title: Molecular dynamics simulations of PAMAM dendrimer-induced pore formation in DPPC bilayers with a coarse-grained model.
abstract: We have performed 0.5-micros-long molecular dynamics (MD) simulations of 0%, 50%, and 100% acetylated third- (G3) and fifth-generation (G5) polyamidoamine (PAMAM) dendrimers in dipalmitoylphosphatidylcholine (DPPC) bilayers with explicit water using the coarse-grained (CG) model developed by Marrink et al. (J.Phys. Chem. B 2004, 108, 750-760), but with long-range electrostatic interactions included. Radii of gyration of the CG G5 dendrimers are 1.99-2.32 nm, close to those measured in the experiments by Prosa et al. (J. Polym. Sci. 1997, 35, 2913-2924) and atomistic simulations by Lee et al. (J. Phys. Chem. B 2006, 110, 4014-4019). Starting with the dendrimer initially positioned near the bilayer, we find that positively charged un-acetylated G3 and 50%-acetylated and un-acetylated G5 dendrimers insert themselves into the bilayer, and only un-acetylated G5 dendrimer induces hole formation at 310 K, but not at 277 K, which agrees qualitatively with experimental observations of Hong et al. (Bioconj. Chem. 2004, 15, 774-782) and Mecke et al. (Langmuir 2005, 21, 10348-10354). At higher salt concentration (approximately 500 mM NaCl), un-acetylated G5 dendrimer does not insert into the bilayer. The results suggest that with inclusion of long-range electrostatic interactions into coarse-grained models, realistic MD simulation of membrane-disrupting effects of nanoparticles at the microsecond time scale is now possible.
authors.affiliation: Department of Biomedical Engineering, Macromolecular Science and Engineering Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hwankyu
authors.initials: H
authors.lastname: Lee
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Larson
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine; D000731:Androstanes / Q000737:chemistry*; D002627:Chemistry, Physical / Q000379:methods*; D003198:Computer Simulation; D050091:Dendrimers; D008051:Lipid Bilayers / Q000737:chemistry; D015233:Models, Statistical; D008968:Molecular Conformation; D011073:Polyamines / Q000737:chemistry*; D012492:Salts / Q000494:pharmacology; D055672:Static Electricity; D013696:Temperature; D013997:Time Factors
chemical_list: C415601:3-oxo-androstan-17-yl-(2'',2'',6'',6''-tetramethyl-N-oxyl)piperidyl butan-1',4'-dioate; D000731:Androstanes; D050091:Dendrimers; D008051:Lipid Bilayers; C104700:PAMAM Starburst; D011073:Polyamines; D012492:Salts; D015060:1,2-Dipalmitoylphosphatidylcholine