Understanding Effects of PAMAM Dendrimer Size and Surface Chemistry on Serum Protein Binding with Discrete Molecular Dynamics Simulations

Polyamidoamine (PAMAM) dendrimers, a class of polymeric nanoparticles (NPs) with highly controllable sizes and surface chemistry, are promising candidates for many biomedical applications, including drug and gene delivery, imaging, and inhibition of amyloid aggregation. In circulation, binding of serum proteins with dendritic NPs renders the formation of protein corona and alters the biological identity of the NP core, which may subsequently elicit immunoresponse and cytotoxicity. Understanding the effects of PAMAM size and surface chemistry on serum protein binding is, therefore, crucial to enable their broad biomedical applications. Here, by applying atomistic discrete molecular dynamics (DMD) simulations, we first uncovered the binding of PAMAM with HSA and Ig and detailed the dependences of such binding on PAMAM size and surface modification. Compared to either anionic or cationic surfaces, modifications with neutral phosphorylcholine (PC), polyethylene glycol (PEG), and hydroxyls (OH) significantly reduced binding with proteins. The relatively strong binding between proteins and PAMAM dendrimers with charged surface groups was mainly driven by electrostatic interactions as well as hydrophobic interactions. Using steered DMD (SDMD) simulations, we conducted a force-pulling experiment in silico estimating the critical forces separating PAMAM-protein complexes and deriving the corresponding free energy barriers for dissociation. The SDMD-derived HSA-binding affinities were consistent with existing experimental measurements. Our results highlighted the association dynamics of protein-dendrimer interactions and binding affinities, whose implications range from fundamental nanobio-interfacial phenomena to the development of "stealth NPs".