Architecture of the paracellular channels formed by claudins of the blood–brain barrier tight junctions

Flaviyan Jerome Irudayanathan, Nan Wang, Xiaoyi Wang, Shikha Nangia

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Tight junctions (TJs) are key players in determining tissue-specific paracellular permeability across epithelial and endothelial membranes. Claudin proteins, the primary determinants of TJs structure and functionality, assemble in paracellular spaces to form channels and pores that are charge and size selective. Here, using molecular dynamics (MD) simulations, we elucidate the molecular assembly of claudin-3 and claudin-5 proteins of blood–brain barrier TJs. Despite having a high degree of sequence and structural similarity, these two claudins form different types of cis-interactions. Molecular docking of the observed cis-interfaces into trans-forms revealed two putative pore models that were also observed in the self-assembly simulations. The observed pore structures (pore I and II) have pore-lining residues that have been previously reported in the literature. The pore I model is consistent with a previously reported claudin-15 model. The pore II model, also consistent with biochemical results, has not been reported previously. Further analysis using in silico site-directed mutations provide convincing support for the validity of the pore II model. Using steered MD and umbrella sampling, we computed the transport properties of water and β-d-glucose through pore II. The study offers new insight into the selectivity of blood–brain barrier TJs.

Original languageEnglish (US)
Pages (from-to)131-146
Number of pages16
JournalAnnals of the New York Academy of Sciences
Issue number1
StatePublished - 2017


  • Claudin
  • Dimer
  • Paracellular transport
  • Pore structure
  • Tight junctions
  • cis-interactions

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • History and Philosophy of Science


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