration shows that no helix can cross the uncharged bilayer model. However, the pAntp interacts more closely with the phospholipid polar heads (Figure 9.8E) than the second helix (Figure 9.8D), which adsorbs to the membrane, and than the first one (Figure 9.8C), which almost does not interact with the polar heads. In conclusion, these Monte Carlo simulations performed with an uncharged bilayer model clearly show that no Antennapedia-derived peptide is predicted to cross the membrane. These results are in agreement with the MHP analysis: the charged and polar residues within the three homeodomain helices make them particularly hydrophilic so that they cannot enter the hydrophobic core of a biological membrane. 9.3.2.2 Charged Bilayer Model Biological membranes are rarely symmetrical in lipid and protein composition. The uncharged model of lipid bilayer used in the first round of simulations described earlier mimics a membrane made of only neutral phospholipids (PL°). However, if the major membrane components of the eukaryotic organisms are PL°, it has been shown 67 that negatively charged phospholipids (PL – ) also enter in the composition of membranes. These PL – are asymmetrically distributed between both leaflets of membranes. Moreover, the asymmetric distribution of PL° and PL – is different according to the cell type and is actively controlled by specific protein machineries. The asymmetric presence of PL – causes an electrostatic gradient in biological membranes. To take this into account, we introduced charges in both leaflets. The question then was to determine to which extent the force field produced by the charge asymmetry might influence passage of peptides through the model membrane. In order to start such simulations, we chose to set up a model of the human erythrocyte membrane. Cullis et al. 67 have calculated a superficial charge density of 8 µC/cm 2 (0.005 e – /Å 2 ) for the erythrocyte membrane. This charge density is due to the presence of PL – in the internal leaflet of the erythrocyte membrane. We performed new simulations, considering that the internal sheet of the bilayer had a charge density ranging from 0.005 e – /Å 2 to 0.04 e – /Å 2 . The results of the different simulations are presented in Table 9.2. According to these simulations, penetratin should cross a membrane when the superficial charge density is 0.01 e – /Å 2 . When the superficial charge density reaches 0.04 e – /Å 2 , the Antennapedia homeodomain, as well as the first helix, partially penetrates the membrane, while the second helix and the penetratin cross this membrane. We detailed two simulations in order to further explain the mechanism. Figure 9.9A shows evolution of the hydrophobic, lipid perturbation (E lip), and charge sum restraints as a function of mass center penetration of the AntHD–DNA, when considering a superficial charge density of 0.02 e – /Å 2 in the inner leaflet. The two dotted lines delimit the phospholipid polar heads of the external leaflet. The bilayer center is defined by the 0 Å ordinate. Because the complex does not cross the membrane, only the outer leaflet bearing the charge was plotted.
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CELL- PENETRATING PEPTIDES Processe
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Pharmacology and Toxicology: Basic
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Library of Congress Cataloging-in-P
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to the handbook are prominent resea
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REFERENCES 1. Green, M. and Loewens
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Contributors Mats Andersson Microbi
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Erin T. Pelkey Department of Chemis
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Contents Section I Classes of Cell-
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Chapter 16 Cell-Penetrating Peptide
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The Tat-Derived Cell-Penetrating Pe
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24 Cell-Penetrating Peptides: Proce
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3 Transportans Margus Pooga, Mattia
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Transportans 55 Indeed, galparan is
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Transportans 57 especially the endo
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Transportans 59 In the penetration
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Transportans 61 A 21-mer antisense
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Transportans 63 Commonly, the prote
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Transportans 65 antibiotin antibodi
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Transportans 67 For cross-linking o
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Transportans 69 and still retain ef
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Model Amphipathic Peptides 73 its D
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Model Amphipathic Peptides 75 pmol/
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TABLE 4.1 Internalization of Peptid
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TABLE 4.2 Internalization of Peptid
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Model Amphipathic Peptides 81 relat
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Model Amphipathic Peptides 87 A cat
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Model Amphipathic Peptides 89 At th
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Model Amphipathic Peptides 91 16. H
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Signal Sequence-Based Cell-Penetrat
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116 Cell-Penetrating Peptides: Proc
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Page 186 and 187: Interactions of Cell-Penetrating Pe
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Page 210 and 211: Structure Prediction of CPPs and It
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Page 268 and 269: Toxicity and Side Effects of Cell-P
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Toxicity and Side Effects of Cell-P
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Toxicity and Side Effects of Cell-P
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Kinetics of Uptake of Cell-Penetrat
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Cell-Penetrating Peptide Conjugatio
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FIGURE 15.9 (Color Figure 15.9 foll
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Cell-Penetrating Peptides as Vector
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TABLE 16.1 Examples of Transport of
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CPP 2 Cargo or mRNA CAP Antisense A
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Microbial Membrane-Permeating Pepti
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Index A Abaecin, 129 Abz radiolabel
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Index 399 Diffraction, 168 Disulphi
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Index 401 structure prediction, 187
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Index 403 pRB proteins, Tat-E1A bin
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Index 405 lipid perturbation (secon
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