@article{fed3afa9b2a34964867c852c03207691,
title = "Architecture of the paracellular channels formed by claudins of the blood–brain barrier tight junctions",
abstract = "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.",
keywords = "Claudin, Dimer, Paracellular transport, Pore structure, Tight junctions, cis-interactions",
author = "Irudayanathan, {Flaviyan Jerome} and Nan Wang and Xiaoyi Wang and Shikha Nangia",
note = "Funding Information: We are thankful for the computational resources provided by the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant Number ACI-1053575. This work is supported by grants from NSF CAREER CBET-1453312 and Syracuse University. We thank Dr. Heidi Kolds{\o} and Jean Helie for sharing the code to fix issues related to the membrane undulations beyond the periodic boundary conditions. F.J.I designed the research, participated in the discussions, performed simulations, analyzed the data, and wrote the manuscript. N.W. and X.W. participated in the discussions, performed simulations, and analyzed the data. S.N. designed the research, participated in the discussions, and wrote the manuscript. Funding Information: We are thankful for the computational resources provided by the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant Number ACI-1053575. This work is supported by grants from NSF CAREER CBET-1453312 and Syracuse University. We thank Dr. Heidi Kolds? and Jean Helie for sharing the code to fix issues related to the membrane undulations beyond the periodic boundary conditions. F.J.I designed the research, participated in the discussions, performed simulations, analyzed the data, and wrote the manuscript. N.W. and X.W. participated in the discussions, performed simulations, and analyzed the data. S.N. designed the research, participated in the discussions, and wrote the manuscript. Publisher Copyright: {\textcopyright} 2017 New York Academy of Sciences.",
year = "2017",
doi = "10.1111/nyas.13378",
language = "English (US)",
volume = "1405",
pages = "131--146",
journal = "Annals of the New York Academy of Sciences",
issn = "0077-8923",
publisher = "Wiley-Blackwell",
number = "1",
}