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Structure Prediction of CPPs and Iterative Development of Novel CPPs 215 phospholipid organization. Importantly, when pAntp has reached the energy minimum, its Trp6 residue interacts with the polar heads, whereas Trp14 is embedded within the hydrophobic core of the bilayer model. Simulations were then performed with a superficial charge density at the inner leaflet of the bilayer model equal to 0.04 e – /Å 2 . As shown in Figure 9.10A, the AntHD–DNA complex is predicted to reach the same position as with the previous membrane model. The increase in charge density induces an increase of the charge restraint when the complex mass center reaches positions below 28 Å, but not before. For the AntHD without DNA (Figure 9.10B), a partial crossing of the bilayer is observed, basically due to the charge restraint, since the hydrophobic restraint is largely unfavorable and the lipid perturbation restraint is important too (20kJ/mol.Å 2 ). In its final configuration, the AntHD mass center is located near the bilayer center (–4 Å), but this implies that part of the third helix interacts with the polar heads domain of the inner leaflet (Arg1, Arg10, Arg16 residues). Taken separately, the first helix (Figure 9.10C) is predicted to enter the polar heads domain of the outer leaflet, with its mass center stabilizing at 15 Å. Then, the Monte Carlo procedure opens the way to a jump over the restraint barrier; indeed, using this method we switch between two local energy minima. The penetration of the first helix in the membrane is driven by the favorable charge restraint because the hydrophobic restraint is still unfavorable during the partial crossing. The second helix entirely crosses the bilayer hydrophobic core (Figure 9.10D bottom) as an effect of the charge restraint, with the hydrophobic restraint, as for the previous simulations, unfavorable during the crossing. Here again, the absence of a continuous path to reach the most favorable position (Figure 9.10D top) is indicative of a rapid crossing. The third helix, pAntp, crosses the membrane, too, but the energy minimum is less favorable than that reached in the case of helix 2 (Figure 9.10E bottom). Moreover, pAntp orientation at its energy minimum indicates that the helix forms an angle of –53° with the bilayer plane (Figure 9.10E top), with the pAntp N-terminal part buried within the hydrophobic core of the membrane and the C-terminal part interacting with the phospholipid polar heads of the inner leaflet. 9.4 CONCLUSIONS We have developed a new computational method to simulate interactions between chemical compounds and a modeled membrane. This method has been tested and validated with peptides and proteins for which experimental data regarding their interactions with membranes were available. We applied this to the Antennapedia homeodomain and its derivatives, such as the penetratin cell-permeant peptides, in order to account for their behavior when facing membrane models. According to our analysis, in the case of an uncharged membrane model, neither the complete Antennapedia homeodomain nor its constitutive helices are able to cross the bilayer. By refining our simulation methods in order to approach more reliably true biological membranes, we elaborated a charged bilayer model. In this context, we observe that, with the increase of the superficial charge density of the bilayer inner
216 Cell-Penetrating Peptides: Processes and Applications A B C (top) 1st Helix (inner leaflet charge: -0.04) Total Restraints (kJ/mol Å 2 ) Mass Center Penetration (A) FIGURE 9.10 Evolution of total restraint vs. mass center penetration of all simulated compounds in a charged bilayer model (inner leaflet charge: 0.04 e – /Å –2 ). (See text for details.) Angle(°)
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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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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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