Poly-sarcosine and Poly(Ethylene-Glycol) Interactions with Proteins Investigated Using Molecular Dynamics Simulations

Giovanni Settanni,Timo Schäfer,Christian Muhl,Matthias Barz,Friederike Schmid

doi:10.1016/j.csbj.2018.10.012

Abstract

Nanoparticles coated with hydrophilic polymers often show a reduction in unspecific interactions with the biological environment, which improves their biocompatibility. The molecular determinants of this reduction are not very well understood yet, and their knowledge may help improving nanoparticle design. Here we address, using molecular dynamics simulations, the interactions of human serum albumin, the most abundant serum protein, with two promising hydrophilic polymers used for the coating of therapeutic nanoparticles, poly(ethylene-glycol) and poly-sarcosine. By simulating the protein immersed in a polymer-water mixture, we show that the two polymers have a very similar affinity for the protein surface, both in terms of the amount of polymer adsorbed and also in terms of the type of amino acids mainly involved in the interactions. We further analyze the kinetics of adsorption and how it affects the polymer conformations. Minor differences between the polymers are observed in the thickness of the adsorption layer, that are related to the different degree of flexibility of the two molecules. In comparison poly-alanine, an isomer of poly-sarcosine known to self-aggregate and induce protein aggregation, shows a significantly larger affinity for the protein surface than PEG and PSar, which we show to be related not to a different patterns of interactions with the protein surface, but to the different way the polymer interacts with water.

Highlights

Huge steps in the production of nanosized materials with specific functionalities have opened the way to a vast variety of applications, one of which is their use as drug delivery systems [1]
The efficiency of most of these processes depends on how the nanoparticle surface interacts with the biological medium in which it is introduced. These interactions determine the composition of the layer of biological material that forms around nanoparticles as they come in contact with an organism
Molecular dynamics simulations were carried out using the program NAMD [34] with the CHARMM force field [35]

Summary

Introduction

Huge steps in the production of nanosized materials with specific functionalities have opened the way to a vast variety of applications, one of which is their use as drug delivery systems [1]. The efficiency of most of these processes depends on how the nanoparticle surface interacts with the biological medium in which it is introduced These interactions determine the composition of the layer of biological material (protein corona) that forms around nanoparticles as they come in contact with an organism. A particular strategy consist in the exploitation of the so called “stealth” effect, that is the capacity of certain materials, especially polymers, to reduce unspecific interactions with the surrounding biological milieu. Nanoparticles coated with these polymers show reduced protein corona formation and in some cases reduced toxicity. Poly(ethyleneglycol) (PEG) is the most common of the polymers showing a stealth effect, but recently other polymers have been investigated like poly-phosphonates [4], poly(N-(2-hydroxypropyl) methacrylamide) [5] or polypeptoids like poly-sarcosine (PSar) [6]

Methods

Results

Conclusion