(613b) Grafting Charged Species to Membrane-Embedded Scaffolds Dramatically Increases the Rate of Bilayer Translocation

Functionalized nanoparticles (NPs) are versatile materials with heterogeneous surface properties that can be engineered to mimic typical biological macromolecules. Recently, a particular class of charged, amphiphilic NPs were shown to embed within lipid bilayers to obtain configurations similar to transmembrane proteins. This behavior is surprising because the NPs must also transport charged groups across the hydrophobic bilayer core within short timescales to stably insert into the bilayer, a process that is conventionally thought to occur on timescales far too long (hours to days) to be experimentally relevant. However, the rapid translocation of charged species across lipid bilayers is not unique to these NPs, but is also observed in disparate membrane protein systems, suggesting that some shared mechanism may lead to short (sub-second) translocation timescales. Here, we use atomistic molecular dynamic simulations with enhanced sampling techniques to gain a mechanistic understanding of this rapid charge transport. We show that charged species grafted to a bilayer-embedded scaffold – such as the NPs or multispanning transmembrane proteins – translocate across the bilayer significantly more rapidly than isolated ions. We find that rapid translocation is enabled by the partial dehydration of charged species in their initial configurations, and is further assisted by cooperative interactions between multiple hydrophilic end groups. This work suggests design guidelines for synthetic materials capable of transporting charged, soluble small molecules across bilayers, which may be useful for ferrying therapeutic molecules to the interior of cells for drug delivery applications.