(31d) Design of Membrane-Embedded Amphiphilic Nanoparticles from Multiscale Simulations

Functionalized, monolayer-protected nanoparticles (NPs) are a versatile materials platform because the protecting surface monolayer can be engineered to tailor interactions with the surrounding environment. NPs are of particular interest in biomedical applications because they can be designed to mimic the physicochemical properties of typical biological macromolecules (i.e., soluble proteins). However, structure-function relationships correlating the nanoscale properties of engineered nanomaterials to their biological interactions remain unclear and can be difficult to determine experimentally. Here, we demonstrate that molecular modeling across multiple length scales can aid in the interpretation of experiments and guide the design of novel nanomaterial functionalities. We focus on understanding the ability of a class of amphiphilic NPs to enter cells via a non-endocytic, non-disruptive mechanism that is of broad interest for applications in drug or gene delivery. This behavior is surprising because bypassing the cell membrane requires the NPs to translocate charged groups across the hydrophobic core of the lipid bilayer. We use atomistic molecular dynamics simulations to gain molecular insight into these experimental observations and predict outcomes in model membrane systems. Our results show that the amphiphilic NPs insert into the bilayer to obtain configurations resembling membrane-embedded proteins due to favorable interactions between the NP surface and the hydrophobic bilayer core. We further develop an implicit solvent modeling approach that facilitates the high-throughput determination of how varying monolayer compositions affect the thermodynamics of bilayer insertion. Finally, we leverage this mechanistic understanding to provide design guidelines for monolayer compositions optimized for non-endocytic cellular uptake. This framework illustrates the power of multiscale modeling to understand and predict behavior at the nano-bio interface.