(739j) Understanding the Molecular Physiology of the Blood-Brain Barrier Tight Junctions

The blood brain barrier is a selective permeability molecular barrier constituted by claudin-5 tight junction strands. Exploring treatment options for neurodegenerative diseases such as Alzheimer’s remains challenging because of our poor understating of the claudin-5 tight junctions. In an effort to overcome this hurdle we use multiscale molecular dynamics simulations to study the intricate self-assembly of claudin-5 transmembrane proteins. Based on the simulation we were able to identify the stable dimer conformations that result from membrane driven claudin-5 cis interactions and their corresponding pore structures. Our results reveal the nature of the molecular interactions that drive claudin-5 aggregation in forming the tight junctions, and are in good agreement with the previous experimental predictions. The insights form this study provides novel insights into the physiology of the blood-brain barrier and will aid in designing the next generation of smart therapeutics that can permeate the blood-brain barrier.