Title: A multiscale biophysical platform for charting design-specific interactions of nanoparticles with model cellular membranes
Nanoparticles (NP) are ever-present in foods and beverages, cosmetics, packaging, cooking products, fertilizers, pesticides, and novel pharmaceuticals, and pose significant challenges related to their increased consumer, occupational, and environmental exposure and their unique bioactivity relative to small molecules and large colloids. Currently, an understanding of the precise influence of NP design parameters like size, surface chemistry, shape, and softness on bioactivity is highly underdeveloped and difficult to reproducibly demonstrate in experiments. In this thesis, we focus on fundamentally probing design-specific interactions between NPs and model cellular membranes, due to their significant role in pharmacological and consumer product performance (biodistribution) as well as adverse outcome pathways in toxicology. We construct a first-of-its kind, multiscale physics-based platform linking detailed molecular dynamics (MD) simulations, continuum mechanical theory, and multi-compartment modeling. Using this platform, we examine the two most influential design parameters—size and surface chemistry—and through two main case studies: (1) the membrane permeability of sub-nanometer particles and (2) the thermodynamic stability of larger-scale, ~1-10 nm particle-membrane interactions. Within (1), we simulate the NP-membrane interactions and transport in full molecular detail to validate a standing microscopic mechanistic continuum model for transport, then directly link the impact of particle chemistry in the MD simulations to the steady-state membrane permeability as well as dynamic transport outcomes in the macroscopic multi-compartment models. Within case study (2), we probe the phase behavior of NP-membrane interactions that implicate macroscopic membrane deformations and whose stability is well described by continuum elastic theories, and also an entirely novel asymmetric mechanism of interaction for ~4 nm, rough, crystalline hydrophobic particles wherein the particle preferentially inserts in one membrane leaflet and flips to the other leaflet over extended time scales. This platform has the potential to more intuitively and effectively inform experiments and physiologically-based pharmacokinetic models for NP biodistribution predictions, as well as structure-activity relationships for direct predictions of product efficacy and toxicity.