Tight junctions regulate the permeability of epithelial and endothelial tissues to ions and small molecules. In the intestinal epithelia, claudin-15 proteins form paracellular channels permeable to water and small cations across epithelia. To understand how structural properties of claudin-15 channels impact pore function and clarify the mechanism of ion selectivity, we used molecular dynamics (MD) simulations to map how mutagenesis of pore-facing residues alters claudin-15 selective permeability. Channel conductance was calculated by applying an electric field to a series of linearly arranged claudin-15 channels embedded in two parallel lipid membranes. Beyond single mutations, we investigate the effect of double and triple mutations distributed along the pore. Charge modifications to amino acid sidechains produced shifts in ion selectivity and impacted ion dehydration events through the channel. Our work suggests that claudin-15 transport is driven primarily by electrostatic interactions and ion solvation dynamics in the pore. These findings shed light on the three-dimensional structure of the claudin-15 pore and the roles of key amino acids in modulating ion selectivity. The conclusions of this study will inform the development of claudin-15 channel blockers, the investigation of channel function across other members of claudin family, and engineering claudin channels with a desired selectivity.
McGuinness et al. (Sun,) studied this question.