(37h) Adhesion and Translocation of Nanoparticles through Lipid Bilayers Studied By Mesoscale Simulations

Understanding of the mechanisms of nanoparticle (NP) adhesion to lipid bilayer (LB) membranes, which constitute the foundation of cell membranes, is of paramount importance for the design of biomedical nanotechnologies, as well as for evaluating health threats related to nanoparticle manufacturing. NPs are employed as intracellular delivery vehicles for controlled release of genes and membrane impermeable chemicals. This process involves internalization, or intake of a drug containing NP, where the NP is first engulfed by the cell membrane, then transferred through the membrane into the cell. Since the NP adhesion is governed by multiple factors (NP size and shape, surface modification, hydrophobicity and charge) that cannot be easily varied in the experiments, the use of in silico modeling helps guide the experiments and optimize NP structure and surface properties. Despite the tremendous progress made recently in molecular simulations of biological systems, modeling of NP-lipid interactions is still difficult due to a complex interplay of distinct characteristic scales: LB thickness of ~5 nm, to NP size of 10-100 nm, to cell size of 5- 50 mm. Also, the dynamic processes of membrane rupture and NP trans-membrane transport involve metastable states and irreversible transformations, modeling of which requires non-trivial calculations of free energies and nucleation barriers.

The current study investigates the mechanisms of nanoparticle adhesion to and penetration through LB membranes. For this purpose, we construct a soft-core coarse-grained models of hydrophobic nanoparticle and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer membrane maintained under constant surface tension conditions using a plank, to which a constant force is applied. In a series of dissipative particle dynamics simulations, we consider NP transport across the LB membrane. The free energy landscape of the NP in the bilayer vicinity is explored using the ghost field method that emulates a lab experiment performed with optical tweezers. Hydrophobic particles adsorb a self-assembled monolayer of lipid. As the NP approaches the LB, the latter deforms. The deformation is followed by a spontaneous fusion of the freestanding bilayer and the adsorbed monolayer and particle incorporation inside the hydrophobic inner space of LB. The encapsulation stage where NP is captured by LB corresponds to a free energy minimum. The transition between a free and encapsulated NP is associated with a free energy barrier. The barrier is insignificant when NP is smaller than LB width but increases rapidly with the NP diameter. NP escape from the LB membrane is also associated with deformation of the latter and a free energy penalty. The free energy barrier associated with NP escape decreases with the NP size, that is, shows a tendency opposite to the entry barrier.

This work was supported by NSF grant 1264702