期刊
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
卷 20, 期 -, 页码 5984-6010出版社
ELSEVIER
DOI: 10.1016/j.csbj.2022.10.038
关键词
Claudin; Tight junctions; Molecular dynamics simulations; Coarse grained molecular dynamics; simulations; Free energy calculations; Protein -protein molecular docking
资金
- IRCCS Ospedale Policlinico San Martino
- Telethon/Glut-1 Onlus Foundations [GSP19002_PAsGlut009, GSA22A002]
Claudins are transmembrane proteins that play a crucial role in tight junction integrity and tissue selectivity. They form barriers or ion-selective channels between cells in the paracellular space. Computational methodologies have helped to elucidate the properties of Claudins and could be useful for designing strategies to control the transport of drugs or molecules.
Claudins (Cldns) define a family of transmembrane proteins that are the major determinants of the tight junction integrity and tissue selectivity. They promote the formation of either barriers or ion-selective channels at the interface between two facing cells, across the paracellular space. Multiple Cldn subunits form complexes that include cis- (intracellular) interactions along the membrane of a single cell and trans- (intercellular) interactions across adjacent cells. The first description of Cldn assemblies was provided by electron microscopy, while electrophysiology, mutagenesis and cell biology experiments addressed the functional role of different Cldn homologs. However, the investigation of the molecular details of Cldn subunits and complexes are hampered by the lack of experimental native structures, currently limited to Cldn15. The recent implementation of computer-based techniques greatly contributed to the elucidation of Cldn properties. Molecular dynamics simulations and docking calculations were extensively used to refine the first Cldn multimeric model postulated from the crystal structure of Cldn15, and contributed to the introduction of a novel, alternative, arrangement. While both these multimeric assemblies were found to account for the physiological properties of some family members, they gave conflicting results for others. In this review, we illustrate the major findings on Cldn-based systems that were achieved by using state-of-the-art computational methodologies. The information provided by these results could be useful to improve the characterization of the Cldn properties and help the design of new efficient strategies to control the paracellular transport of drugs or other molecules. (c) 2022 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
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