title: Aromatic residue position on the nonpolar face of class a amphipathic helical peptides determines biological activity.
abstract: The apolipoprotein A-I mimetic peptide 4F (Ac-DWFKAFYDKVAEKFKEAF-NH(2)), with four Phe residues on the nonpolar face of the amphipathic alpha-helix, is strongly anti-inflammatory, whereas two 3F analogs (3F(3) and 3F(14)) are not. To understand how changes in helix nonpolar face structure affect function, two additional 3F analogs, Ac-DKLKAFYDKVFEWAKEAF-NH(2) (3F-1) and Ac-DKWKAVYDKFAEAFKEFL-NH(2) (3F-2), were designed using the same amino acid composition as 3F(3) and 3F(14). The aromatic residues in 3F-1 and 3F-2 are near the polar-nonpolar interface and at the center of the nonpolar face of the helix, respectively. Like 4F, but in contrast to 3F(3) and 3F(14), these peptides effectively inhibited lytic peptide-induced hemolysis, oxidized phospholipid-induced monocyte chemotaxis, and scavenged lipid hydroperoxides from low density lipoprotein. High pressure liquid chromatography retention times and monolayer exclusion pressures indicated that there is no direct correlation of peptide function with lipid affinity. Fluorescence studies suggested that, although the peptides bind phospholipids similarly, the Trp residue in 4F, 3F-1, and 3F-2 is less motionally restricted than in 3F(3) and 3F(14). Based on these results and molecular modeling studies, we propose that the arrangement of aromatic residues in class A amphipathic helical molecules regulates entry of reactive oxygen species into peptide-phospholipid complexes, thereby reducing the extent of monocyte chemotaxis, an important step in atherosclerosis.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Datta
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Epand
authors.forename: Richard M
authors.initials: RM
authors.lastname: Epand
authors.forename: Manjula
authors.initials: M
authors.lastname: Chaddha
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Kirksey
authors.forename: David W
authors.initials: DW
authors.lastname: Garber
authors.forename: Sissel
authors.initials: S
authors.lastname: Lund-Katz
authors.forename: Michael C
authors.initials: MC
authors.lastname: Phillips
authors.forename: Susan
authors.initials: S
authors.lastname: Hama
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: Mayakonda N
authors.initials: MN
authors.lastname: Palgunachari
authors.forename: Jere P
authors.initials: JP
authors.lastname: Segrest
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
mesh_terms: D000595:Amino Acid Sequence; D002633:Chemotaxis; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D008027:Light; D008054:Lipid Peroxides / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008074:Lipoproteins / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry*; D011312:Pressure; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012542:Scattering, Radiation; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D014364:Tryptophan / Q000737:chemistry
chemical_list: D008054:Lipid Peroxides; D008055:Lipids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D010455:Peptides; D010743:Phospholipids; D011506:Proteins; D014364:Tryptophan