Poly(amidoamine) Dendrimers on Lipid Bilayers I: Free Energy and Conformation of Binding

Abstract

Third-generation (G3) poly(amidoamine) (PAMAM) dendrimers are simulated approaching 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers with fully atomistic molecular dynamics, which enables the calculation of a free energy profile along the approach coordinate. Three different dendrimer terminations are examined: protonated primary amine, uncharged acetamide, and deprotonated carboxylic acid. As the dendrimer and lipids become closer, their attractive force increases (up to 240 pN) and the dendrimer becomes deformed as it interacts with the lipids. The total energy release upon binding of a G3-NH 3 + , G3-Ac, or G3-COO -dendrimer to a DMPC bilayer is, respectively, 36, 26, or 47 kcal/mol or, equivalently, 5.2, 3.2, or 4.7 × 10 -3 kcal/g. These results are analyzed in terms of the dendrimers' size, shape, and atomic distributions as well as proximity of individual lipid molecules and particular lipid atoms to the dendrimer. For example, an area of 9.6, 8.2, or 7.9 nm 2 is covered on the bilayer for the G3-NH 3 + , G3-Ac, or G3-COO -dendrimers, respectively, while interacting strongly with 18-13 individual lipid molecules.

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

“…EC50 for HaCaT cell line and SW480 cell line was about 30 μg/mL and 20 μM respectively for G4-HN2, compare with hNPCs which was 6.17 μg/mL (Bielawski et al, 2011). Reactions of positively charged nanoparticles with lipid bilayer of cellular membrane may result in nano-scale hole formation in the membrane layers, allowing molecular transport across the membranes (Thiagarajan et al, 2013;Hong et al, 2004Hong et al, , 2006Mecke et al, 2005;Martin et al, 2007;Kelly et al, 2008aKelly et al, , 2008b. Moreover, uptake of positively charged PAMAM-NH 2 of hNPCs was proved in our study (Fig.…”

Simulating the interaction of lipid membranes with polymer and ligand-coated nanoparticles

“…Each arm contains a branching point, and the number of branching points is often referred to as a 'generation' (G1, G2, G3, etc.). Branching allows a very precise control of the molecular weight [71], and allows fine control of electrostatic properties -which, in turn, makes dendrimers good candidates for biological applications [72]. Simulations of dendrimers have been covered by other recent reviews [73], while here we focus on one more precise aspect: the interaction with membranes.…”

“…Early simulations of PAMAM dendrimers in the presence of lipid bilayers were performed at the atomistic level [71] and showed that charged dendrimers adsorbed onto lipids more favorably than neutral ones. Besides electrostatic interactions, also hydrophobic interactions play an important role in dendrimer binding [77].…”

A mechanistic view of lipid membrane disrupting effect of PAMAM dendrimers

“…The interaction between cell membranes and nanocarriers, such as dendrimers, is very important, because in the most cases carriers have to get across the lipid bilayer without disrupting it. Previous studies based on atomic force microscopy (AFM) [12][13][14][15][16][17] isothermal titration calorimetry (ITC), fluorescence correlated spectroscopy (FCS) [17][18], in vitro experiments [13,[19][20] and molecular dynamics simulations (MD) [14,17,[21][22][23][24] showed that cationic dendrimers disrupt lipid bilayers by forming holes on the bilayer surface and may remove lipids from it. The degree of the disruption depends on the size and charge of the dendrimer.…”