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ACS Sustain Chem Eng. 2018 Sep 4;6(9):11704-11715. doi: 10.1021/acssuschemeng.8b01959. Epub 2018 Jul 31.

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

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department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA.
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Contributed equally


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".


PAMAM dendrimer; discrete molecular dynamics simulations; serum protein binding; steered molecular dynamic simulations; surface chemistry

[Available on 2019-09-04]

Conflict of interest statement

Conflicts of interest The authors declare no conflicting interests.

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