☆ 4.6 Article

Computational Assessment of Different Structural Models for Claudin-5 Complexes in Blood-Brain Barrier Tight Junctions

ACS CHEMICAL NEUROSCIENCE (2022)

Journal

ACS CHEMICAL NEUROSCIENCE

Volume 13, Issue 14, Pages 2140-2153

Publisher

AMER CHEMICAL SOC

DOI: 10.1021/acschemneuro.2c00139

Keywords

tight junctions; Claudin-5; blood-brain barrier; biological pore models; molecular dynamics; free energy calculations

Funding

IRCCS Ospedale Policlinico San Martino (Ricerca Corrente and 5 x 1000 grants)
Telethon/Glut-1 Onlus Foundations [GSP19002_PAsGlut009, GSA22A002]

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Abstract

In this study, two Cldn5 pore models were assessed using molecular dynamics simulations and free energy calculations. The thermodynamic properties of water and physiological ions permeating through these models were investigated. The results revealed that both models are compatible with the physiological role of Cldn5 TJ strands.

The blood-brain barrier (BBB) strictly regulates the exchange of ions and molecules between the blood and the central nervous system. Tight junctions (TJs) are multimeric structures that control the transport through the paracellular spaces between the adjacent brain endothelial cells of the BBB. Claudin-S (Cldn5) proteins are essential for TJ formation and assemble into multiprotein complexes via cis-interactions within the same cell membrane and trans-interactions across two contiguous cells. Despite the relevant biological function of Cldn5 proteins and their role as targets of brain drug delivery strategies, the molecular details of their assembly within TJs are still unclear. Two different structural models have been recently introduced, in which Cldn5 dimers belonging to opposite cells join to generate paracellular pores. However, a comparison of these models in terms of ionic transport features is still lacking. In this work, we used molecular dynamics simulations and free energy (FE) calculations to assess the two Cldn5 pore models and investigate the thermodynamic properties of water and physiological ions permeating through them. Despite different FE profiles, both structures present single/ multiple FE barriers to ionic permeation, while being permissive to water flux. These results reveal that both models are compatible with the physiological role of Cldn5 TJ strands. By identifying the protein-protein surface at the core of TJ Cldn5 assemblies, our computational investigation provides a basis for the rational design of synthetic peptides and other molecules capable of opening paracellular pores in the BBB.

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Modifying the blood-brain barrier by targeting claudin-5: Safety and risks

Erika Wakayama, Taiki Kuzu, Keisuke Tachibana, Ryuichi Hirayama, Yoshiaki Okada, Masuo Kondoh

Summary: The blood-brain barrier poses a challenge to drug delivery to the central nervous system. Among the components of the tight junctions in the blood-brain barrier, claudin-5 has been studied extensively as a target for enhancing drug permeation into the brain. However, sustained knockdown of claudin-5 is lethal in mice and administration of an anti-claudin-5 antibody can cause convulsions in nonhuman primates.

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES (2022)