title: Probing the binding of cationic lipids with dendrimers.
abstract: Polycationic polymers are used extensively in biology to disrupt cell membranes and thus enhance the transport of materials into the cell. We report the bindings of several lipids cholesterol (Chol), 1,2-dioleoyl-3-trimethylammonium-propane(DOTAP), dioctadecyldimethylammoniumbromide (DDAB), and dioleoylphosphatidylethanolamine (DOPE) to dendrimers of different compositions such as mPEG-PAMAM (G3), mPEG-PAMAM (G4), and PAMAM (G4) under physiological conditions. FTIR, UV-visible spectroscopic, methods and molecular modeling were used to analyze the lipid binding mode, the binding constant, and the effects of lipid complexation on the dendrimer structure. The structural analysis showed that lipids bind dendrimers through both hydrophilic and hydrophobic contacts with overall binding constants of K(chol-mPEG-G3) = 1.7 × 10(3) M(-1), K(chol-mPEG-PAMAM-G4) = 2.7 × 10(3) M(-1), K(chol-PAMAM-G4) = 1.0 × 10(3) M(-1), K(DOPE-mPEG-G3) = 1.5 × 10(3) M(-1), K(DOPE-mPEG-PAMAM-G4) = 1.6 × 10(3) M(-1), K(DOPE-PAMAM-G4) = 5.3 × 10(2) M(-1), K(DDAB-mPEG-G3) = 1.5 × 10(3) M(-1), K(DDAB-mPEG-PAMAM-G4) = 1.9 × 10(2) M(-1), K(DDAB-PAMAM-G4) = 7.0 × 10(2) M(-1), K(DOTAP-mPEG-G3) = 1.9 × 10(3) M(-1), K(DOTAP-mPEG-PAMAM-G4) = 1.5 × 10(3) M(-1), and K(DOTAP-PAMAM-G4) = 5.7 × 10(2) M(-1). Weaker interaction was observed as dendrimer cationic charges increased. The free binding energies from docking were -5.15 (cholesterol), -5.79 (DDAB), and -5.36 kcal/mol (DOTAP) with the order of stability DDAB-PAMAM-G-4 > DOTAP-PAMAM-G4 > cholesterol-PAMAM-G4, consistent with the spectroscopic results. Dendrimers might act as carriers to transport lipids in vitro.
authors.affiliation: Département de Chimie-Biologie, Université du Québec à Trois-Rivières, C. P. 500, Trois-Rivières (Québec), G9A 5H7, Canada.
authors.forename: J S
authors.initials: JS
authors.lastname: Mandeville
authors.forename: P
authors.initials: P
authors.lastname: Bourassa
authors.forename: H A
authors.initials: HA
authors.lastname: Tajmir-Riahi
mesh_terms: D001665:Binding Sites / Q000502:physiology; D002412:Cations; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism*; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D009757:Nylons / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D002412:Cations; D050091:Dendrimers; D009757:Nylons; C520550:PAMAM-G4; D002784:Cholesterol