Targeting tight junctions in the blood-brain barrier: Hints from molecular dynamics simulations of ion conduction in two Claudin-5 structural models.

Abstract

The fight against neurological and neurodegenerative diseases represents one of the hardest challenges of our times. Indeed, the treatment of these pathologies is hampered by the difficulties to efficiently deliver drugs to the brain, which is isolated from the blood flow in brain capillaries by the blood-brain barrier (BBB). The BBB is a highly selective structure formed by endothelial cells held together by the tight junctions (TJs), heterogeneous protein aggregates organized in strands that hamper the passage of particles through the space between the cells (the paracellular space). A comprehensive knowledge of TJs structure is pivotal to identify the target sites for a reversible and non-disruptive opening of the BBB paracellular space, with the aim of providing a pathway for direct drug delivery to the brain. Determinant components of the BBB TJs are the Claudin (Cldn) 5 proteins, which polymerize in the strands in ways that are yet to be fully clarified. Recently, structural models have been introduced for complexes of Cldn5 and other claudins. In our work, we reproduced two models of Cldn5 tetramers spanning the paracellular space and evaluated their selectivity by means of Molecular Dynamics simulations and free energy calculations of ions and water permeation. Our findings suggest that both models are compatible with the physiological role of Cldn5 in BBB TJs, and offer high-resolution details on the multimeric structures, including how residues at the interfaces between protomers and those lining the pore are arranged.