Date of Award
Master of Science (MS)
Biomedical and Chemical Engineering
Tight junctions, found in all epithelial cells, are selective barriers that restrict the diffusion of ions and molecules within the paracellular space. They are important for maintaining cell polarity as well as for compartmentalization and establishing homeostasis within the human body. Tight junctions are comprised of complex protein assemblies. Within this protein assemble are a family of transmembrane proteins known as claudins that play a crucial role in establishing the tight junction network. Claudins are also influential in controlling the tight junction permeability. When mutations or malfunctioning occurs within a claudin gene, tight junction function is impaired. Disruption of their function is associated with a variety of human conditions, such as brain disease, deafness, renal failure, and various cancers. A deeper understanding of claudins and of their contribution towards tight junction’s function will provide researchers additional insight as to how to eventually approach creating therapeutics to treat tight junction-related diseases.
In this thesis, homotypic and heterotypic cis self-assembly of claudin-claudin interactions were studied for both classic and non-classic claudins (-2, -4, -11, -14, -16, -18, -19, and -23). Homology modeling was utilized to generate structures for each of the eight claudins studied, which were then equilibrated and refined in a DOPC (1,2-Dioleoyl-sn-glycero-3-phosphocholine) lipid bilayer system. Consequently, self-assemble simulations were carried out to study the cis interaction in either homotypic or heterotypic fashion. Each self-assembly system contained 72 monomers and was simulated for 4 µs. Results showed aggregation of claudin monomers into strand-like assemblies, which were then analyzed through a dimer distribution and orientation analysis. Four dimer types (dimers A, B, C, D) were identified and dimer populations were calculated in each of the claudin self-assembly systems. An additional new analysis method developed by a colleague and still in the refining phase is also introduced and discussed. Results for a single test system are discussed, but nonetheless provide an alternative means of analyzing dimers, representing them through various energy state profiles rather than of population density probabilities.
Nguyen, Lisa Danielle, "Homotypic and Heterotypic Self-Assembly of Claudin Family of Tight Junction Proteins" (2018). Theses - ALL. 269.