Molecular dynamics simulations of PAMAM dendrimer-induced pore formation in DPPC bilayers with a coarse-grained model

J Phys Chem B. 2006 Sep 21;110(37):18204-11. doi: 10.1021/jp0630830.

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.

MeSH terms

  • 1,2-Dipalmitoylphosphatidylcholine
  • Androstanes / chemistry*
  • Chemistry, Physical / methods*
  • Computer Simulation
  • Dendrimers
  • Lipid Bilayers / chemistry
  • Models, Statistical
  • Molecular Conformation
  • Polyamines / chemistry*
  • Salts / pharmacology
  • Static Electricity
  • Temperature
  • Time Factors

Substances

  • 3-oxo-androstan-17-yl-(2'',2'',6'',6''-tetramethyl-N-oxyl)piperidyl butan-1',4'-dioate
  • Androstanes
  • Dendrimers
  • Lipid Bilayers
  • PAMAM Starburst
  • Polyamines
  • Salts
  • 1,2-Dipalmitoylphosphatidylcholine