(699f) Design of Membrane-Embedded Amphiphilic Nanoparticles from Atomistic Molecular Dynamics Simulations

Monolayer-protected nanoparticles (NPs) are a versatile materials platform useful for biological applications because features of the protecting monolayer can be engineered to tailor interactions with the biological milieu. Recently, amphiphilic NPs with surface properties that mimic typical globular proteins were shown to enter cells via a non-endocytic, non-disruptive process that could be of broad interest for applications in drug or gene delivery. Here, we use detailed atomistic molecular dynamics simulations to gain molecular insight into these experimental observations. We find that the amphiphilic NPs insert into the bilayer to obtain a configuration resembling a membrane-embedded protein due to favorable interactions between hydrophobic molecules on the NP surface and the hydrophobic bilayer core. We identify a kinetic pathway for insertion that mimics the early onset of vesicle-vesicle fusion. Our calculations also suggest that charged ligand end groups cross the bilayer on experimentally relevant timescales that are significantly more rapid than expected. Finally, we leverage this mechanistic understanding to design monolayer compositions optimized for bilayer insertion and cellular uptake. This work emphasizes that carefully tuning NP surface coatings to resemble existing biological materials permits favorable interactions with the cell membrane, enabling the creation of new nano-bio hybrid materials with properties similar to those of membrane proteins.