(581b) Mechanism of Selective Ion Transport through Kidney Tight Junctions

The human renal disorder familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is characterized by an excessive urinary loss of Ca²⁺ and Mg²⁺. Patients have nephrocalcinosis and renal failure that may progress toward end-stage renal disease early in life. FHHNC is genetically linked to mutations in the gene of the claudin-16 and claudin-19, which encodes the structural proteins of tight junctions (TJs) in the kidneys. TJs are the principal regulators of paracellular permeability. Paracellular channels with cation-selectivity are critical to maintaining in normal levels of Ca²⁺ and Mg²⁺ reabsorption. However, the oligomeric structure of claudin-16 and claudin-19 complex and the molecular basis for charge selectivity of paracellular channels are still not clear. In this work, firstly, we employed the Protein AssociatioN Energy Landscape (PANEL) method at the coarse-grained (CG) length scales, developed in our group, to identify energetically stable claudin-16 and claudin-19 conformations that form the charge- and ion-selective tight junction pores. Then, based on the stable conformations obtained via PANEL, we predicted the claudin-16/19 tight junction pore structure, pore size, pore-lining residues and computed the ion transport through the pore at the atomistic level. The pore-lining charged aspartic, and glutamic acid residues in claudin-16 hindered calcium ions' transport via electrostatic interactions. Transport kinetics of Ca²⁺, Cl^−, and other ions was also computed. Our results show the mechanism of ion transport in the claudin-16/19 tight junctions and the role of critical residues in maintaining normal kidney function.