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• Articles by C.R. Flach
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• Melittin and the 8–26 fragment. Differences in ionophoric pr...

  Melittin and the 8–26 fragment. Differences in ionophoric properties as measured by monolayer method Biophysical Journal, Volume 45, Issue 6, 1 June 1984, Pages 1079-1083 V.S. Gevod and K.S. Birdi Abstract Melittin is a major (approximately 50%) protein component of bee venom. This peptide is an amphiphilic protein, because, while the amino acid residues 1–20 are predominantly hydrophobic (with the exception of Lys-7), residues 21–26 are hydrophilic. The binding properties to vesicles and lipid bilayers of melittin have provided much useful information regarding biological (hemolytic) activity (Habermann, E., 1972, Science [Wash. DC], 177:314–322). Recent studies have convincingly established that the melittin monolayer (at air-water interface) model membrane system allows one to analyze the various forces present in such structures. We present comparative monolayer studies of melittin and the peptide fragment 8–26 regarding the channel formation for the selective anion (Cl-) penetration in monolayers, analogous to melittin (tetramer) channel function in lipid bilayer. The differences in surface pressure and surface potential of monolayers between native melittin and the 8–26 fragment suggest that these may be ascribed to Lys-7. Abstract | PDF (365 kb)

• Antimicrobial Peptide-Lipid Binding Interactions and Binding...

  Antimicrobial Peptide-Lipid Binding Interactions and Binding Selectivity Biophysical Journal, Volume 92, Issue 10, 15 May 2007, Pages 3575-3586 Mitaben D. Lad, Fabrice Birembaut, Luke A. Clifton, Richard A. Frazier, John R.P. Webster and Rebecca J. Green Abstract Surface pressure measurements, external reflection-Fourier transform infrared spectroscopy, and neutron reflectivity have been used to investigate the lipid-binding behavior of three antimicrobial peptides: melittin, magainin II, and cecropin P1. As expected, all three cationic peptides were shown to interact more strongly with the anionic lipid, 1,2 dihexadecanoyl--glycerol-3-(phosphor-rac-(1-glycerol)) (DPPG), compared to the zwitterionic lipid, 1,2 dihexadecanoyl--glycerol-3-phosphocholine (DPPC). All three peptides have been shown to penetrate DPPC lipid layers by surface pressure, and this was confirmed for the melittin-DPPC interaction by neutron reflectivity measurements. Adsorption of peptide was, however, minimal, with a maximum of 0.4mg m seen for melittin adsorption compared to 2.1mg m for adsorption to DPPG (from 0.7M solution). The mode of binding to DPPG was shown to depend on the distribution of basic residues within the peptide -helix, although in all cases adsorption below the lipid layer was shown to dominate over insertion within the layer. Melittin adsorption to DPPG altered the lipid layer structure observed through changes in the external reflection-Fourier transform infrared lipid spectra and neutron reflectivity. This lipid disruption was not observed for magainin or cecropin. In addition, melittin binding to both lipids was shown to be 50% greater than for either magainin or cecropin. Adsorption to the bare air-water interface was also investigated and surface activity followed the trend melittin>magainin>cecropin. External reflection-Fourier transform infrared amide spectra revealed that melittin adopted a helical structure only in the presence of lipid, whereas magainin and cecropin adopted helical structure also at an air-water interface. This behavior has been related to the different charge distributions on the peptide amino acid sequences. Abstract | Full Text | PDF (349 kb)

• Melittin-Induced Bilayer Leakage Depends on Lipid Material P...

  Melittin-Induced Bilayer Leakage Depends on Lipid Material Properties: Evidence for Toroidal Pores Biophysical Journal, Volume 88, Issue 3, 1 March 2005, Pages 1828-1837 Daniel Allende, S.A. Simon and Thomas J. McIntosh Abstract The membrane-lytic peptide melittin has previously been shown to form pores in lipid bilayers that have been described in terms of two different structural models. In the “barrel stave” model the bilayer remains more or less flat, with the peptides penetrating across the bilayer hydrocarbon region and aggregating to form a pore, whereas in the “toroidal pore” melittin induces defects in the bilayer such that the bilayer bends sharply inward to form a pore lined by both peptides and lipid headgroups. Here we test these models by measuring both the free energy of melittin transfer (Δ°) and melittin-induced leakage as a function of bilayer elastic (material) properties that determine the energetics of bilayer bending, including the area compressibility modulus (), bilayer bending modulus (), and monolayer spontaneous curvature (). The addition of cholesterol to phosphatidylcholine (PC) bilayers, which increases and , decreases both Δ° and the melittin-induced vesicle leakage. In contrast, the addition to PC bilayers of molecules with either positive , such as lysoPC, or negative , such as dioleoylglycerol, has little effect on Δ°, but produces large changes in melittin-induced leakage, from 86% for 8:2 PC/lysoPC to 18% for 8:2 PC/dioleoylglycerol. We observe linear relationships between melittin-induced leakage and both and However, in contrast to what would be expected for a barrel stave model, there is no correlation between observed leakage and bilayer hydrocarbon thickness. All of these results demonstrate the importance of bilayer material properties on melittin-induced leakage and indicate that the melittin-induced pores are defects in the bilayer lined in part by lipid molecules. Abstract | Full Text | PDF (202 kb)

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Abstract

The interaction of melittin with monolayers of 1,2-dipalmitoylphosphatidylcholine and 1,2-dipalmitoylphosphatidylserine has been investigated with infrared external reflection-absorption spectroscopy. Improved instrumentation permits determination of acyl chain conformation and peptide secondary structure in situ at the air/water interface. The IR frequency of the 1,2-dipalmitoylphosphatidylcholine antisymmetric acyl chain CH2 stretching vibration decreases by 1.3 cm-1 upon melittin insertion, consistent with acyl chain ordering, whereas the same vibrational mode increases by 0.5 cm-1 upon peptide interaction with the 1,2-dipalmitoylphosphatidylserine monolayer, indicative of chain disordering. Thus the peptide interacts quite differently with zwitterionic compared with negatively charged monolayer surfaces. Melittin in the monolayer adopted a secondary structure with an amide l(l') frequency (1635 cm-1) dramatically different from the alpha-helical motif (amide l frequency 1656 cm-1 in a dry or H2O hydrated environment, amide l' frequency 1645 cm-1 in an H-->D exchanged alpha-helix) assumed in bilayer or multibilayer environments. This work represents the first direct in situ spectroscopic indication that peptide secondary structure in lipid monolayers may differ from that in bilayers.