One of the possible mechanisms of nanoparticle cytotoxicity is associated with increase of permeability of cellular membranes. The current work is focused on theoretical and computational investigation of nanoparticle-induced pore formation in lipid bilayers. Specifically, we investigate dynamics of initial instability of a DPPC lipid bilayer induced by charged spherical nanoparticles. Molecular dynamics (MD) simulations show that the nanoparticles with a sufficiently large charge lead to pore formation in this zwitterionic bilayer. On the other hand, electrically neutral nanoparticles with otherwise identical properties do not induce the bilayer instability. A series of MD simulations is performed with nanoparticles of varying charges in order to identify the critical nanoparticle charge leading to the bilayer instability.
The MD simulations are complemented by development of a theoretical model of the bilayer instability. This model is developed by extending an existing model for bilayer elasticity (Watson et al., J. Chem. Phys., 135, 244701, 2011) which accounts for contributions of internal bilayer degrees of freedom (e.g., lipid tilt) to the bilayer free energy. Our MD simulations indicate that these degrees of freedom play a crucial role in the membrane destabilization. However, the current elasticity model is harmonic, i.e. it cannot describe significant deviations of the membrane from its equilibrium shape. Hence, an extension of this model is developed to include anharmonic effects. This model is then applied to predict the membrane deformations and lipid tilt involved in the pore formation. The model predictions are compared with the MD simulations.