Effect of fullerenol surface chemistry on nanoparticle binding-induced protein misfolding

Abstract

Fullerene and its derivatives with different surface chemistry have great potential in biomedical applications. Accordingly, it is important to delineate the impact of these carbon-based nanoparticles on protein structure, dynamics, and subsequently function. Here, we focused on the effect of hydroxylation - a common strategy for solubilizing and functionalizing fullerene - on protein-nanoparticle interactions using a model protein, ubiquitin. We applied a set of complementary computational modeling methods, including docking and molecular dynamics simulations with both explicit and implicit solvent, to illustrate the impact of hydroxylated fullerenes on the structure and dynamics of ubiquitin. We found that all derivatives bound to the model protein. Specifically, the more hydrophilic nanoparticles with a higher number of hydroxyl groups bound to the surface of the protein via hydrogen bonds, which stabilized the protein without inducing large conformational changes in the protein structure. In contrast, fullerene derivatives with a smaller number of hydroxyl groups buried their hydrophobic surface inside the protein, thereby causing protein denaturation. Overall, our results revealed a distinct role of surface chemistry on nanoparticle-protein binding and binding-induced protein misfolding.

Probing the modulated formation of gold nanoparticles–beta-lactoglobulin corona complexes and their applications

“…DMD is special type of molecular dynamic simulation algorithm with enhanced sampling efficiency, which has been extensively used to model protein folding, protein-ligand interactions as well as protein-nanoparticle interactions 7, 33 . We adopt a united-atom representation of simulated molecules, where all heavy atoms and polar hydrogens are explicitly modelled.…”

Actual questions raised by nanoparticle radiosensitization

“…Elevated level of reactive oxygen species (ROS) could be a possibility, as well as the misfolding of proteins by NP binding. It begins to be documented that protein conformational changes can occur at the NP surface at the secondary or tertiary levels (Shao et al, 2011;SimonVazquez et al, 2014) and that the NP surface chemistry is decisive (Radic et al, 2014). Proteins forming the protein corona might be particularly affected.…”

Applications of Discrete Molecular Dynamics in biology and medicine

“…The accelerated sampling of DMD is well-suited characterization of binding properties in simulations, which requires study of many interactions. Radic et al [29] utilized DMD simulations to illustrate the effects of surface chemistry on the binding of nanoparticles to their target proteins. They demonstrated that highly hydroxylated fullerene nanoparticles form hydrogen bonds with protein surfaces, stabilizing them without inducing structural changes, while less hydroxylated fullerene particles are hydrophobic and can cause proteins to misfold.…”