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Structure Prediction of CPPs and Iterative Development of Novel CPPs 205 Restraint (kJ/molÅ 2 ) 0 -20 -40 -60 -80 -100 -120 -8 Restraint (kJ/molÅ 2 ) -6 Penetration (A) -4 -2 0 2 4 -90 Penetration (A) -80 (A) Bacteriorhodopsin -70 -60 -50 Insertion angle (°) -25 0 -100 -200 -300 -400 -500 -600 -14 -30 -35 -40 -12 -10 -45 -8 -6 -50 -4 -55 -2 0 -60 FIGURE 9.6 The different plots correspond to the bacteriorhodopsin (A) and to the maltoporin (B). 3D envelopes are shown as in Figure 9.5. An MHP plot is added. Dark gray surfaces of MHP are hydrophilic, light gray are hydrophobic. protein is to facilitate diffusion of the maltodextrines across the E. coli cell wall. The protein structure was determined at a 2.4 Å resolution by Wang et al. 65 In the Monte Carlo minimization, the reference strand is the vector between the C α of Thr40 and Gln48 of the monomer A. All strands are tilted to about 45° as compared -40 (B) Maltoporin -20 Insertion angle (°)
206 Cell-Penetrating Peptides: Processes and Applications to the axis of the barrel. In Figure 9.6B, the 3D envelope of the restraints shows a local minimum at –40° for orientation of the β-sheet and a mass center penetration at about –7 Å. The mass center is shifted because of all the hydrophilic loops at the extremity of the pore of each monomer which move into an aqueous environment. Validation of the method now allows testing ab initio or homology models of membrane proteins of unknown structures, to try to authenticate the insertion and structure of the model within a lipid environment. 9.3.2 PENETRATIN Penetratins are cell-permeant peptides that can carry various sorts of cargoes into live cells and hence are now considered as vectors to develop new therapeutic tools. However, the mechanisms of penetratin cellular entry remain unknown. To get insight into the process of its membrane crossing and to provide a framework for further design of new derivatives, we have used the Monte Carlo method to model the penetratin membrane interactions. For this aim, different analyses have been performed on: Antennapedia homeodomain in complex with a double-stranded DNA cognate site (AntHD–DNA complex) Antennapedia homeodomain alone (AntHD) First helix of AntHD (RYQTLELEKEFHF) Second helix of AntHD (RRRRIEIAHAL) Third helix of AntHD corresponding to the penetratin sequence (pAntp; RQIKIWFQNRRMKWKK) The AntHD–DNA complex structure, 9ent, has been determined by x-ray and NMR analysis. 66 The complex is represented in Figure 9.7A with each of the AntHD helices. For sake of clarity, hydrogen atoms are not represented but are accounted for in subsequent analysis. The 9ent structure and three homeodomain helices have been imported in the HyperChem V6 (Hypercube, Inc., Florida) software, and the AMBER force field has allowed us to attribute the atomic charges (Figure 9.7B). The AntHD–DNA complex is highly negatively charged due to the phosphate groups of the double-strand DNA. The sum of the atomic charges, obtained from the AMBER force field, leads to a total charge of –18.23, whereas the AntHD peptide in the absence of the DNA sequence has a total charge of +11.76. The first homeodomain helix (Figure 9.7B, top) contains three negatively charged (Glu), one positively charged (Arg), and two polar residues (Tyr, His). Nevertheless, according to the AMBER force field, its total charge is equal to zero. The second homeodomain helix (Figure 9.7B, middle) has five charged residues: four arginines at its N-terminal, a glutamic acid, and a polar amino acid (His). Its global charge is about +4.00. Among the 16 amino-acid residues of the penetratin sequence (Figure 9.7B, bottom), only four are hydrophobic. The others are charged or polar, conferring to this helix a global charge of +6.76. If calculation of atomic charges gives information about the polarity of the Antennapedia homeodomain and its constitutive α-helices, calculation of molecular
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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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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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