A closer look into the ubiquitin corona on gold nanoparticles by computational studiesby Francesco Tavanti, Alfonso Pedone, Maria Cristina Menziani

New J. Chem.


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This journal is©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2014 New J. Chem.

Cite this:DOI: 10.1039/c4nj01752h

A closer look into the ubiquitin corona on gold nanoparticles by computational studies†

Francesco Tavanti, Alfonso Pedone and Maria Cristina Menziani*

In this study, coarse-grained computational simulations of the ubiquitin corona around gold nanoparticles have been carried out, and the effect of the nanoparticle size (10, 16, 20, and 24 nm diameter) and environment (bare nanoparticle surface, and citrate-coated surface, where citrate are treated with implicit and explicit models) has been analysed. The results showed that the corona is obtained after a slow reorientation step that occurs at the nanoparticle surface in order to optimize the nanoparticle– ubiquitins interaction. The ubiquitin binding modalities depend on the nanoparticle environment, while conformational changes of ubiquitins upon binding and their aggregation propensity slightly depend on nanoparticle size. 1 Introduction

It has been long recognized that the contact of NPs with biological fluids rapidly results in the formation of a protein corona on the NP surface, whose composition changes over time.1–8 A ‘‘soft corona’’ that reflects the relative abundance of individual medium proteins is immediately formed. Then, protein–protein competition takes place, and displacement of low-affinity proteins by high-affinity proteins occurs, at the origin of the ‘‘hard corona’’ (known as the Vroman effect). In their recent review, Walkey and Chan9 showed that the plasma protein corona follows a general structure, with 2 to 6 proteins adsorbed at high abundance, and many more adsorbed at low abundance; moreover, they identify the family of 125 unique plasma proteins that have been associated with formation of the NP biocorona on many different nanomaterials. Therefore, the composition, structure, dynamics and stability of the protein corona (rather than the bare NP surface) control the interaction of the NP with the cell and the subsequent biological response of an organism to NP exposure.1,9

The characteristics of the protein corona are determined by the physiological environment, duration of exposure, and compatibility of the physico-chemical properties of the interacting proteins with those of the NP surface. Targeted NP usage in nanobiology, nanomedicine, and nanotoxicology could then be improved by manipulating the surface properties of NPs to bind proteins selectively in order to control signalling, kinetics, transport, accumulation, and toxicity.10 However, the NP itself may alter the structure of the adsorbed proteins, leading to denaturation or significant conformational changes, with concomitant loss of their biological function and hazardous consequences.11–13

Despite the ever-increasing number of experimental studies, dedicated to uncovering the detailed relationships between the synthetic identity, biological identity, and physiological response of NP–protein complexes, a comprehensive picture is still missing due to the complexity inherent in the systems and the experimental dilemma of measuring without changing the nature of the original protein corona.2

Thus, the opportunity of assisting the experimental studies via computational simulations is of great importance in most nanotechnology applications, as demonstrated by the increasing number of studies, which are appearing in the literature.3

In this paper, the results of Coarse-Grained (CG) computer simulations carried out to gain insight into the gold NP–ubiquitin corona formation will be described.

Human ubiquitin (Ubq) is a convenient target for the analysis of its interaction with NP at the atomic level since it is a small protein composed of 76 amino acids, folded up into a compact globular structure comprising a long a-helix, a short piece of 3(10)-helix, and a mixed b-sheet with five strands. Its three-dimensional structure is well characterized both in its crystallized form and in solution.14,15

This highly conserved protein is found only in eukaryotic organisms, where it exerts a regulatory role: proteins that are to be degraded are first tagged by conjugating them with Ubq, then recognized and shuttled to the proteasome for degradation.

Experimental and computational data on the ubiquitin corona on gold or silver NPs have become recently available in the literature.

Unfortunately, the results obtained are often contradictory and can only be used for comparison (not for validation) of the CG approach used in the present paper.

Recently, Ding et al.16 studied the interaction between a number of Ubq molecules and the surface of a silver NP by

Dipartimento di Scienze Chimiche e Geologiche, Universita` di Modena e Reggio

Emilia, Via G. Campi 183, 41125, Modena, Italy. E-mail: menziani@unimore.it † Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nj01752h

Received (in Montpellier, France) 7th October 2014,

Accepted 15th December 2014

DOI: 10.1039/c4nj01752h www.rsc.org/njc



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New J. Chem. This journal is©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2014 means of a combined experimental and multiscale molecular dynamics simulations approach. Their results uncovered: (a) a specific binding orientation between Ubq molecules and AgNP surfaces, driven by electrostatic interactions and regulated by a stretched exponential kinetics, (b) competition of Ubq molecules and citrate for binding to the NP surface, and (c) a loss of a-helical structure upon adsorption of Ubq onto the silver surfaces. The importance of taking into account citrate molecules for reproducing experimental results was also pointed out by Brancolini et al.,17 who studied the adsorption of one Ubq molecule on a flat gold surface by means of a combination of simulation methods at different levels of theory (including