title: Bilayer disruption and liposome restructuring by a homologous series of small Arg-rich synthetic peptides.
abstract: The effects of a series of low molecular weight water-soluble cationic linear peptide analogs (LPAs, <1000 MW) with increasing hydrophobic/hydrophilic balance on lipid bilayer phase behavior and permeability were examined using liposomes composed of zwitterionic dipalmitoylphosphatidylcholine (DPPC) and mixed zwitterionic/anionic DPPC/dipalmitoylphosphatidylglycerol (DPPG) lipid bilayers. LPAs were synthesized using a previously reported alkyl linkage strategy as Arg-C(n)-Arg-C(n)-Lys, where C(n) represents the saturated alkyl linkage separating the cationic residues (n=4, 7, or 11) (Ye et al., 2007 [1]). Differential scanning calorimetry results show that the cationic LPAs bound to and disrupted DPPC and, to a greater extent, DPPC/DPPG phase behavior. When added to preformed unilamellar liposomes, the LPAs led to significant structural changes based on cryogenic transmission electron microscopy (cryo-TEM). Coupling cryo-TEM with carboxyfluorescein leakage studies indicate that the LPAs induced permeabilization through bilayer expansion, which caused membrane thinning. The effects were inconsistent with increasing LPA hydrophobicity, which suggests that a cooperative effect between electrostatic binding and hydrophobic insertion determined the location of LPAs within the bilayer and their membrane activity. Our results for LPA-induced membrane disruption correlate with previous breast cancer cell uptake studies that showed minimal LPA-C(4) uptake, but high LPA-C(11) uptake through a non-endocytic mechanism.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ye
authors.forename: Anju
authors.initials: A
authors.lastname: Gupta
authors.forename: Robert
authors.initials: R
authors.lastname: DeLuca
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Bothun
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D001120:Arginine / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D010715:Phosphatidylglycerols / Q000737:chemistry; D012995:Solubility; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D008051:Lipid Bilayers; D008081:Liposomes; D010455:Peptides; D010715:Phosphatidylglycerols; D014867:Water; D015060:1,2-Dipalmitoylphosphatidylcholine; D001120:Arginine; C030345:1,2-dipalmitoylphosphatidylglycerol