Physical Properties of Claudin-15 Strands in Tight Junctions

Abstract

Tight junction claudins seal the paracellular pathway between two adjacent cells by forming selective permeation pathways. These barriers comprise a network of sealing strands in the cell membrane of one cell associating laterally with strands in the membrane of an adjacent cell. Tight junction strands are dynamic and maintain their barrier function during cell movements and large-scale tissue rearrangements. Strand formation requires coordinated claudin side-by-side (cis-) interactions within the same membrane and head-to-head (trans-) interactions between monomers from adjoining cells. To study the flexibility of claudin strands and the protein-protein interactions that provide this flexibility, we have constructed large-scale hybrid models of claudin-15 strands of various lengths ranging from 35nm to 215nm in their native environments. In this model, using the PACE forcefield, the protein is represented with atomic resolution and lipids and solvent molecules are coarse-grained using the MARTINI forcefield to reduce the computational cost. We have used molecular dynamics simulation to characterize physical properties of claudin strands including their bending modulus and persistence length from equilibrium simulations. In addition, we have identified the side-by-side (cis-) interactions in claudin-15 that are responsible for maintaining the strand conformation and providing flexibility. Our studies provide novel molecular insight into the mechanisms of claudin strand formation which is key to understanding how claudins interact and maintain selectively permeable paracellular barriers.