Free Energy of PAMAM Dendrimer Adsorption onto Model Biological Membranes

Abstract

We investigated the thermodynamic, structural, and dynamics changes in dendrimer-membrane systems during dendrimer adsorption to biological membrane systems by combining atomistic molecular dynamics simulations with umbrella sampling techniques to understand the atomistic interactions between the dendrimer and biological membranes. An ethylenediamine core polyamidoamine dendrimer (generation 3) with amine terminal groups and both zwitterionic dipalmitoyl-phosphatidyl-choline (DPPC) and anionic palmitoyl-oleoyl-phosphatidyl glycerol (POPG) lipid bilayer membranes were used as the model dendrimer and biological membranes, respectively, in this study. The free energy of the dendrimer adsorption onto two model membranes with different charge states was quantitatively determined. For the zwitterionic DPPC membrane, the dendrimer has a minimum free energy of approximately 50 kcal/mol, which is 15 kcal/mol higher than that observed in previous studies. The dominant contribution to the adsorption potential energy is the van der Waals attraction between the dendrimer and the DPPC membrane. However, the anionic POPG membrane pulls the positively charged dendrimer with an attractive mean force of about 200 pN, finally positioning the dendrimer in the membrane headgroup region. As a result of these strong attractive dendrimer and membrane interactions, the dendrimer structurally undergoes the transition from spherical to a pancake conformation, which slows its lateral mobility, especially in the presence of the POPG membrane. The bilayer lipid membranes are also perturbed by the dendrimer adsorption.

Selective aggregation of PAMAM dendrimer nanocarriers and PAMAM/ZnPc nanodrugs on human atheromatous carotid tissues: a photodynamic therapy for atherosclerosis

“…In addition, different size agglomeration between G0 and G0/ZnPc and selective aggregation of the dendrimers to the atheromatous carotid tissues is observed. However, in addition to the size and composition of G0 aggregates, the penetration of dendrimers across the endothelial barrier depends on other important features, such as concentration, incubation time, efflux transport, surface charge, modification [ 85 ], local thermodynamic conditions [ 28 ] and polar-entropic competition [ 83 ]; therefore, future studies comprising all these parameters are necessary.…”

PAMAM dendrimer - cell membrane interactions

“…Kim et al [121] used atomistic models to study the interactions between a G3 PAMAM dendrimer and both zwitterionic (DPPC) and anionic (POPG) bilayer membranes. Van der Waals interactions were dominant for the DPPC membrane interactions.…”

Molecular Modeling to Study Dendrimers for Biomedical Applications

“…Recently, a full all atom simulation was performed with a PAMAM G3 with amine terminal groups on a DPPC membrane and a discrepancy of 15 kcal/mol larger over the previous simulation was found. This result suggested that the explicit treatment of water significantly affects the adsorption thermodynamics as it contributed to the more entropic favorable interactions by releasing water molecules while pushing the dendrimer out of the water phase [142].…”