title: Conformational study of new amphipathic alpha-helical peptide models of apoA-I as potential atheroprotective agents.
abstract: Aiming at contributing to the development of potential atheroprotective agents, we report on the concept and design of two peptide models, which mimic the amphipathic helices of apoA-I and incorporate Met into their sequences to validate its role as oxidant scavenger: Ac-ESK(Palm)KELSKSW(10)SEM(13)LKEK(Palm)SKS-NH(2) (model 1 [W(10), M(13)]) and Ac-ESK(Palm)KELSKSM(10)SEW(13)LKEK(Palm)SKS-NH(2) (model 2 [M(10), W(13)]). Hydrophobic residues of both models cover about the half of the surface, while the positively and negatively charged residues constitute two separate clusters on the hydrophilic face. Palmitoyl groups were introduced into the Lys-N(epsilon)H(2) groups at positions 3 and 17 to contribute to the amphipathic character of the peptides and stabilize the nonpolar face of the helix. Conformational study by the combined application of 2D-NMR and molecular dynamics simulations, CD, FTIR, and fluorescence spectroscopy revealed that model 1 adopts helical conformation and Met is well exposed to the microenvironment. Model 2 that derives from model 1 by exchanging W(10) (model 1) with M(10) and M(13) (model 1) with W(13) also displays helical characteristics, while Met is rather shielded. Oxidation experiments indicated that model 1 exhibits a 2-fold more potent antioxidant activity towards LDL oxidation, compared to model 2, confirming the role of Met, when is devoid of steric hindrances, as oxidant scavenger for the protection of LDL.
authors.affiliation: Laboratoire de Chimie-Physique Macromoléculaire, UMR 7568 CNRS-INPL, ENSIC, 1 rue Grandville, BP 20451, 54001 Nancy Cedex, France.
authors.forename: Chrystel
authors.initials: C
authors.lastname: Beaufils
authors.forename: Charalampos
authors.initials: C
authors.lastname: Alexopoulos
authors.forename: Maria P
authors.initials: MP
authors.lastname: Petraki
authors.forename: Alexandros D
authors.initials: AD
authors.lastname: Tselepis
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coudevylle
authors.forename: Maria
authors.initials: M
authors.lastname: Sakarellos-Daitsiotis
authors.forename: Constantinos
authors.initials: C
authors.lastname: Sakarellos
authors.forename: Manh Thong
authors.initials: MT
authors.lastname: Cung
mesh_terms: D000595:Amino Acid Sequence; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000737:chemistry*; D050197:Atherosclerosis / Q000517:prevention & control*; D002942:Circular Dichroism; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry
chemical_list: D000975:Antioxidants; D016632:Apolipoprotein A-I; D010455:Peptides; D014364:Tryptophan