Molecular Dynamics Simulations of Membrane Translocation of Dendrimers

Abstract

Dendrimers are a class of hyperbranched polymer whose structure and surface chemistry can be precisely controlled, which makes them suitable for applications in nanomedicine, such as delivery of therapeutics. Terminal groups of dendrimers have been shown to influence the rate of internalization into cells. For instance, previous articles have demonstrated that dendrimers PAMAM-NH2, PAMAM-OH and PAMAM-COOH of generation 4 (G4) can be taken up by A549 lung cells, but at varying rates, depending on the nature of the terminal groups. It was concluded that amine-terminated dendrimers are more rapidly internalized, since they are prone to interact with negative groups of the cell membrane, such as sialic acid. Several studies have addressed the phenomenon of dendrimer translocation across membranes using computer simulations. However, these studies are challenging and largely infeasible, due to the slow diffusion of lipids composing the membranes. In the present study, we take advantage of coarse-grained models based on MARTINI force field, which have been successfully employed to assess membrane binding of proteins. Furthermore, a highly mobile membrane mimetic, HMMM based on a biphasic solvent model was also employed, to compare the behavior of dendrimers in full-atom and a coarse grained system. Both models permit us to study the translocation of new G3-guanidine, G3-NH2 and G3-OH dendrimers on a reasonable time scale. We expect to delineate why some dendrimers have faster rates of translocation and why some produce membrane perturbations that induce cytotoxicity. These results will further the development of dendrimers as carriers of therapeutic molecules.