Elucidating the Molecular Architecture 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 and therapeutics options for neurodegenerative diseases such as Alzheimer’s and Parkinson’s remains challenging because of limited understanding of the claudin-5 tight junction permeability. In an effort to overcome this hurdle, we use multiscale molecular simulations to study the intricate self-assembly of claudin-5 transmembrane proteins in explicit membrane and solvent environment. Based on the simulation we were able to identify the stable dimer conformations that result from membrane driven claudin-5 cis interactions and the 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 will help in designing the next generation of smart therapeutics that can permeate the blood-brain barrier.