Effect of Oxidation on Cx26 Gap Junctions: A Molecular Dynamics Study

Gap junctions (GJs) are transmembrane channels composed of connexin (Cx) proteins, responsible for communication and transfer of electrical signals and molecules/nutrients between neighboring cells. GJs play an important role in many physiological functions, including the propagation of survival and death signals between cells. Considering the promising anticancer effects of cold atmospheric plasma (CAP), which acts via generation of reactive oxygen and nitrogen species (RONS), the intercellular exchange of RONS through GJs is of interest to understand the propagation of CAP-induced cell death in cancer cells. Moreover, RONS can also be induced by other oxidative stress-based anticancer therapies, such as photodynamic therapy and sonodynamic therapy. However, the effect of RONS on GJs themselves is not well explored, and the question arises as to how oxidative post-translational modifications may affect the functionality of GJs. We investigate here, by atomistic molecular dynamics (MD) simulations, the effect of oxidative stress on GJs composed of Cx26 proteins (Cx26-GJs). Specifically, we simulate the effects of amino acid oxidation in a Cx26-GJ structure, never studied before at the atomic scale, and compare this with a nonoxidized Cx26-GJ structure to investigate whether oxidation can affect the structure, conformation, stability, and permeability of the GJs. Our MD results demonstrate that oxidation affects the structure and interactions of Cx26-GJs. In addition, it reduces the binding free energy between hemichannels and the central pore diameter that can affect GJ formation/stability and the permeation of molecules.