BPS2026 – Structural differentiation ion transport across channel-forming and barrier-forming claudin pores

Claudins are one of the key components of tight junctions that control paracellular permeability. Claudins polymerize to form strand-like structures that either seal the paracellular space (barrier-forming claudins) or to form charge-selective ion channels (pore-forming claudins) across tight junctions. However, the structural assembly of claudins and the molecular structure of claudin channels is not yet determined. Based on our previously modeled claudin-15 ion channels, we constructed atomic models of seven functionally distinct claudin pores including claudin-2, claudin-3, claudin-5, claudin-10a, claudin-10b, claudin-18.1, and claudin-18.2. We performed molecular dynamics simulations of ion transport through these channels and calculated selective permeability of the pores within the same setup and under the same conditions. The simulations confirmed cation-selectivity of claudin-2, claudin-10b, anion selectivity of claudin-10a, and barrier function of claudin-3, claudin-5, claudin-18.1, and claudin-18.2. Key residues conferring charge-selectivity to pore-forming claudins were identified for cation- and anion-selective channels, and their effect were corroborated by charge-reversing mutations. The simulation results revealed distinct selectivity mechanisms among charge-selective channels, which is not only a function of charge distribution along the pore, but is also governed by the pore geometry.