Lipid Bilayer Curvature and Pore Formation Induced by Charged Linear Polymers and Dendrimers: The Effect of Molecular Shape

Abstract

We performed molecular dynamics (MD) simulations of multiple copies of poly-L-lysine (PLL) and charged polyamidoamine (PAMAM) dendrimers in dimyristoylphosphatidylcholine (DMPC) bilayers with explicit water using the coarse-grained model developed by Marrink et al. (J. Chem. Theory and Comput. 2008, 4, 819). Membrane disruption is enhanced at higher concentrations and charge densities of both spheroidally shaped dendrimers and linear PLL polymers, in qualitatively agreement with experimental studies by Hong et al. (Bioconjugate Chem. 2006, 17, 728). However, larger molecular size enhances membrane disruption and pore formation only for dendrimers and not for the linear PLL. Despite more intimate electrostatic interactions of linear molecules than are possible for spheroidal dendrimers, only the dendrimers were found to perforate membranes, apparently because they cannot spread onto a single leaflet, and so must penetrate the bilayer to get favorable electrostatic interactions with head groups on the opposite leaflet. These results indicate that a relatively rigid spheroidal shape is more efficient than a flexible linear shape in increasing membrane permeability. These results compare favorably with experimental findings.

Multiscale Modeling for Host-Guest Chemistry of Dendrimers in Solution

“…For the membrane under tension, pore formation of the membrane was stable if the tension exceeded a critical value. They also found that higher generations of the dendrimer provided more stable pore structure in the membrane; this result is consistent with that using coarse-grained simulation based on the MARTINI model [99]. Recently, Ting et al proposed more sophisticated model using SCFT combined with the string method [100] to calculate the minimum energy path to membrane pore formation and rupture [98].…”

Relation between biophysical properties of nanostructures and their toxicity on zebrafish

“…These results are in opposition to those observed in cell culture, where there is a directly proportional relationship between the generation and the toxicity of the dendrimer. The observed difference could be due to the fact that, in cell culture, the cationic molecules bind to the cell membrane that has negative charge and destabilize it, leading to cell lysis (Lee and Larson 2008;Tajarobi et al 2001). It has been shown that positively charged dendrimers form pores in the cell membrane and the efficiency of this depends on the size of the nanoparticle, which explains that the higher the generation, the higher the toxicity (Lee and Larson 2008).…”

“…The observed difference could be due to the fact that, in cell culture, the cationic molecules bind to the cell membrane that has negative charge and destabilize it, leading to cell lysis (Lee and Larson 2008;Tajarobi et al 2001). It has been shown that positively charged dendrimers form pores in the cell membrane and the efficiency of this depends on the size of the nanoparticle, which explains that the higher the generation, the higher the toxicity (Lee and Larson 2008). On the other hand, zebrafish embryos are organisms with greater complexity, and the mechanism by which dendrimers can be incorporated is still unknown.…”

Influence of dendrimers on red blood cells

“…2). Because of their nanometric size, dendrimers may interact effectively and specifically with cell components such as the membrane, organelles and proteins [15,16]. Cationic dendrimers can be used as vectors for gene transfection as they have the ability to interact with various forms of nucleic acids and form complexes that protect the nucleic acid from degradation [17,18].…”