(192y) Solute Transport across Blood-Brain Barrier Tight Junction Pores

The blood-brain barrier tight junctions present a formidable challenge in the development of therapeutics for the treatment of neurodegenerative diseases. Claudin-5 membrane proteins that are the functional component of the tight junctions assemble in the paracellular space to constitute the tight junction strands. Here using a multiscale molecular dynamics simulation approach, we have elucidated the nature of claudin-5 assembly at the tight junction interface. Significantly, claudin-5 protomers assemble in four preferred dimeric conformations, which subsequently interact across the membranes of two adjacent cells to constitute tight junction pores. Two distinct tight junction pores were observed that corroborate with the experimental findings reported in the literature. Starting from the pore assemblies that were observed in the simulations, we have characterized the potential of mean force (PMF) of different biologically relevant solutes across these pores. It is evident from these calculations that claudin-5 pores form a formidable barrier for small molecule transport while still being permissive of water. The main conclusions from this study will serve to further the understanding of the blood-brain barrier.