Molecular Dynamics simulations of the interaction between silica and phospholipid membranes in the context of biomineralization and nanotoxicity
Physical Chemistry of Solids and Surfaces, Material Characterisation
Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
Final Report Abstract
The project has dealt with the atomistic details of the interactions between silica nanoparticles and the cytoplasmic membrane of red blood cells (RBC) in the context of both biomineralization and toxicity. Biomineralization is relevant to an emerging line of research in which very precise inorganic replicas of biological organisms are produced and employed for biomedical research. Here, it is an open question how dissolved silicic acid molecules (Si(OH)4) are able to diffuse across phospholipid membranes leaving them intact, and then aggregate into Stöber-like silica materials preserving the membranes’ structural integrity. Nanotoxicity has become a major issue due to the incredibly wide diffusion of silica nanoparticles in a large range of consumer products. Here the puzzling question relates to the observation than some silica forms (e.g. Stöber silica) do not elicit a toxic response, while other silica forms (e.g. fumed silica) cause rupture of the RBS’s membrane, a process known as hemolysis. In our project, we have first produced realistic models of the RBC membrane including only the most relevant type of phospholipids, both regarding their hydrophilic heads and their hydrophobic tails. We have then developed computational protocols to generate realistic models of both Stöber and fumed silica nanoparticles, putting special attention to the distribution of defects in the silica bulk and on the hydroxyl termination of the silica surface. The interaction of silicic acid molecules and of smaller silica clusters has been studied with all-atom, advancedsampling molecular dynamics techniques. We found that the free-energy barrier encountered by Si(OH)4 molecules while crossing the RBC membrane is not larger than the barrier encountered by water molecules; this could explain why silicic acid can, given enough time, penetrate into cellular structures and subsequently give rise to well-conserved biomineralized replicas. The biomineralization itself has not been studied explicitly, though. An unexpected observation was that no local free-energy minima for Si(OH)4 are observed at the interface between the membrane and the surrounding water. This indicates that, in the absence of covalent interactions, heterogeneous nucleation at the membrane should not be particularly favored, which contradicts the experimental reality. We thus hypothesize an active role of the phosphate heads in promoting the initial formation of mineral phases at membrane-water interfaces. Concerning the translocation of larger silica clusters, we have observed the interesting formation of deep solvent pores into the hydrophobic regions associated with the translocation process. However, whether such pores could critically reach the opposite side of the membrane causing a direct hemolysis effect, could not be determined so far. This is not impossible, but an alternative hypothesis is that hemolysis is caused indirectly, by the interaction of silica particles with transmembrane proteins regulating the osmotic pressure across the membrane. Such process should be investigated in future projects. As a preliminary step towards such studies, we have investigated how the change of secondary structure of proteins change upon contact with extended silica surfaces. In particular, we have elucidated the limits of theoretical predictions of the Circular Dichroism spectral response of proteins, in particular of their disordered or poorly-folded regions. Such predictions are essential to rationalize on the atomic scale the perturbation of biological systems due to interaction with inorganic matter. However, current semi-empirical parametrizations used to theoretically compute CD spectra are optimized for well-folded structures such as helices, and to a lesser extent, sheets structures. How to accurately compute the CD response of poorly folded protein regions or entirely disordered oligopeptides is still an open question that needs to be addressed in future investigations.
Publications
- Atomistic details of chymotrypsin conformational changes upon adsorption on silica. ACS Biomaterials Science & Engineering 4, 4036-4050 (2018)
N. Hildebrand, M. Michaelis, N. Wurzler, Z. Li, J.D. Hirst, A. Micsonai, J. Kardos, A. Gil- Ley, G. Bussi, S. Köppen, M. Delle Piane, L. Colombi Ciacchi
(See online at https://doi.org/10.1021/acsbiomaterials.8b00819) - “Molecular Dynamics Simulations of the Silica–Cell Membrane Interaction: Insights on Biomineralization and Nanotoxicity”, Journal of Physical Chemistry C 122, 21330-21343 (2018)
M. Delle Piane, S. Potthoff, C.J. Brinker, L. Colombi Ciacchi
(See online at https://doi.org/10.1021/acs.jpcc.8b04537) - Impact of the conformational variability of oligopeptides on the computational prediction of their CD spectra. Journal of Physical Chemistry B 123, 6694-6704 (2019)
M. Michaelis, N. Hildebrand, R.H. Meißner, N. Wurzler, Z. Li, J. D. Hirst, A. Micsonai, J. Kardos, M. Delle Piane, L. Colombi Ciacchi
(See online at https://doi.org/10.1021/acs.jpcb.9b03932) - The puzzling issue of silica toxicity: are silanols bridging the gaps between surface states and pathogenicity? Particle and Fibre Toxicology 16, 32 (2019)
C. Pavan, M. Delle Piane, M. Gullo, F. Filippi, B. Fubini, P. Hoet, C. Horwell, F. Huaux, D. Lison, C. Lo Giudice, G. Martra, E. Montfort, R. Schins, M. Sulpizi, M. Wyart-Remy, C. Ziemann, F. Turci
(See online at https://doi.org/10.1186/s12989-019-0315-3)
