Helical conformation peptide amphiphiles

In addition to finding small organic molecules that bind to a protein, covalent capture methods can identify peptides that interact with proteins. Kohda and colleagues used this approach to study the mitochondrial protein Tom20, an import receptor that recognizes an epitope on proteins targeted for the mitochondria.1301 Previous work had characterized this epitope as a five-residue peptide that assumes an amphiphilic helical conformation, and coarse sequence preferences had been worked out. However, Tom20 has both low affinity... 

Figure 3.10 Molecular model of the amphiphilic P-peptide H-(P 3-HVal-P 3-HLys-P 3-HLeu)4-OH in an L+2 helical conformation. This axial view shows the segregation of hydrophobic and positively charged residues on opposite sides of the helix. Reproduced with permission Y. Hamuro, J.P. Schneider and W.F. DeGrado,/o ma/ of American Chemical Society, 1999,121, 12200. 1999, American Chemical Society [59]...

Biophysical studies of synthetic mTPs also tend to reinforce the amphiphilic helix idea. Such peptides adopt a helical conformation in the presence of lipids, bind strongly to lipid monolayers with the helical axis parallel to the smface of the membrane, and disrupt liposomes even at low concentrations and in a potential-dependent manner (a negative-inside potential enhances the l3rtic effect) . ... 

The largest group of facial amphiphilic peptides consists of the alpha-helical peptides. Facial amphiphilic alpha helices, often referred to as amphipathic alpha helices, are not amphiphilic in their random coil conformation and their amphiphilicity is not directly obvious from then-sequence. However, folding of the peptide into its preferred secondary structure, leads to the formation of an alpha helix, of which the hydrophilic amino acids occupy one face and the hydrophobic amino acids are located at the other face. Alpha-helical peptides have a periodicity of 3.6 amino acid residues per turn, and because of this, for two turns, roughly every third and seventh amino acids are on the same face of the alpha helix. In order to make a helix amphiphilic, the sequence of amino acids should alternate between hydrophobic and hydrophilic every three to four residues, which becomes more clear in a helical wheel representation (Figure 3). An example of such a facial amphiphilic alpha helix is magainin 2, a 23 amino acid antibiotic peptide. Studies have shown that magainin... 

Calmodulin (CaM) undergoes drastic conformational change when it binds Ca2+ and amphiphilic peptides such as mas to po ran and endorphin, which results in the modulation of many important biochemical reactions. The N-terminal and C-terminal of rigid structured globular domains are bridged with a long flexible peptide of a-helical structure. Each domain binds two Ca2+ ions to its hydrophobic sites. 

Each of the natural peptides derived from MLCK contains a 16-residue segment that conforms to the structural paradigm derived from the studies of model amphiphilic peptides. When aligned as in Fig. 8, hydrophobic and basic residues tend to occupy invariant positions in their sequences. As illustrated in the helical net diagram (Fig. 9), all three peptides display a potential apolar ridge. This ridge is formed by hydrophobic residues that occur at positions — 3,, -+- 3 over a 10-residue stretch of the chain. This repeat has been found in many helix-helix packings (Chothia, 1984). 

In order to examine the possibility of this speculation, an approach using synthetic peptides was made [10]. Three kinds of peptides (H, S, and R) with 16 amino acid residues were synthesized, and their secondary structure and surface properties were investigated to clarify the effects of conformational amphiphilicity. The amino acid compositions of the three peptides were the same (8 Leu and 8 Glu residues), but their sequences were different. The helical wheel structure of peptide H is shown in Fig. 2e [5], As shown in this structure, peptide H was designed to form an amphiphilic a-helix, whereas the other peptides were designed not to show such amphiphilicity, even when... 

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