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Claudin-15 (CLDN15) molecules form channels that directly regulate cation and water transport. In the gastrointestinal tract, this transport indirectly impacts nutrient absorption. However, the mechanisms governing ion transport through these channels remain poorly understood. We addressed this question by building on our previous cell culture studies and all atom molecular dynamic simulation model of CLDN15. By mutating D55 to a bulkier glutamic acid (E) or neutral amino acid asparagine (N), our in vitro measurements showed that the D55E mutation decreased charge selectivity and favored small ion permeability, while the D55N mutation led to reduced charge selectivity without markedly altering size selectivity. By establishing a simplified (reduced) CLDN15 molecular dynamics model that excludes non-essential transmembrane regions, we were able to probe how D55 modified cation dehydration, charge interaction, and permeability. These results provide novel insight into organization of the CLDN15 selectivity filter and suggests that D55 plays a dual role in shaping both electrostatic and steric properties of the pore, but its electrostatic role is more prominent in determining CLDN15 cation permeability. This knowledge can be used toward the development of effective strategies to modulate CLDN15 function. The experimental approach established can be further extended to study the function of other claudin channels. Together, these advancements will help us to modulate tight junctions to promote human health.
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This content will become publicly available on April 16, 2026
Squaramide-based ion pair receptors can facilitate transmembrane transport of KCl and zwitterions including highly polar amino acids
Misregulation of transmembrane ion transport in biological systems has been linked to a variety of diseases. As a result, supramolecular chemists have been trying to develop small molecules that facilitate the transmembrane transport of several ionic species. However, ion transport by small molecules is a passive process and needs to be overall charge neutral (i.e., when an ion is transported across a membrane, another ion needs to be transported as well to avoid charge separation). Ion pair receptors could therefore have great potential as transmembrane ion transporters because they can facilitate transport of an overall neutral species. Furthermore, ditopic ion pair receptors also have the potential to transport biologically important zwitterionic species, such as amino acids. In this manuscript, we report the synthesis of a series of ditopic receptors based on squaramides as the anion binding unit and 18-crown-6 as the cation binding unit. UV-vis and NMR titrations revealed that these compounds can bind a variety of chloride salts, especially KCl. Furthermore, liquid–liquid extractions and transport experiments using bulk liquid membranes and liposomes indicate that these ditopic receptors are capable of transporting chloride salts and hydrophilic amino acids. In fact, compound 5 was even able to facilitate the transport of amino acids with charged side chains at physiological pH (arginine and glutamate), making it the first example of a small molecule that can transport these highly polar and charge-dense species. These findings open up the possibility of using these receptors in a wide range of biological applications.
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- Award ID(s):
- 2108699
- PAR ID:
- 10594085
- Publisher / Repository:
- Royal Society of Chemistry
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 16
- Issue:
- 16
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 6982 to 6990
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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