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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - BioMNP (Understanding the interaction between metal nanoparticles and biological membranes)

Teaser

Summary

Nanomaterials are nowadays produced in large scale for the most diverse applications, such as catalysis, material reinforcement, data storage, cosmetics, biomedicine. In most cases, their design has to take into account the prediction and assessment of their toxicity to the human body, as well as, of course, their functionality. In the field of biomedicine, inorganic nanoparticles are being studied as promising diagnostic, therapeutic agents and drug delivery agents. By encapsulating inorganic nanoparticles, such as metal or oxide nanoparticles, into shells of organic molecules that make them biocompatible, researchers are experimenting their use as contrast agents for optical and magnetic imaging of tissues, as photothermal agents for photothermal anticancer therapies, and as vehicles of drugs to specific target cells.
During its journey via intravenous route into our body, though, nanoparticles have to overcome a number of natural obstacles: they interact with the proteins of our blood, and need to overcome the plasma membrane to successfully enter the interior of our cells. Unfortunately, there is still poor understanding of the molecular processes that drive the interactions of metal NPs with proteins and cells. In this project we aim at comprehend, with molecular resolution, these mechanisms of interactions. We plan to achieve this objective by means of computational tools, such as Molecular Dynamics, which allow to simulate in silico the interaction of the nanoparticles with the biological environment.
The BioMNP objective is the molecular-level understanding of the interactions between surface functionalized metal nanoparticles and biological membranes, by means of cutting- edge computational techniques and new molecular models. BioMNP aims at answering fundamental questions at the crossroads of physics, biology and chemistry.
The understanding and control of the interaction of nanoparticles with biological membranes is of paramount importance to understand the molecular basis of the NP biological effects and guide the rational design of nanoparticles with biomedical applications. BioMNP will go beyond the state of the art by rationalizing the complex interplay of NP size, composition, functionalization and aggregation state during the interaction with model biomembranes. Its results will have an impact on nanomedicine, toxicology, nanotechnology and material sciences.

Work performed

We set up the computational framework for the simulation of NP-membrane and NP-protein interactions. These activities included the development of new molecular models, both for the nanoparticle and for the organic ligands that functionalize it, and the identification of the simulation protocols that allow for the study of their interaction with the biological environment, in physiological and non-physiological conditions (e.g. during the non-equilibrium transfer of heat from an irradiated NP to a model cell membrane).
This preliminary work has been functional to the achievement of important results, such as:
â€¢ We comprehended the role played by surface charges during the interaction of NPs with model lipid membranes. (see Fig.1)
â€¢ We showed that not only the chemical composition of the ligands around the NP, but also their physical conformation and surface arrangement are important to drive their interactions with cell membranes and proteins.
â€¢ With a more explicit reference to photoporation applications, we were able to quantitatively predict the thermal gradient in the surrounding of a laser-irradiated NP embedded in a model cell membrane (see Fig.2)

Final results

All the results reported in the previous section represent a progress with respect to the state of the art. The role of the NP surface charges at shaping the interaction with model cell membranes was the object of some debate in the literature. We can now state that small nanoparticles, able to passively translocate through cell membranes, interact with zwitterionic lipid bilayers independently on the sign of their charged moieties (anionic or cationic). Moreover, we could conclude that it is always important to take into explicit consideration the molecular nature of the NP interface, as only at this level of resolution it is possible to interpret the experimental results that show how nanoparticles can induce phase transitions, e.g. from the gel to the liquid phase, of model lipid bilayers. The interaction of NPs with membranes that show some degree of phase separation is far from being understood, and we are collaborating with our experimental partners to shed light on on this aspect of NP-membrane interactions before the end of the project.

Another important contribution of our work to the comprehension of NP-bio interactions is that not only the chemical composition of the NP ligand shell, but also its physical conformation can be fundamental to drive the NP interaction with proteins. We have showed this in the case of interactions between a monolayer-protected Au NP and an abundant serum protein, albumin, but we believe the statement is quite general and we intend to proof its general validity in the forthcoming period.

We will devote many efforts to the study of NP-NP aggregation and of its repercussions on NP-membrane interactions. This is an extremely interesting task as NP aggregation is usually observed, at experimental level, only after the interaction with model liposomes has been achieved. But what is the role of NP-NP aggregation in solution? Is the interaction between membranes and NP aggregates similar or dissimilar from the interaction of membranes with single, monodispersed NPs?

Last but not least, we expect that before the end of the project we will have developed and validated a new classical potential to describe the interactions between Au and S. This new potential will be parameterized to be able to accurately reproduce both binding energies and diffusion barriers of thiols on the surface of Au nanoparticles, and will thus be suited to the study of a) ligand exchange reactions and b) NP-bio interactions during which the thiols are realistically free to diffuse on the surface of the NP.

Overall, we expect our project to have an immediate impact on the researcher community dealing with nano-bio interfaces, and on a longer run to contribute to the rational design of nanoparticles with controlled interactions with proteins and cell membranes.