Steve L. Reichow
Date of Award
Bachelor of Science (B.S.) in Computer Science and University Honors
Connexins, Gap junctions (Cell biology), Molecular dynamics
Connexins form intercellular channels known as gap junctions that facilitate diverse physiological roles, from long-range electrical and chemical coupling to nutrient exchange. Recent structural studies on Cx46 and Cx50 have defined a novel and stable open state and implicated the amino-terminal (NT) domain as a major contributor to functional differences between connexin isoforms. This thesis presents two studies which use molecular dynamics simulations with these new structures to provide mechanistic insight into the function and behavior of the NTH in Cx46 and Cx50. In the first, residues in the NTH that differ between Cx46 and Cx50 are swapped between the two isoforms to identify the particular positions that form the key structural and energetic barriers of ion permeation. In the second, a known cataract-associated mutation is modeled and simulated in Cx50, demonstrating potential atomic interactions with the NTH that could lead to the observed disease phenotype. Together, these studies deepen the field's knowledge of the role of the connexin NT domain, with novel atomic-level detail, and demonstrate how simulation can be combined with experimental methods to better understand the interplay between gap junction structure and function.
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Khan, Umair, "Functional Role of the N-terminal Domain in Connexin 46/50 by in silico Mutagenesis and Molecular Dynamics Simulation" (2021). University Honors Theses. Paper 1036.