期刊
ACS CHEMICAL NEUROSCIENCE
卷 13, 期 14, 页码 2140-2153出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.2c00139
关键词
tight junctions; Claudin-5; blood-brain barrier; biological pore models; molecular dynamics; free energy calculations
资金
- IRCCS Ospedale Policlinico San Martino (Ricerca Corrente and 5 x 1000 grants)
- Telethon/Glut-1 Onlus Foundations [GSP19002_PAsGlut009, GSA22A002]
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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