A symmetric region produces a novel calcium binding mode in the human Cx46 connexon

The human connexon formed by connexin 46 (C-hCx46) is a channel with high voltage sensitivity and selective permeability to cations. In this work, we studied the interaction of Ca²⁺ with C-hCx46 and C-hCx26 using molecular dynamics simulations. Unlike other connexons such as the connexon formed by human connexin 26 (C-hCx26), where Ca²⁺ binds to specific sites, in C-hCx46 Ca²⁺ interacts with a toroidal confinement zone limited by negatively charged residues, whose symmetrical distribution allows it to move freely without varying its total attraction potential. This symmetry is lost in C-hCx26 due to the substitution of one of these residues by a lysine, which causes Ca²⁺ to be trapped in specific regions where the electrostatic attraction force is greater. In C-hCx46 a negative electrostatic potential is observed inside the pore, which is screened when interacting with Ca²⁺. In addition, the presence of Ca²⁺ reduces potassium and water permeability.