(673f) Protein Self-Assembly at the Blood-Brain Barrier Tight Junction Interface

The macromolecular interface of the blood brain barrier (BBB) is constituted by the self-assembly of claudin-5 membrane proteins into tight junctions. Tight junctions which appear as an anatomizing network of strands between two endothelial cells, have semi-permeable molecular pores formed by claudin-5 adhesion interactions. These pores are impermeable to a vast majority of drugs including those that are vital for neurodegenerative diseases. Understanding the complex architecture of the tight junction molecular interface is critical to the design of novel targeted therapeutic agents targeting neurodegenerative diseases. Here we have elucidated the self-assembly of claudin-5 into tight junction strands and further investigated the influence of membrane micro-environment in driving claudin-5 assembly. We employed coarse grained molecular dynamics simulation to characterize the self-assembly of claudin-5 into the tight junctions. Altering the membrane composition especially with cholesterol and sphingolipids affects the orientation and consequently the conformations of claudin-5 interactions. Using umbrella sampling and steered molecular dynamics we assessed the potential mean of force of the dimeric interactions, which provided distinctions on the stability of each dimers. These molecular insights are vital to the advancement of tight junction research.