The workshop will address the methodological issues arising within the modelling of interactions of common inorganic nanomaterials such as metal or metal oxide nanoparticles, semiconductor quantum dots, and fullerenes with biological fluids and bio-interfaces. The central questions are: (i) development of atomistic and coarse-grained force fields governing the interaction of inorganic materials with proteins, lipids, DNA and outer cell surfaces (glycan lining), (ii) development of coarse-grained models for biomolecules forming the interface such as proteins, glycoproteins, glycolipids, and lipids, and (iii) prediction of the energetics and kinetics of the adsorption of these materials at the interface, (iv) modelling the structure and dynamics or nanoparticle protein corona.

A number of tasks in modern biotechnology and medicine require a quantitative description of interaction between engineered nanomaterials and bio-interfaces [1,2]. The applications include lab-on-a-chip devices for biomolecular analysis, nanoparticle-based diagnostics, implants and drug delivery techniques [3]. In medicine, the interest in modeling particle interaction with bio-interfaces is driven by studies of blood clotting, thrombosis, or in-stent restenosis phenomena, as well as by nanoparticle toxicity issues [1,4-5]. However, the development of nanoscale diagnostic or therapeutic devices as well as toxicity assessment is often based on empirical data or on much simplified physicochemical picture of the interface.
The major obstacle for successful implementation of the bio-nanotechnologies in medicine and for understanding the nanoparticle toxicity mechanisms is the formation of protein corona and poor understanding of protein–nanomaterials interactions [1]. Protein corona is recognized as the protein (and other biomolecules) layers, formed at the surface of nanomaterials, upon their contact with the biological medium [6]. Therefore, the properties of the nanomaterials when they finally get in contact with the cell are completely different from the original pristine surface of the nanomaterials. This new biological identity of the nanomaterials is formed via the creation of a new interface between the nanomaterials and the biological medium, which is referred to as the bio-nano interface [1,6-7].
Due to complexity of the problem, it appears that methodological issues are central for the predictive description of interactions at the bio-nano interface. A key issue for the simulations is the enormous range of involved time and length scales. Nanoparticle-biointerface systems span lengthscales from the atomistic subnanometer distances (local interactions between amino acids and the surface) to hundreds of nanometers (as in endocytosis or protein corona). In what regards the timescales, the protein adsorption and desorption is controlled by strong forces with the corresponding timescales of milliseconds, while the membrane rearrangement can take even longer. For this reasons, the development of coarse-grained models and multiscale methods for these systems is of primary importance [8]. Another challenge we face when attempting to model the nanoparticle protein corona formation is the absence of consistent, accurate and universal forcefields both at the atomistic and at the coarse-grained level. A community effort in this direction would be therefore very timely.
On the other hand, the need for the new “full-cycle” modelling methodologies are dictated by several issues: (i) relative immaturity of experimental nanotoxicology, which suffers, despite the enormous number of groups and methods involved, from an absence of common toxicity criteria and definitions, suitable nanoparticle descriptors, as well as data validation protocols; (ii) the absence of molecular level understanding of the nanoparticle toxicity mechanisms, which impedes the attempts to relate nanoparticle descriptors to the toxic action; (iii) lack of consistent and detailed data on the content and dynamics of nanoparticle protein corona; (iv) lack of time-resolved data on the kinetics of nanoparticle adsorption and translocation into the cell.
The current modelling effort aims to fill the gaps in molecular level knowledge and understanding of the essential interactions at the bio-nano interface. Although it is currenlty beyond the reach of molecular modelling to follow the complete nanoparticle pathway starting from its intake from the environment to the biological endpoint and the effect, we can concentrate on the most crucial stage of the process.
The theme of the workshop is associated with the activity of the Modelling group of EU Nanosafety cluster (www.nanosafetycluster.eu), in particular with the collaborative effort on the NMP topic “Modelling toxicity behaviour of engineered nanoparticles”, which includes 7 EU and EU-US consortia. A part of the funding will be provided by some of the participating projects. In addition, we expect that the workshop will be supported by the EU COST action Modena “Modelling Nanomaterial Toxicity”. We envision that our workshop will also serve as a ground for formulating the scope for future collaboration of the participating researchers within the EU Horizons 2020 framework.

In biomedical applications, the computer simulations have already become a significant and reliable tool and is widely used for predicting toxicity and some therapeutic effects of molecular drugs [9-11]. The simulations, however, usually cover relatively small number of molecules and small lengthscales as compared to those relevant for bio-nano interface. At the larger scale, the control factors determining the efficient targeting of the cells by nanoparticles remain largely unknown due to absence of the accurate models of the interface. For example, the outer cell lining, glycocalyx, which plays the major role in gatekeeping, i.e. modulating the transport near the cell surface and mediating the access of biomolecules, cells, and antigens to the cell membrane and intracellular space [12-13], is usually ignored in the modelling. Similarly, while the mechanics of lipid membranes in contact with nanoscale particles has been studied by a number of authors either at coarse-grained or atomistic level [14-16], the modelling of surface and molecular specific interactions at the scale of tens or hundreds of nanometers remains inaccessible. Moreover, the dynamics of the cellular lipid membrane in contact with nanoparticles also depends on the energetics of the interaction and involvement of various membrane constituents such as proteins mediating endocytosis. Furthermore, among the factors determining the outcome of nanoparticle-membrane interaction, the surface properties of nanomaterials play a critical role, which can implicate the membrane glycans or plasma proteins in conditioning the nanoparticle prior to cell penetration [1,6-7]. In addition, the size and shape of nano-objects are known to be important for their fate inside the living organism [5].
In the recent years, a considerable effort was directed to modelling protein-surface interactions [8,17-18], in particular using mesoscopic approaches [19]. The classical MD simulations remain the most useful approach taking into account the covered length and timescales. Ab initio methods have been used to model the adsorption of amino acids on inorganic surfaces [20-21] and proved their ability to deliver useful information on the protein-surface interactions and the role of water [22]. Ab initio calculations have been also used to parameterize classical forcefields for amino acid - surface interactions [23-24].
Once the interactions at the atomic and molecular scale are known, one can use the classical MD to set up the coarse-grained mesoscale forcefields and finally attack the problem of protein globule adsorption on the nanoparticle surface and formation of the protein corona, or model nanoparticle-glycocalyx or lipid membrane interaction. There are several examples of systematic construction of multiscale models in soft matter modelling, which appear to be promising for modelling of the bio-nano interface [27-29]. We, therefore expect a significant progress in this field in the nearest future.
A number of these questions were previously addressed at the CECAM workshop ProSurf - Modeling Protein Interactions with Solid Surfaces held in 2011. It was stated in their report that the required methodologies are not yet settled and a further significant effort is needed. The present workshop, on one hand, will be focussed on more specific issues such as materials relevant for engineered nanoparticle-cell interaction, on the other hand, we will put more weight on the multiscale and coarse-grained methodologies, which are crucial to achieve a sensible predictive power for nanotoxicity and nanomedicine questions in the foreseen future. Emphasis will also be given to interactions with relevant bio-pharma and medical device industry representatives.