(713f) Multiscale Simulations to Characterize the Blood Brain Barrier Tight Junctions

The blood brain barrier (BBB) is a selective permeability barrier formed by endothelial cell at the blood-brain interface that prevents toxins and pathogens from entering the brain. The endothelial cells form a complex cell to cell adhesion interface called tight junctions that act as charge and size selective gatekeepers in regulating the passive diffusion of chemicals into the brain. Integral components of these tight junctions are specialized transmembrane proteins called claudin-5 that oligomerize in the cell-membrane and interact head-on with the adjacent cell to form paracellular barriers and pores. Molecular understanding on how claudin-5 interacts to form the tight junction is essential in exploring treatment options for brain related ailments such as Alzheimer’s and Parkinson’s diseases. Here we show the results of our in silico multi-scale molecular dynamics simulations on claudin-5 oligomerization in the model cell membrane. Claudin-5 forms dimers which later aggregate into large strands and higher order oligomers. We characterize three unique dimer interface using potential of mean force calculation to establish the most stable conformation. Further analysis revealed that the most stable dimer is formed by a leucine zipper interface between two monomers. Our results provide new insight into how claudin-5 proteins come together in a membrane to make the tight junctions, and subsequently the BBB.