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Shadi Fuladi, Sarah McGuinness, and Fatemeh Khalili-Araghi (University of Illinois at Chicago)
Tight junction claudins polymerize across two neighboring cell membranes to form a perm-selective barrier. Although how claudins self-polymerize into flexible strands is still cloaked in mystery, computational studies have shed some light on the molecular characteristics of this flexibility. We carried out all-atom and hybrid molecular dynamics simulations of claudin-15 strands between 30 and 130 nm in two parallel lipid membranes and revealed that a mutation influencing the claudin subtype-specific structure restricts the architectural flexibility of claudin strands. Our results indicate that wild-type claudin-15 strands exhibit bending and arching because of the ability of individual monomers to displace and rotate relative to their neighboring monomers. In contrast, mutant strands are significantly more rigid and do not express the same monomer maneuverability. We have established that this alteration in strand flexibility is caused by introducing a kink in the third transmembrane helix of claudin-15 monomers, which indirectly affects the conformational flexibility of side-to-side (cis-) interactions between adjacent claudin monomers in the same cell membrane.