Ion and water permeation through Claudin-10b paracellular channels

Abstract The structural scaffold of epithelial and endothelial tight junctions (TJ) comprises multimeric strands of claudin (Cldn) proteins, which anchor adjacent cells and control the paracellular flux of water and solutes. Based on the permeability properties they confer to the TJs, Cldns are classified as channel- or barrier-forming. Some of them, however, show mixed features. For instance, Cldn10b, expressed in kidneys, lungs, and other tissues, displays high permeability for cations and low permeability for water. Along with its high sequence similarity to the cation- and water-permeable Cldn15, this makes Cldn10b a valuable test case for investigating the molecular determinants of paracellular transport. In lack of high-resolution experimental information on TJ architectures, here we use Molecular Dynamics simulations to study two atomistic models of Cldn10b strands and compare their ion and water transport with those of Cldn15. Our data, based on extensive standard simulations and Free Energy calculations, reveal that both Cldn10b models form cation-permeable pores narrower than Cldn15, which, together with the stable coordination of Na + ions to acidic pore-lining residues (E153, D36, D56), limit the passage of water molecules. By providing a mechanism driving a peculiar case of paracellular transport, these results provide a structural basis for the specific permeability properties of Cldn isoforms that define their physiological role. Graphical abstract